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REVIEW ARTICLE
From the Department of Internal Medicine III
(Hematology and Oncology), University of Ulm, Ulm, Germany.
A series of alterations in the cellular genome affecting the
expression or function of genes controlling cell growth and
differentiation is considered to be the main cause of cancer. These
mutational events include activation of oncogenes and inactivation of
tumor suppressor genes. The elucidation of human cancer at the
molecular level allows the design of rational, mechanism-based
therapeutic agents that antagonize the specific activity of biochemical
processes that are essential to the malignant phenotype of cancer
cells. Because the frequency of RAS mutations is among the
highest for any gene in human cancers, development of inhibitors of the
Ras-mitogen-activated protein kinase pathway as potential anticancer
agents is a very promising pharmacologic strategy. Inhibitors of Ras
signaling have been shown to revert Ras-dependent transformation and
cause regression of Ras-dependent tumors in animal models. The most promising new class of these potential cancer therapeutics are the
farnesyltransferase inhibitors. The development of these compounds has
been driven by the observation that oncogenic Ras function is dependent
upon posttranslational modification, which enables membrane binding. In
contrast to many conventional chemotherapeutics, farnesyltransferase inhibitors are remarkably specific and have been demonstrated to cause no gross systemic toxicity in animals. Some
orally bioavailable inhibitors are presently being evaluated in phase
II clinical trials. This review presents an overview on some inhibitors
of the Ras signaling pathway, including their specificity and
effectiveness in vivo. Because Ras signaling plays a
crucial role in the pathogenesis of some hematologic malignancies, the
potential therapeutic usefulness of these inhibitors is discussed.
(Blood. 2000;96:1655-1669) At the cellular surface, many different receptors
are expressed that allow cellular response to extracellular signals
provided by the environment. After ligand binding, receptor activation leads to a large variety of biochemical events in which small guanosine
triphosphate hydrolases (GTPases; eg, Ras) are crucial. Ras proteins
are prototypical G-proteins that have been shown to play a key role in
signal transduction, proliferation, and malignant transformation.
G-proteins are a superfamily of regulatory GTP hydrolases that cycle
between 2 conformations induced by the binding of either guanosine
diphosphate (GDP) or GTP1-3 (Figure 1). The Ras-like small GTPases are a
superfamily of proteins that include Ras, Rap1, Rap2, R-Ras, TC21, Ral,
Rheb, and M-Ras. The RAS gene family consists of 3 functional genes, H-RAS, N-RAS, and
K-RAS. The RAS genes encode 21-kd proteins, which
are associated with the inner leaflet of the plasma membrane (H-Ras,
N-Ras, and the alternatively spliced K-RasA and K-RasB). Whereas H-Ras,
N-Ras, and K-RasB are ubiquitously expressed, K-RasA is induced during differentiation of pluripotent embryonal stem cells in
vitro.4
Regulatory proteins that control the GTP/GDP cycling rate of Ras
include GTPase-activating proteins (GAPs), which accelerate the rate of
GTP hydrolysis to GDP, and guanine nucleotide exchange factors (GEFs;
eg, SOS and CDC25), which induce the dissociation of GDP to allow
association of GTP.3 In the GTP-bound state, Ras couples
the signals of activated growth factor receptors to downstream
mitogenic effectors. By definition, proteins that interact with the
active GTP-bound form of Ras (and thus become GTP-dependently activated) to transmit signals are called Ras
effectors.5-8 Mechanisms by which GTP-Ras influences the
activity of its effectors include direct activation (eg, B-Raf, PI-3
kinase), recruitment to the plasma membrane (eg, c-Raf-1), and
association with substrates (eg, Ral-GDS). Other candidates for Ras
effectors include protein kinases, lipid kinases, and
GEFs.3,5-8
Ras proteins are produced as cytoplasmatic precursor proteins and
require several posttranslational modifications to acquire full
biologic activity. These modifications include prenylation, proteolysis, carboxymethylation, and palmitoylation9-13
(Figure 2).
Prenylation of proteins by intermediates of the isoprenoid biosynthetic
pathway represents a newly discovered form of posttranslational modification and is catalyzed by 3 different enzymes: protein farnesyltransferase (FTase), protein geranylgeranyltransferase type I
(GGTase I), and geranylgeranyltransferase type II (GGTase II).9-13 Prenylated proteins share characteristic
carboxy-terminal consensus sequences and can be separated into the
proteins with a CAAX (C, cysteine; A, aliphatic amino acid; X, any
amino acid) motif and proteins containing a CC or CXC
sequence.14-17 FTase I transfers a farnesyl group from
farnesyldiphosphate (FPP), and GGTase I transfers a geranylgeranyl
group from geranylgeranyldiphosphate (GGPP) to the cysteine residue of
the CAAX motif.18 GGTase II transfers the geranylgeranyl
groups from GGPPs to both cysteine residues of CC or CXC motifs.
Farnesylation is the first step in the posttranslational modification
of Ras. This modification occurs by covalent attachment of a 15-carbon
farnesyl moiety in a thioether linkage to the carboxy-terminal cysteine
of proteins that contain the CAAX motif. The reaction is catalyzed by
FTase, a heterodimer consisting of a 48-kd and a 45-kd subunit
( Farnesylation of Ras proteins is followed by endoproteolytic removal of
the 3 carboxy-terminal amino acids (AAX) by a cellular thiol-dependent
zinc metallopeptidase.22 This endoproteolytic activity
(RACE, or Ras and a-factor converting enzyme) is a composite of 2 different CAAX proteases: a zinc-dependent activity encoded by AFC1 and
the type IIb signal peptidase-like RCE1 (Ras converting enzyme
1).23 The final step in the carboxy-terminal modification of proteins with a CAAX motif (eg, Ras) is the methylation of the
carboxyl group of the prenylated cysteine residue by an as yet
uncharacterized methyltransferase.
Some Ras proteins (H-Ras, N-Ras, Ras2) are further lipidated by
palmitoylation at 1 or 2 cysteines near the farnesylated
carboxy-terminus.9-13,24-27 Like farnesylation, H-Ras
palmitoylation plays an important role for signaling functions in
vivo.27 Microinjection experiments in Xenopus
oocytes revealed that palmitoylation of H-Ras dramatically enhances its
affinity for membranes as well as its ability to activate
mitogen-activated protein kinase (MAPK) and initiate meiotic
maturation.11,27 Both a Ras-specific protein
(palmitoyltransferase) and a palmitoyl-protein (thioesterase) have been
characterized.28,29 In contrast to farnesylation and
proteolysis, palmitoylation and methylation of Ras are thought to be
reversible and may have a regulatory role.11,12
The MAPK signaling cascades
Ras-to-MAPK signaling via receptor tyrosine kinases and
cytokine receptors
In contrast to receptor tyrosine kinases, cytokine receptors (such as
the prototypical IL-3, IL-5, GM-CSF receptors) do not contain a kinase
domain. These receptors are heterodimers of a ligand-specific
The SH3 domain of Grb-2 binds to SOS, which is a GEF for Ras and
facilitates the replacement of GDP with GTP.3-8,36-40 When Ras becomes GTP-loaded, Ras effectors (such as Rafs, MEKK, PI-3K, and
Ral) bind to Ras and become activated. The Raf kinases (A-Raf, B-Raf,
c-Raf-1) are important Ras effectors and have been demonstrated to act
as MAPKKKs/MEKKs in the Ras-to-MAPK (or ERK)
pathway.36-40,43-45 Raf kinases have been shown to
selectively phosphorylate and activate MAPKKs MEK-1 and
MEK-2.36-40,43-45 Other MEK-1/MEK-2 activators include TPL-2, MEKK-1, and c-Mos.46-48 MEK-1 and MEK-2 are
dual-specificity kinases that activate the MAPKs of the ERK subgroup
(ERK-1 and ERK-2).30-35,49-52 ERK-1 and ERK-2 are
proline-directed protein kinases that phosphorylate Ser/Thr-Pro motifs
in the consensus sequence Pro-Xaan-Ser/Thr-Pro, where Xaa
is any amino acid and n = 1 or 2. Several cytoplasmatic and nuclear
substrates of the ERKs have been identified. The best-characterized ERK
substrates are cytoplasmatic phospholipase A2
(cPLA2), the ribosomal protein S6 kinases (RSKs), and the
transcription factor Elk-1.30,32,53,54
The Ras-to-Ral and the Ras-to-PI-3K signaling pathways
Ral-GEFs are activated via binding to GTP-Ras. Ral-GEFs in turn activate Ral-GTPases by promoting the GTP-bound state of Ral. As members of the Ras subfamily of Ras-related GTPases, Ral proteins (RalA and RalB) also cycle between the active GTP-bound states and inactive GDP-bound states. Ral-GTP binds Ral-BP1 (Ral-binding protein-1 or Rlip1 = Rip1 [Ral-interacting protein-1]), which is a GAP for CDC42 and Rac. These 2 GTPases are involved in the regulation of the actin cytoskeleton, the SAPK/JNK pathway, and the p38 pathway (Figure 3). Ras-GTP also binds to and activates the catalytic domain of PI-3K. The lipid second-messenger molecules produced (eg, phosphatidylinositol phosphates PtdIns 3,4-P2 and PtdIns 3,4,5-P3) activate the phosphoinositide-dependent kinases PDK-1 and PDK-2, which then activate Akt kinase and nonconventional isoforms of protein kinase C (ncPKC). PI-3K has been implicated in 4 apparently distinct cellular functions, including mitogenic signaling (DNA synthesis), inhibition of apoptosis, intracellular vesicle trafficking and secretion, and regulation of actin and integrin functions. These functions are most likely mediated by distinct phosphoinositide products of PI-3K56 (Figure 4).
The constitutive activation of Ras appears to be an important
factor for the malignant growth of human cancer cells. Recently, the
Ras-related proteins R-Ras, M-Ras, and TC21 have also been shown to
possess transforming activities similar to those of
Ras.57-59 However, their role in human malignancies is
unclear. Mutations of the RAS proto-oncogenes
(H-RAS, N-RAS, K-RAS) are frequent genetic aberrations found in 20% to 30% of all human tumors, although the incidences in tumor type vary greatly.60,61 The
highest rate of RAS mutations was detected in
adenocarcinomas of the pancreas (90%), the colon (50%), and the lung
(30%). In follicular and undifferentiated carcinomas of the thyroid,
the incidence of RAS mutations is also considerable (50%).
The most commonly observed RAS mutations arise at sites
critical for Ras regulation Ras activation is frequently observed in hematologic malignancies such
as myeloid leukemias and multiple myelomas. In about one-third of the
myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML),
RAS genes are mutationally activated62-73 (Table 1). N-RAS is mutated and
activated in most of the cases, and the presence of the mutation is not
associated with any particular FAB type, cytogenetic abnormality, or
clinical feature, including prognosis.71 RAS
mutations occur in about 40% of newly diagnosed multiple myeloma
patients, and the frequency increases with disease progression.74 Mutations in N-RAS
In addition to activation by mutation, Ras is thought to be deregulated by constitutive activation of proto-oncogenes and inactivation of tumor suppressor genes.79,80 Several types of human cancers show oncogenic activation of RTKs or NRTKs. Constitutively activated versions of normal receptor tyrosine kinases contain single point mutations (eg, CSF-1 receptor, the Neu/Erb-B2 receptor, and the c-Kit receptor), duplications of juxtamembrane domain-coding sequences (eg, FLT3 receptor), or deletions of the negative regulatory regions in the ligand binding or the transmembrane domains (eg, Erb-B receptor). Point mutations of the CSF-1 receptor (c-FMS) at codons 301 and 969 were found in 10% to 20% of AML or MDS.81,82 Point mutations in the catalytic domain of the c-Kit receptor are found in some cases of myeloproliferative disorders and in 10% of the patients with mastocytosis.83-85 Furthermore, activating tandem internal duplication of the FLT3 receptor has been reported in 20% of AML.86 The members of the c-Kit/c-FMS receptor kinase family (eg, c-Kit, c-FMS, FLT3) are linked with components of the Ras-to-MAPK signaling pathway (eg, Grb-2 and Shc), suggesting that activating mutations of c-FMS and FLT3 may induce activation of Ras.87,88 In addition, translocations involving receptor tyrosine kinases produce
chimeric proteins in which varying N-terminal portions of either
the ligand-binding or the transmembrane domain are replaced with novel
protein sequences.79,80 Several of these chimeric proteins
have been found in human hematologic malignancies. The Npm-Alk fusion
protein, a fusion of the N-terminal portion of Npm with the entire
cytoplasmatic domain of the receptor tyrosine kinase Alk, is generated
by the t(2;5) chromosomal translocation in anaplastic large cell
lymphoma.89,90 Tel-PDGFR In addition to oncogenes, tumor suppressor genes have also been found to be involved in the deregulation of Ras. Neurofibromin, the product of the NF1 gene, encodes a Ras-GAP and is mutated in the autosomal dominant type 1 neurofibromatosis.98 Interestingly, neurofibromatosis type 1 is associated with an increased tendency to develop myeloid leukemias, especially juvenile myelomonocytic myeloid leukemia (JMML).99-107 About 15% of children with JMML cases have clinical neurofibromatosis.99 Additionally, inactivating mutations of the NF1 gene have been found in 15% of JMML without clinical diagnosis of neurofibromatosis, suggesting the existence of NF1 mutations in approximately 30% of all JMML cases.100,102 The involvement of Ras is demonstrated by the finding that leukemic cells from children with neurofibromatosis type 1 show a moderate elevation in the percentage of GTP-Ras.103-106 Furthermore, 15% to 30% of JMML cases lacking the NF1 mutation have activating RAS mutations.107 The observation that human JMML cells exhibit hypersensitivity to GM-CSF suggests a common pathophysiologic mechanism involving downstream Ras signaling.106-108 The pathophysiologic importance of the Ras-MAPK signaling pathway is underscored by the positioning of several oncogene and tumor suppressor gene products on this pathway (Figure 4). Furthermore, it has recently been demonstrated that mutant N-RAS induces myeloproliferative disorders resembling human chronic myelogenous leukemia, AML, and apoptotic syndromes similar to human MDS in bone marrow-repopulated mice.109 These observations make Ras and the Ras-MAPK pathway an attractive target for the development of new anticancer agents.
Inhibitors of Ras farnesyltransferase Elimination of Ras function by homologous gene recombination or antisense RNA has demonstrated that expression of activated Ras is necessary for maintaining the transformed phenotype of tumor cells.110-113 Inhibitors of oncogenic Ras activity may therefore prove useful as anticancer agents against Ras-induced tumors. One strategy to impede oncogenic Ras function in vivo is the inhibition of Ras posttranslational modification. It has been demonstrated that mutation of the evolutionarily conserved CAAX motif in Ras abolishes plasma membrane binding as well as transforming activity.114-121 Although Ras undergoes several steps of posttranslational modification, only farnesylation is necessary for its membrane localization and cell-transforming activity.121 Therefore, it has been proposed that the activity of oncogenic Ras could be blocked by inhibiting the FTase responsible for this modification. However, many CAAX-containing proteins need additional palmitoylation for stable membrane association.FTase has become a very attractive target for the development of
anticancer agents because control of Ras farnesylation can control the
function of oncogenic Ras.114-121 Numerous inhibitors of
Ras FTase have been synthesized or identified. These Ras FTase inhibitors can be grouped into 3 classes: (1) FPP analogues such as
(
In addition to chemically synthesized compounds, several natural products have been identified as FTase inhibitors. These include limonene,153 manumycin (UCF1-C) and its related compounds UCF1-A and UCF1-B,154-156 chaetomellic acid A and B, zaragozic acids, pepticinnamins, gliotoxin,115 barceloneic acid A,157 RPR113228,158 actinoplanic acids A and B,159 oreganic acid,160 lupane derivatives,161 saquayamycins,162 valinoctin A and its analogues,163 and ganoderic acid A and C.164 Effects of FTase inhibitors in intact tumor cells.
Several FTase inhibitors were demonstrated to be active in intact cells
(Table 2). These compounds have been
shown to modulate several critical aspects of Ras transformation in
whole cells, including selective inhibition of anchorage-independent
growth of Ras-transformed fibroblasts in soft agar, morphologic
reversion of the Ras-induced phenotype, and inhibition of oocyte
maturation induced by oncogenic Ras without gross cytotoxic effects on
normal cells. One of the first FTase inhibitors found to be active in intact tumor cells, the FPP analogue (
Biologic mechanisms of FTase inhibitors in intact cells. Recent investigations into the biologic mechanism of the growth inhibition of Ras-transformed cells have shown that farnesylation of K-Ras and N-Ras is more resistant to FTase inhibitors than farnesylation of H-Ras.126,144,167,168 In part, this phenomenon is a result of a 10- to 50-fold higher affinity of FTase for K-Ras4B than for other Ras isoforms.126,170 In the absence of FTase inhibitors, all Ras proteins are present only in the farnesylated form. However, K-Ras and N-Ras (but not H-Ras) become geranylgeranylated by GGTase I in vivo in a dose-dependent manner when intracellular farnesylation is inhibited by an FTase inhibitor.126,169-171 Subsequently, both FTase and GGTase I inhibitors are required for inhibition of K-Ras processing.168,172 The lack of growth inhibition and gross cytotoxic effects of FTase inhibitors on normal cells is thought to be a result of the resistance of K-Ras processing to FTase inhibitors.167 Treatment of Ras-transformed cells with FTase inhibitors results in selective suppression of Ras-dependent oncogenic signaling. This includes the inhibition of Ras processing, which results in a decrease in the relative amount of fully processed Ras; the progressive, dose-dependent cytoplasmatic accumulation of unprocessed Ras and inactive Ras-Raf complexes; inhibition of the Ras-induced constitutive activation of MAPK138,140,141,146,173; and decreased transcriptional activity of both c-Jun and Elk-1.138 Transformation by mutationally activated Raf, MEK, Mos, or Fos (all of which are downstream effectors of Ras) is not blocked by FTase inhibitors.129,136 Although FTase inhibitors block Ras farnesylation and the Ras-induced transformed phenotype, proteins other than Ras may be targets of these compounds.174,175 FTase inhibitors block anchorage-independent growth of many human tumor cell lines in soft agar culture, but there is no correlation between biologic susceptibility and the presence of Ras mutations.136,144 In addition, anchorage-independent growth of K-Ras-transformed cells is abrogated by FTase inhibitors even though K-Ras processing is not affected.172 Although it is unclear whether soluble species of oncogenic Ras exert any biologically significant effect in drug-treated cells, it has recently been shown that nonfarnesylated H-Ras proteins can be palmitoylated and thus are biologically active. These proteins bound modestly to the plasma membranes (40%) but were still able to trigger exaggerated differentiation of PC12 cells and potent transformation of NIH3T3 fibroblasts.176 Recently, it has been suggested that the antitransforming effects of FTase inhibitors are mediated at least in part by alteration of farnesylated Rho proteins, including RhoB.174,175,177,178 In contrast to Ras proteins, RhoB exists normally in vivo in a farnesylated (RhoB-FF) and a geranylgeranylated version (RhoB-GG).179 RhoB-GG is essential for the degradation of p27KIP1 and facilitates the progression of cells from G1 to S phase. Treatment with FTase inhibitors results in a loss of RhoB-FF and a gain of RhoB-GG.178 Expression of a mutant RhoB-GG protein induces phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1 in cells sensitive to FTase inhibitors, including Ras-transformed cells.178,180 P21WAF1 mediates the inhibition of cyclinE-associated protein kinase activity, pRB hypophosphorylation, and inhibition of DNA replication, which results in G1 arrest.180 In addition to the induction of the G1 block, treatment of tumor cells with FTase inhibitors induces apoptosis by upregulating Bax and Bcl-xs expression and by activating caspases.131,181-183 Synergy of FTase inhibitors with established anticancer treatments such as radiation and chemotherapeutic treatment was recently reported. Agents that prevent microtubule depolymerization, such as taxol and epothilones, act synergistically with FTase inhibitors to block cell growth. FTase inhibitors cause increased sensitivity to induction of the metaphase block by taxol and epothilones.184 In addition, FTase inhibitors have been shown to increase the radiosensitivity of human tumor cells with activating mutations of RAS oncogenes.143Effects of FTase inhibitors in animal models.
FTase inhibitors have also been shown to inhibit the growth of
Ras-induced tumors in mouse xenograft models and, more dramatically, in
transgenic mouse models (Table 3).
Manumycin was reported to inhibit the growth of K-Ras-transformed
fibrosarcoma transplanted into nude mice by approximately 70% compared
with untreated controls.154 The CAAX peptide analogue
L-739,749 specifically suppressed the tumor growth of H-Ras-, N-Ras-,
and K-Ras-induced Rat-1 cell tumors in nude mice by 51% to
66%.129 Interestingly, L-739749 exhibited no evidence of
systemic toxicity. The peptidomimetic FTase inhibitors B956 and B1086
were shown to inhibit tumor growth of EJ-1 human bladder carcinoma, HT
1080 human fibrosarcoma and, to a lesser extent, HCT116 human colon
carcinoma xenografts in nude mice. Inhibition of Ras processing
correlated with the inhibition of the tumor growth by
B956.144 Analogues of the tetrapeptide
CVFM,189 the compound Nos. 46 and 51, showed inhibition of
anchorage-independent growth of stably H-Ras-transformed NIH3T3
fibroblasts as well as antitumor activity in an athymic mouse model
implanted with H-Ras-transformed Rat-1 cells.187
J-104871, an FPP-competitive FTase inhibitor, suppressed tumor growth
in nude mice transplanted with activated H-RAS-transformed
NIH3T3 cells.124 In contrast to these results, however,
treatment of irradiated mice engrafted with NF-1 deficient
hematopoietic cells (
and MMTV-TGF- /neu transgenic
mice.183 Because the mammary tumor cells harbor an
activated receptor tyrosine kinase but wild-type Ras, a feature common
in breast cancer, these mice provide a useful model system for
breast cancer research. Tumor regression by L-744,832 was demonstrated
biochemically by inhibition of MAPK activity and biologically by an
increase in G1-phase, a decrease in S-phase fractions, and induction of
apoptosis.183
In both cell culture and mouse models, there is essentially no
cytotoxicity or apparent systemic toxicity at doses capable of
reverting Ras-induced transformation or of causing tumor regression. FTase inhibitors seem to selectively target a unique aspect of the
transformed cell physiology.
Mechanisms of resistance to FTase inhibitors. As with any drug, the development of tumor resistance to FTase inhibitors is an important issue. To date, the relative frequency, the mechanisms, and the development of tumor resistance to FTI are unclear. K-RAS-transformed cell lines have been shown to be more resistant to FTase inhibitors than H-RAS- or N-RAS-transformed cells.126,144,167 This phenomenon is thought to be a result of a higher affinity of FTase for K-Ras than for other Ras isoforms.126,167 In addition, K-Ras and N-Ras become geranylgeranylated in the presence of FTI.169,171 Subsequently, both FTI and geranylgeranyltransferase inhibitor (GGTI) are required for inhibition of K-Ras processing.168,172 Recently, a variant RAS-transformed cell line was identified that was resistant to phenotypic reversion by FTI.193 This phenomenon was not due to mutation of the FTase subunits, changes in intracellular drug accumulation, or amplification of the multiple-drug resistance gene. The precise mechanism of resistance in these cells remained unclear. However, mutational alteration of FTase might also lead to resistance toward FTI. The Y361L mutant of FTase has been shown to exhibit increased resistance to FTI while maintaining FTase activity toward substrates possessing CIIS carboxy-termini.194 Withdrawal of FTI from successfully treated tumor-bearing mice led to subsequent tumor growth in the absence of the drug. A second FTI treatment resulted in a second response in some mice, but some tumors were found to become resistant to FTI.135 Therefore, chronic, uninterrupted treatment with FTI might be required. Inhibitors of geranylgeranyl transferase I Until recently, the emphasis has been on designing specific FTase inhibitors to block Ras processing. This strategy was employed to avoid possible toxic effects originating from inhibition of GGTase I. Because K-RAS mutations are most common in human cancers,60,61 a critical goal is the development of inhibitors that block the growth of human tumors that harbor K-Ras. The resistance of K-Ras to FTase inhibitors,167 the lack of potency of FTase inhibitors against K-Ras-transformed cells,144 and the observation that K-Ras becomes geranylgeranylated in the presence of FTase inhibitors126,169-172 led to the development of GGTase I inhibitors (Figure 7). GGTI-279, GGTI-287, GGTI-297, and GGTI-298 are CAAL-based peptidomimetics that are selective for GGTase I over FTase.173,195-199 In contrast, FTI-276 and FTI-277 are CAAM-based peptidomimetics that are potent and selective inhibitors of FTase over GGTase I.173 H-Ras processing in human tumor cell lines was highly sensitive to FTI-277 and resistant to GGTI-286, whereas K-Ras4B processing was more sensitive to GGTI-286 than FTI-277.173 Processing of H-Ras and N-Ras was inhibited by FTI-277, but inhibition of K-Ras processing required both FTase and GGTase I inhibitors. Whereas FTI-277 preferentially blocks activation of MAPK by oncogenic H-Ras, GGTase inhibitors selectively inhibit the activation of MAPK by oncogenic K-Ras4B.173 Although GGTI-298 had very little effect on soft agar growth of several human tumor cell lines harboring H-RAS, N-RAS, or K-RAS mutations, the combination of FTI-277 and GGTI-298 resulted in significant soft agar growth inhibition.172 Both FTase inhibitors and GGTase inhibitors have been reported to arrest Ras-transformed cells in G0/G1 phase of the cell cycle and to induce apoptosis.142,180,196,198,199 In nude mouse xenografts, the GGTase inhibitor GGTI-297 suppressed human lung A-549 and Calu-1 carcinoma tumor growth by 60%. However, both FTase and GGTase inhibitors were required to inhibit K-Ras processing.168 Treatment of cells with GGTI-298 blocks PDGF- and EGF-dependent tyrosine phosphorylation of their respective receptors and induces G0/G1-phase arrest and apoptosis.196-198 GGTI-298 has also been shown to induce the cyclin-dependent kinase inhibitor p21WAF but not p27KIP.199
Inhibitors of the prenylated protein methyltransferase The C-terminal prenylated protein methyltransferase (PPMTase) is another potential therapeutically relevant target in the development of inhibitors against the posttranslational processing of Ras. N-acetyl-trans, trans-farnesyl-L-cysteine (AFC) is a substrate for PPMTase and acts as a competitive inhibitor.201 Although AFC has been shown to inhibit Ras methylation in Ras-transformed NIH3T3 fibroblasts, it does not inhibit the growth of these cells.201 New farnesyl derivatives of rigid carboxylic acid, eg, S-trans, trans-farnesylthiosalicylic acid (FTS), were found to inhibit the growth of H-Ras-transformed cells and to reverse their transformed morphology by a mechanism unrelated to the inhibition of Ras methylation by PPMTase202,203 (Figure 5). It is thought that FTS specifically interacts with Ras farnesylcysteine binding domains and affects membrane anchorage of Ras.202,203 In addition, it has been reported that FTS dislodges Ras from H-Ras-transformed cell membranes and renders the Ras protein susceptible to proteolytic degradation.188 At the same concentration, growth and morphology of non-Ras-transformed or nontransformed cells were not affected by FTS.203 Despite the lack of FTS-induced cytotoxicity in nontransformed cells, FTS reduced Ras levels in cell membranes and inhibited Ras-dependent cell growth.203 In contrast to FTase inhibitors (eg, BZA-5B), FTS also inhibited the growth signaling of receptor tyrosine kinases.203 FTS was shown to decrease total cellular Ras levels, MAPK activity, Raf-1 activity, and DNA synthesis in Ras-transformed EJ-1 cells. This inhibition was also demonstrated in serum-, EGF-, and thrombin-stimulated, untransformed Rat-1 cells.204,205 S-farnesyl-thioacetic acid (FTA), another competitive inhibitor of PPMTase, has been shown to suppress growth and induce apoptosis in HL-60 cells.206 Five-chloro- and 4- or 5-fluoro-derivatives of FTS and a C20 S-geranylgeranyl derivative of thiosalicyclic acid also cause inhibition of Ras-dependent MAPK activity, DNA synthesis, and EJ-1 cell growth. However, several other derivatives were inactive, suggesting stringent structural requirements for the anti-Ras activity of S-prenyl analogues.207 Recently, FTS was shown (1) to reduce the amount of activated N-Ras and wild-type Ras isoforms in human melanoma cells and Rat-1 fibroblasts, (2) to disrupt ERK signaling, (3) to revert their transformed phenotype, and (4) to cause a significant reduction in the growth of human melanoma in SCID mice.188,205The dorrigocins are novel antifungal antibiotics that were found to reverse the morphology of Ras-transformed NIH3T3 fibroblasts. Dorrigocin A did not inhibit protein prenylation or protein synthesis but was instead found to inhibit the C-terminal methylation in K-Ras-transformed cells.208 Selective inhibitors of Ras C-terminal sequence-specific endoprotease UM96001, TPCK, and BFCCMK are Ras C-terminal sequence-specific endoprotease inhibitors (REPI) and potently inhibit ras-transformed rat kidney cell growth as well as growth of human cancer cells.209 These compounds have been reported to almost completely block the anchorage-independent clonogenic growth of these cancer cells. REPIs may selectively induce apoptosis in these cells.209Selective inhibitors of MAPKKs, or MEK PD098059 is a synthetic inhibitor of the Ras-MAPK pathway that selectively blocks the activation of MEK-1 and, to a lesser extent, the activation of MEK-2.210,211 The inhibition of MEK-1 activation was demonstrated to prevent activation of MAPKs ERK-1/2 and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. In contrast to FTase inhibitors, PD098059 inhibited stimulation of cell growth by several growth factors.210,211 Furthermore, PD098059 reversed the transformed phenotype of Ras-transformed BALB3T3 mouse fibroblasts and rat kidney cells.211 PD098059 failed to inhibit the stress, and IL-1 stimulated JNK/SAPK and the p38 pathways,210 demonstrating its specificity for the ERK pathway. PD098059 has subsequently been used as a tool to study MAPK signaling in various cell types and in carcinogenesis.Recently, 2 novel inhibitors of MEK-1 and MEK-2 have been identified: U0126212,213 and Ro 09-2210.214 Ro 09-2210, which was identified by screening microbial broths, exhibits potent antiproliferative effects on activated T cells.214 Similarly, U0126 was found to inhibit T-cell proliferation in response to both antigenic stimulation and cross-linked anti-CD3 plus anti-CD28 antibodies.212 U0126 and PD098059 are noncompetitive inhibitors with respect to both MEK substrates (ATP and ERK) and bind to free MEK as well as MEK*ERK and MEK*ATP complexes. U0126 displays significantly higher affinity for all forms of MEK (44- to 357-fold) than does PD098059. U0126 and Ro 09-2210 have an inhibitory concentration of 50% (IC50) of 50 to 70 nmol/L, whereas PD098059 has an IC50 of 5 µmol/L.212-214 PD098059 and U0126 impede the growth of Ras-transformed cells in soft agar but show minimal effects on cell growth under normal culture conditions.210,213 In contrast to U0126 and PD098059, Ro 09-2210 is also able to inhibit other dual-specificity kinases such as MKK-4, MKK-6, and MKK-7, albeit at 4- to 10-fold higher IC50 concentrations compared with its effect on MEK-1.214 Inhibitors of Ras transformation with unknown mechanisms of action Screening tests for drugs that revert RAS-transformed cells to a normal phenotype led to the identification of a number of compounds, such as azatyrosine, oxanosine, and antipain.215-217 The mechanism by which these compounds revert the RAS-induced phenotype is not understood. The pyrazolo-quinoline compound SCH51344 was identified based on its ability to depress human smooth muscle -actin promoter activity in
RAS-transformed cells. Treatment of v-abl-,
v-mos-, v-raf-, RAS-, and mutant
active MEK-transformed NIH3T3 cells resulted in growth inhibition of
these cells in soft agar.218 SCH51344 had very little
effect on the activities of proteins in the ERK pathway. The ability of
SCH51344 to inhibit the anchorage-independent growth of
RAC-V12-transformed Rat-1 cells suggests that the point of inhibition
is downstream from RAC.219
The nonsteriodal, anti-inflammatory drug sulindac has been demonstrated to attenuate the growth and progression of colonic neoplasms in animal models and in patients with familial adenomatous polyposis.220,221 Recently, it has been shown that sulindac sulfide (the active metabolite of sulindac) inhibits Ras signaling and transformation by noncovalent binding to the Ras protein. Furthermore, it has been demonstrated that sulindac sulfide impairs Ras-Raf binding, Raf activation, and nucleotide exchange on Ras and that it accelerates the Ras-GTPase reaction.222 Sulindac is being investigated in a randomized study for the prevention of colon cancer (protocol RUH-SSH-190-0698, NCI-V98-1425). Disruption of the Ras-to-MAPK signaling pathway has also been shown for the benzoquinone ansamycin geldanamycin. Geldanamycin binds to HSP90 and disrupts the HSP90-Raf-1 multimolecular complex, which causes destabilization of Raf-1 through enhanced degradation of Raf-1.223 However, the geldanamycin-HSP90 complex also causes depletion of other HSP90 substrates such as protein kinases and nuclear hormone receptors (including mutant p53 and ErbB2).224 Several National Cancer Institute-sponsored clinical phase I trials are currently studying the effects of geldanamycin analogues in patients with advanced malignancies.
FTase and GGTase inhibitors have strong growth inhibitory and antitumor activity in cell culture and animal tumor models without showing nonspecific gross toxicity in animals. The specificity and the lack of nonspecific toxicity contrasts dramatically with the nonspecificity and high toxicity of currently available chemotherapeutic drugs. The recent development of orally bioavailable FTase inhibitors with potent and selective in vivo antitumor activity underscores their potential usefulness in the future treatment of human malignancies. The observation that FTase and GGTase inhibitors induce apoptosis in treated tumor cells as well as a G0-G1 arrest suggests that they are not merely cytostatic but cytotoxic for tumor cells. However, the absence of toxicity due to FTase inhibitors in normal cells and tissues in mice at doses that inhibit tumor growth is poorly understood. Ras knockout experiments have demonstrated that H-RAS- and N-RAS-deficient mice are born and grow normally, whereas K-RAS-deficient embryos die between embryonic day 12.5 and term. This finding suggests a partial functional overlap within the RAS gene family.225-228 However, H-RAS and N-RAS cannot compensate for the loss of K-RAS function in K-RAS-deficient mice. Functionally redundant pathways might allow normal cells to tolerate treatment with FTase inhibitors. Because mutated RAS genes have a high prevalence in human cancers (eg, pancreatic, lung, and colon cancers), inhibitors specific for FTase, GGTase, and MEK were initially designed to block the Ras-to-MAPK signaling in solid tumor cells. More than 90% of RAS mutations found in human tumors occur in N-RAS or K-RAS. Whereas the reversion of the H-RAS-induced transformation by FTase inhibitors correlates well with the intracellular inhibition of H-Ras processing, N-Ras and K-Ras are cross-prenylated by GGTase I in cells treated with FTase inhibitors. However, many of these N-RAS- or K-RAS-transformed cell lines (and even tumor cell lines that do not harbor RAS mutations) are sensitive to FTase inhibitors. Cell biology studies suggest that FTase and GGTase inhibitors may act at additional levels beyond the inhibition of Ras processing. The exact mechanism of action has emerged as a question of major interest, especially because transformed tumor cells respond to treatment with these inhibitors while normal cells remain largely unaffected. Non-Ras targets of FTase and GGTase inhibitors may include other cellular proteins (eg, Rho) that are farnesylated or geranylgeranylated.174,175,178,229-231 FTase inhibitors (eg, R115777, L-778,123, and SCH66336) have
entered several phase I/II clinical trials (Table
4). These trials are still ongoing, and
preliminary results have not been published. Because favorable
synergistic effects have been described for combinations of FTase
inhibitors with traditional anticancer treatments such as radiation and
chemotherapy,143,184 it will be interesting to see if
these results translate into improved patient outcome in clinical
trials. The high prevalence of mutationally activated Ras in solid
tumors has been the driving force of Ras inhibitor research. However,
recent studies in cell culture and animal models suggest that
transformed cells with an activated Ras pathway (eg, via mutations
upstream of Ras) are also highly sensitive for FTase inhibitors. The
involvement of N-RAS in the molecular pathophysiology of
myeloid leukemias and multiple myeloma suggests that these malignancies
may also represent promising targets for inhibitors of Ras signaling.
While it is impossible to predict the outcome of the clinical trials,
the biologic properties of these inhibitors are potentially informative
because transformation-specific mechanisms are targeted.
We thank Dr Kristine A. Henningfeld for help with the figures and for critical reading of the manuscript.
Submitted August 24, 1999; accepted March 30, 2000.
Supported by a grant to C.W.M.R. from the German Research Council (Deutsche Forschungsgemeinschaft Re 864/4-1) and a grant from the University of Ulm (P.541).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: C. Reuter, Dept of Internal Medicine III, University of Ulm, Robert-Koch-Str 8, D-89081 Ulm, Germany; e-mail: christoph.reuter{at}medizin.uni-ulm.de.
1. Sprang SR. G protein mechanisms: insights from structural analysis. Annu Rev Biochem. 1997;66:639-678[Medline] [Order article via Infotrieve]. 2. Bos JL. All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. EMBO J. 1998;17:6776-6782[Medline] [Order article via Infotrieve].
3.
Rebollo A, Martinez CA.
Ras proteins: recent advances and new functions.
Blood.
1999;94:2971-2980 4. Pells S, Divjak M, Romanowski P, et al. Developmentally-regulated expression of murine K-ras isoforms. Oncogene. 1997;15:1781-1786[Medline] [Order article via Infotrieve]. 5. Wittinghofer A. Signal transduction via Ras. Biol Chem. 1998;379:933-937.
6.
Van Aelst L, White M, Wigler MH.
Ras partners.
Cold Spring Harbor Symp Quant Biol.
1994;59:181-186 7. Marshall CJ. Ras effectors. Curr Opin Cell Biol. 1996;8:197-204[Medline] [Order article via Infotrieve]. 8. Katz ME, McCormick F. Signal transduction from multiple Ras effectors. Curr Opin Genet Dev. 1997;7:75-79[Medline] [Order article via Infotrieve]. 9. Glomset JA, Farnsworth CC. Role of protein modification reactions in programming interactions between Ras-related GTPases and cell membranes. Annu Rev Cell Biol. 1994;10:181-205. 10. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241-269[Medline] [Order article via Infotrieve].
11.
Gelb MH.
Protein prenylation, et cetera: signal transduction in two dimensions.
Science.
1997;275:1750-1751 12. Mumby SM. Reversible palmitoylation of signaling proteins. Curr Opin Cell Biol. 1997;9:148-154[Medline] [Order article via Infotrieve].
13.
Casey PJ, Seabra MC.
Protein prenyltransferases.
J Biol Chem.
1996;271:5289-5292 14. Reiss Y, Goldstein JL, Seabra MC, Casey PJ, Brown MS. Inhibition of purified p21ras farnesyl protein transferase by cys-AAX tetrapeptides. Cell. 1990;62:81-88[Medline] [Order article via Infotrieve].
15.
Reiss Y, Stradley SJ, Gierasch LM, Brown MS, Goldstein JL.
Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase.
Proc Natl Acad Sci U S A.
1991;88:732-736
16.
Yokoyama K, Goodwin GW, Ghomashchi F, Glomaset JA, Gelb MH.
A protein geranylgeranyltransferase from bovine brain: implications for protein prenylation specificity.
Proc Natl Acad Sci U S A.
1991;88:5302-5306
17.
Moores SL, Schaber MD, Mosser SD, et al.
Sequence dependence of protein isoprenylation.
J Biol Chem.
1991;266:14603-14610
18.
Trueblood CE, Ohya Y, Rine J.
Genetic evidence for in vivo cross-specificity of the CAAX-box protein prenyltransferases farnesyltransferase and geranylgeranyltransferase I in Saccharomyces cerevisiae.
Mol Cell Biol.
1993;13:4260-4275 19. Pellicena P, Scholten JD, Zimmerman K, Creswell M, Huang CC, Miller WT. Involvement of the alpha subunit of farnesyl-protein transferase in substrate recognition. Biochemistry. 1996;35:13494-13500[Medline] [Order article via Infotrieve].
20.
Trueblood CE, Boyartchuk VL, Rine J.
Substrate specificity determinants in the farnesyltransferase
21.
Park H-W, Boduluri SR, Moomaw JF, Casey PJ, Beese LS.
Crystal structure of protein farnesyltransferase at 2.25 Angstrom resolution.
Science.
1997;275:1800-1804 22. Akopyan TN, Couedel Y, Orlowski M, Fournie-Zaluski MC, Roques BP. Proteolytic processing of farnesylated peptides: assay and partial purification from pig brain membranes of an endopeptidase which has the characteristics of E.C. 3.4.24.15. Biochem Biophys Res Commun. 1994;198:787-794[Medline] [Order article via Infotrieve].
23.
Boyartchuk VL, Ashby MN, Rine J.
Modulation of Ras and a-factor function by carboxyl-terminal proteolysis.
Science.
1997;275:1796-1800 24. Hancock J, Magee A, Childs J, Marshall C. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989;57:1167-1177[Medline] [Order article via Infotrieve]. 25. Milligan G, Parenti M, Magee AI. The dynamic role of palmitoylation in signal transduction. Trends Biochem Sci. 1995;20:181-187[Medline] [Order article via Infotrieve]. 26. Ross EM. Palmitoylation in G-protein signaling pathways. Curr Biol. 1995;5:107-109[Medline] [Order article via Infotrieve].
27.
Dudler T, Gelb MH.
Palmitoylation of Ha-Ras facilitates membrane binding, activation of downstream effectors and meiotic maturation in Xenopus oocytes.
J Biol Chem.
1996;271:11541-11547
28.
Liu L, Dudler T, Gelb MH.
Purification of a protein palmitoyltransferase that acts on H-Ras protein and on a C-terminal N-Ras peptide.
J Biol Chem.
1996;271:23269-23276
29.
Camp LA, Verkruyse LA, Afendis SJ, Slaughter CA, Hofmann SL.
Molecular cloning and expressing of palmitoyl-protein thioesterase.
J Biol Chem.
1994;269:23212-23219 30. Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996;8:205-215[Medline] [Order article via Infotrieve]. 31. Fanger GR, Gerwins P, Widmann C, Jarpe MB, Johnson GL. MEKKs, GCKs, MLKs, PAKs, TAKs, and Tpls: upstream regulators of the c-Jun amino-terminal kinases? Curr Opin Genet Dev. 1997;7:67-74[Medline] [Order article via Infotrieve]. 32. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180-186[Medline] [Order article via Infotrieve]. 33. Garrington TP, Johnson GL. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol. 1999;11:211-218[Medline] [Order article via Infotrieve].
34.
Schaeffer HJ, Weber MJ.
Mitogen-activated protein kinases: specific messages from ubiquitous messengers.
Mol Cell Biol.
1999;19:2435-2444
35.
Elion EA.
Routing MAP kinase cascades.
Science.
1998;281:1625-1626 36. Schlessinger J. How receptor tyrosine kinases activate Ras. Trends Biol Sci. 1993;18:273-275. 37. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995;80:179-185[Medline] [Order article via Infotrieve]. 38. Marshall CJ. Raf gets it together. Nature. 1996;383:127-128[Medline] [Order article via Infotrieve]. 39. Porter AC, Vaillancourt RR. Tyrosine kinase receptor-activated signal transduction pathways which lead to oncogenesis. Oncogene. 1998;17:13434-13452.
40.
Pawson T, Saxton TM.
Signaling networks
41.
Adachi T, Alam R.
The mechanism of IL-5 signal transduction.
Am J Physiol.
1998;275:C623-C633
42.
Guthridge MA, Stomski FC, Thomas D, et al.
Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors.
Stem Cells.
1998;16:301-313 43. Daum G, Eisenmann-Tappe I, Fries HW, Troppmair J, Rapp U. The ins and outs of Raf kinases. Trends Biol Sci. 1994;19:474-480. 44. Catling AD, Schaeffer H-J, Reuter CWM, Reddy GR, Weber MJ. A proline-rich sequence unique to MEK1 and MEK2 is required for Raf binding and regulates MEK function. Mol Cell Biol. 1995;15:5214-5225[Abstract].
45.
Reuter CWM, Catling AD, Jelinek T, Weber MJ.
Biochemical analysis of MEK activation in NIH3T3 fibroblasts.
J Biol Chem.
1995;270:7644-7655
46.
Patriotis C, Makris A, Chernoff J, Tsichlis PN.
Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-activated protein kinase.
Proc Natl Acad Sci U S A.
1994;91:9755-9759 47. Sameron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC. Activation of MEK-1 and SEK-2 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase. EMBO J. 1996;15:817-826[Medline] [Order article via Infotrieve].
48.
Posado J, Yew N, Ahn NG, Vande-Woude GF, Cooper JA.
Mos stimulates MAP kinase in Xenopus oocytes and activates MAP kinase kinase in vitro.
Mol Cell Biol.
1993;13:2546-2553 49. Bardwell L, Thorner J. A conserved motif at the amino termini of MEKs might mediate high affinity interaction with the cognate MAPKs. Trends Biol Sci. 1996;21:373-374.
50.
Crews CM, Alessandrini A, Erikson RL.
The primary structure of MEK, a protein that phosphorylates the ERK gene product.
Science.
1992;258:478-480 51. Wu J, Harrison JK, Dent P, Lynch KR, Weber MJ, Sturgill TW. Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Mol Cell Biol. 1993;8:4539-4548.
52.
Zheng C-F, Guan K-L.
Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.
J Biol Chem.
1993;268:11435-11439 53. Xing J, Ginty DD, Greenberg ME. Coupling of the Ras-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996;273:959-963[Abstract].
54.
Jaaro H, Rubinfeld H, Hanoch T, Seger R.
Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation.
Proc Natl Acad Sci U S A.
1997;94:3742-3747 55. Feig LA, Urano T, Cantor S. Evidence for a Ras/Ral signaling cascade. Trends Biochem Sci. 1996;21:438-441[Medline] [Order article via Infotrieve]. 56. Carpenter CL, Cantley LC. Phosphoinositide kinases. Curr Opin Cell Biol. 1996;8:153-158[Medline] [Order article via Infotrieve].
57.
Graham SM, Cox AD, Drivas G, Rush MG, D'Eustachio P, Der CJ.
Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation.
Mol Cell Biol.
1994;14:4108-4115 58. Cox AD, Brtva TR, Lowe DG, Der CJ. R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells. Oncogene. 1994;9:3281-3288[Medline] [Order article via Infotrieve].
59.
Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C.
M-Ras/R-Ras3, a transforming ras protein regulated by SOS1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6.
J Biol Chem.
1999;274:23850-23857
60.
Bos JL.
RAS oncogenes in human cancer: a review.
Cancer Res.
1989;49:4682-4689 61. Clark GJ, Der CJ. Ras proto-oncogene activation in human malignancy. In: Garrett CT,Sell S, eds. Cellular Cancer Markers. Totowa, NJ: Humana Press; 1995:17-52.
62.
Janssen J, Steenvoorden A, Lyons J, et al.
Ras gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes.
Proc Natl Acad Sci U S A.
1987;84:9228-9232
63.
Bos JL, Verlaan-de-Vries M, van-der-Eb AJ, et al.
Mutations in N-Ras predominate in acute myeloid leukemia.
Blood.
1987;69:1237-1241
64.
Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ.
Analysis of Ras gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucteotide probes.
Proc Natl Acad Sci U S A.
1988;85:1629-1633 65. Padua RA, Carter G, Hughes D, et al. Ras mutations in myelodysplasia detected by amplification, oligonucteotide hybridization and transformation. Leukemia. 1988;2:503-510[Medline] [Order article via Infotrieve]. 66. Senn HP, Tran-Thang C, Wodnar-Filipowicz A, et al. Mutational analysis of the N-RAS proto-oncogene in active and remission phase acute leukemias. Int J Cancer. 1988;41:59-64[Medline] [Order article via Infotrieve]. 67. Toksoz D, Farr CJ, Marshall CJ. Ras genes and acute myeloid leukemia. Br J Haematol. 1989;71:1-6[Medline] [Order article via Infotrieve]. 68. Browett PJ, Yaxley JC, Norton JD. Activation of Harvey ras oncogene by mutation at codon 12 is very rare in hematopoietic malignancies. Leukemia. 1989;3:86-88[Medline] [Order article via Infotrieve]. 69. Browett PJ, Norton JD. Analysis of RAS gene mutations and methylation state in human leukemias. Oncogene. 1989;4:1029-1036[Medline] [Order article via Infotrieve]. 70. Parker J, Mufti GJ. Ras and myelodysplasia: lessons from the last decade. Semin Hematol. 1996;33:206-224[Medline] [Order article via Infotrieve]. 71. Byrne JL, Marshall CJ. The molecular pathophysiology of myeloid leukaemias: Ras revisited. Br J Haematol. 1998;100:256-264[Medline] [Order article via Infotrieve]. 72. Vogelstein B, Civin CI, Preisinger AC, et al. Ras gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study. Genes Chromosomes Cancer. 1990;2:159-162[Medline] [Order article via Infotrieve].
73.
Hirsch-Ginsberg C, LeMaistre AC, Kantarjian H, et al.
Ras mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia.
Blood.
1990;76:1214-1219
74.
Hallek M, Leif Bergsagel P, Anderson KC.
Multiple myeloma: increasing evidence for a multistep transformation process.
Blood.
1998;91:3-21
75.
Neri A, Knowes DM, Greco A, McCormick F, Dalla-Favera R.
Analysis of Ras oncogene mutations in human lymphoid malignancies.
Proc Natl Acad Sci U S A.
1988;85:9268-9272
76.
Neri A, Murphy JP, Cro L, et al.
Ras oncogene mutation in multiple myeloma.
J Exp Med.
1989;170:1715-1725 77. Tanaka K, Takechi M, Asaoku H, Dohy H, Kamada N. A high frequency of N-Ras oncogene mutations in multiple myeloma. Int J Hematol. 1992;56:119-127[Medline] [Order article via Infotrieve].
78.
Corradini P, Ladetto M, Voena C, et al.
Mutational activation of N- and K-RAS oncogenes in plasma cell dyscrasias.
Blood.
1993;81:2708-2713 79. Hunter T. Oncoprotein networks. Cell. 1997;88:333-346[Medline] [Order article via Infotrieve]. 80. Sawyers CL, Denny CT. Chronic myelomonocytic leukemia: Tel-a-kinase what Ets all about. Cell. 1994;77:171-173[Medline] [Order article via Infotrieve]. 81. Tobal K, Pagliuca A, Bhatt B, Bailey N, Layton DM, Mufti GJ. Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia. Leukemia. 1990;4:486-489[Medline] [Order article via Infotrieve]. 82. Padua RA, Guinn BA, Al-Sabah AI, et al. Ras, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998;12:887-892[Medline] [Order article via Infotrieve]. 83. Nakata Y, Kimura A, Katoh O, et al. c-kit point mutation of extracellular domain in patients with myeloproliferative disorders. Br J Haematol. 1995;91:661-663[Medline] [Order article via Infotrieve]. 84. Buttner C, Henz BM, Welker P, Sepp NT, Grabbe J. Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavior. J Invest Dermatol. 1998;111:1227-1231[Medline] [Order article via Infotrieve].
85.
Nagata H, Worobec AS, Oh CK, et al.
Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder.
Proc Natl Acad Sci U S A.
1995;92:10560-10564
86.
Kiyoi H, Naoe T, Nakano Y, et al.
Prognostic implication of FLT3 and N-Ras gene mutations in acute myeloid leukemia.
Blood.
1999;93:3074-3080
87.
Dosil M, Wang S, Lemischka IR.
Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells.
Mol Cell Biol.
1993;13:6572-6585 88. Rohrschneider LR, Bourette RP, Lioubin MN, Algate PA, Myles GM, Carlberg K. Growth and differentiation signals regulated by the M-CSF receptor. Mol Reprod Dev. 1997;46:96-103[Medline] [Order article via Infotrieve].
89.
Elmberger PG, Lozano MD, Weisenburger DD, Sanger W, Chan WC.
Transcripts of the npm-alk fusion gene in anaplastic large cell lymphoma, Hodgkin's disease, and reactive lymphoid lesions.
Blood.
1995;86:3517-3521 90. Waggott W, Lo YM, Bastard C, et al. Detection of NPM-ALK DNA rearrangement in CD30 positive anaplastic large cell lymphoma. Br J Haematol. 1995;89:905-907[Medline] [Order article via Infotrieve].
91.
Golub T, Barker G, Lovett M, Gilliland D.
Fusion of PDGF receptor
92.
Jousset C, Carron C, Boureux A, et al.
A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR
93.
Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM.
The novel activation of abl by fusion to an ets-related gene, tel.
Cancer Res.
1995;55:34-38 94. Golub TR, Goga A, Barker GF, et al. Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. Mol Cell Biol. 1996;16:4107-4116[Abstract]. 95. Kurzrock R, Gutterman J, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988;319:990-998[Medline] [Order article via Infotrieve].
96.
Faderl S, Talpaz M, Estrow Z, O'Brien S, Kurzrock R, Kantarjian HM.
The biology of chronic myeloid leukemia.
N Engl J Med.
1999;341:164-172
97.
Zou X, Calame K.
Signaling pathways activated by oncogenic forms of Abl tyrosine kinase.
J Biol Chem.
1999;274:18141-18144 98. Xu G, O'Connell P, Viskochil D, et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990;62:599-608[Medline] [Order article via Infotrieve].
99.
Niemeyer CM, Arico M, Basso G, et al.
Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases.
Blood.
1997;89:3534-3543
100.
Shannon KM, O'Connell P, Martin GA, et al.
Loss of the normal NF-1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders.
N Engl J Med.
1994;330:597-601 101. Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukemia/lymphoma: a population based UKCCSG study. Br J Cancer. 1994;70:969-972[Medline] [Order article via Infotrieve].
102.
Side L, Taylor B, Cayouette M, et al.
Homozygous inactivation of the NF-1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders.
N Engl J Med.
1997;336:1713-1720 103. DeClue JE, Papageorge AG, Fletcher JA, et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell. 1992;69:265-273[Medline] [Order article via Infotrieve].
104.
Kalra R, Paderanga DC, Olson K, Shannon KM.
Genetic analysis is consistent with the hypothesis that NF-1 limits myeloid cell growth through p21ras.
Blood.
1994;84:3435-3439 105. Bollag G, Clapp DW, Shih S, et al. Loss of NF-1 results in activation of the Ras signaling pathway and leads to aberrant growth in hematopoietic cells. Nat Genet. 1996;12:144-148[Medline] [Order article via Infotrieve]. 106. Largaespada DA, Brannan CI, Jenkins NA, Copeland NG. NF-1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukemia. Nat Genet. 1996;12:137-143[Medline] [Order article via Infotrieve].
107.
Miyauchi J, Asada M, Sasaki M, Tsunematsu Y, Kojima S, Mizutani S.
Mutations of N-ras gene in juvenile chronic myelogenous leukemia.
Blood.
1994;83:2248-2254 108. Birnbaum RA, O'Marcaigh A, Wardak Z. NF1 and GM-CSF interact in myeloid leukemogenesis. Mol Cell. 2000;5:189-195[Medline] [Order article via Infotrieve].
109.
MacKencie KL, Dolnikov A, Millington M, Shounan Y, Symonds G.
Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice.
Blood.
1999;93:2043-2056 110. Saison-Behmoaras T, Tocque B, Rey I, Chassignol M, Thuong NT, Helene C. Short modified antisense oligonucleotides directed against Ha-RAS point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation. EMBO J. 1991;10:1111-1118[Medline] [Order article via Infotrieve].
111.
Mukhopadhyah T, Tainsky M, Cavender AC, Roth JA.
Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA.
Cancer Res.
1991;51:1744-1748
112.
Shirasawa S, Furuse M, Yokoyama N, Sasazuki T.
Altered growth of human colon cancer cell lines disrupted at activated Ki-Ras.
Science.
1993;260:85-88
113.
Kashani-Sabet M, Funato T, Florenes VA, Fodstad O, Scanlon KJ.
Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme.
Cancer Res.
1994;54:900-902 114. Gibbs JB. Ras C-terminal processing enzymes: new drug targets? Cell. 1991;65:1-4[Medline] [Order article via Infotrieve]. 115. Tamanoi F. Inhibitors of Ras farnesyltransferases. Trends Biochem Sci. 1993;18:349-353[Medline] [Order article via Infotrieve]. 116. Gibbs JB, Oliff A. Pharmaceutical research in molecular oncology. Cell. 1994;79:193-198[Medline] [Order article via Infotrieve]. 117. Gibbs JB, Oliff A, Kohl NE. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell. 1994;77:175-178[Medline] [Order article via Infotrieve]. 118. Lowy DR, Willumsen BM. Rational cancer therapy. Nat Med. 1995;1:747-748[Medline] [Order article via Infotrieve]. 119. Gibbs JB, Oliff A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol. 1997;37:143-166[Medline] [Order article via Infotrieve]. 120. Omer CA, Kohl NE. CA1A2X-competitive inhibitors of farnesyltransferase as anti-cancer agents. Trends Pharmacol Sci. 1997;18:437-444[Medline] [Order article via Infotrieve]. 121. Heimbrook DC, Oliff A. Therapeutic intervention and signaling. Curr Biol. 1998;10:284-288.
122.
Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ.
Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity.
Proc Natl Acad Sci U S A.
1992;89:6403-6407 123. Kang MS, Stemerick DM, Zwolshen JH, Harry BS, Sunkara PS, Harrison BL. Farnesyl-derived inhibitors of Ras farnesyl transferase. Biochem Biophys Res Commun. 1995;217:245-249[Medline] [Order article via Infotrieve].
124.
Yonemoto M, Satoh T, Arakawa H, et al.
J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner.
Mol Pharmacol.
1998;54:1-7
125.
James GL, Goldstein JL, Brown MS, et al.
Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells.
Science.
1993;260:1937-1942
126.
James GL, Goldstein JL, Brown MS.
Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro.
J Biol Chem.
1995;270:6221-6226
127.
Dalton MB, Fantle KS, Bechtold HA, et al.
The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization.
Cancer Res.
1995;55:3295-3304
128.
Kohl NE, Mosser SD, DeSolms SJ, et al.
Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor.
Science.
1993;260:1934-1937
129.
Kohl NE, Wilson FR, Mosser SD, et al.
Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice.
Proc Natl Acad Sci U S A.
1994;91:9141-9145
130.
Prendergast GC, Davide JP, DeSolms JS, et al.
Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton.
Mol Cell Biol.
1994;14:4193-4202
131.
Lebowitz PF, Sakamuro D, Prendergast GC.
Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment.
Cancer Res.
1997;57:708-713
132.
Emanuel PD, Snyder RC, Wiley T, Gopurala B, Castleberry RP.
Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors.
Blood.
2000;95:639-645 133. Koblan KS, Culberson JC, DeSolms SJ, et al. NMR studies of novel inhibitors bound to farnesyl-protein transferase. Protein Sci. 1995;4:681-688[Medline] [Order article via Infotrieve].
134.
Barrington RE, Subler MA, Rands E, et al.
A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis.
Mol Cell Biol.
1998;18:85-92 135. Kohl NE, Omer CA, Conner MW, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med. 1995;1:792-797[Medline] [Order article via Infotrieve].
136.
Sepp-Lorenzino L, Ma Z, Rands E, et al.
A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines.
Cancer Res.
1995;55:5302-5309
137.
Mangues R, Corral T, Kohl NE, et al.
Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-RAS in transgenic mice.
Cancer Res.
1998;58:1253-1259
138.
Cox AD, Garcia AM, Westwick JK, et al.
The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic ras signaling and transformation.
J Biol Chem.
1994;269:19203-19206
139.
Qian Y, Blaskovich MA, Saleem M, et al.
Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase.
J Biol Chem.
1994;269:12410-12413
140.
Sun J, Qian Y, Hamilton AD, Sebti SM.
Ras CAAX peptidomimetic FTI-276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion.
Cancer Res.
1995;55:4243-4247
141.
Lerner EC, Qian Y, Blaskovich MA, et al.
Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic ras signaling by inducing cytoplasmatic accumulation of inactive Ras-Raf complexes.
J Biol Chem.
1995;270:26802-26806 142. Bredel M, Pollack IF, Freund JM, Hamilton AD, Sebti SM. Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth. Neurosurgery. 1998;43:124-131[Medline] [Order article via Infotrieve].
143.
Bernhard EJ, McKenna WG, Hamilton AD, et al.
Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes.
Cancer Res.
1998;58:1754-1761
144.
Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM.
Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956.
Cancer Res.
1995;55:5310-5314
145.
Bishop WR, Bond R, Petrin J, et al.
Novel tricyclic inhibitors of farnesyl protein transferase.
J Biol Chem.
1995;270:30611-30618 146. Njoroge FG, Vibulbhan B, Pinto P, et al. Potent, selective, and orally bioavailable tricyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity. J Med Chem. 1998;41:1561-1567[Medline] [Order article via Infotrieve]. 147. Njoroge FG, Taveras AG, Kelly J, et al. (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cycloheptal[1,2b]-pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem. 1998;41:4890-4902[Medline] [Order article via Infotrieve]. 148. Mallams AK, Rossman RR, Doll RJ, et al. Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2b]pyridin-11-yl)piperazine. J Med Chem. 1998;41:877-893[Medline] [Order article via Infotrieve]. 149. Liu M, Bryant MS, Chen J, et al. Effects of SCH59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice. Cancer Chemother Pharmacol. 1999;43:50-58[Medline] [Order article via Infotrieve]. 150. Patel DV, Gordon EM, Schmidt RJ, et al. Phosphinyl acid-based bisubstrate analog inhibitors of ras farnesyl protein transferase. J Med Chem. 1995;38:435-442[Medline] [Order article via Infotrieve]. 151. Manne V, Yan N, Carboni JM, et al. Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of ras-transformed cells. Oncogene. 1995;10:1763-1779[Medline] [Order article via Infotrieve]. 152. Patel DV, Young MG, Robinson SP, Hunihan L, Dean BJ, Gordon EM. Hydroxamic acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase. J Med Chem. 1996;39:4197-4210[Medline] [Order article via Infotrieve]. 153. Gelb MH, Tamanoi F, Yokoyama K, Ghomashchi F, Esson K, Gould MN. The inhibition of protein prenyltransferases by oxygenated metabolites of limonene and perillyl alcohol. Cancer Lett. 1995;91:169-175[Medline] [Order article via Infotrieve].
154.
Hara M, Akasaka K, Akinaga S, et al.
Identification of Ras farnesyltransferase inhibitors by microbial screening.
Proc Natl Acad Sci U S A.
1993;90:2281-2285 155. Nagase T, Kawata S, Tamura S, et al. Manumycin and gliotoxin derivative KT7595 block Ras farnesylation and cell growth but do not disturb lamin farnesylation and localization in human tumour cells. Br J Cancer. 1997;76:1001-1010[Medline] [Order article via Infotrieve]. 156. Kainuma O, Asano T, Hasegawa M, et al. Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin. Pancreas. 1997;15:379-383[Medline] [Order article via Infotrieve]. 157. Jayasuriya H, Bali RG, Zink DL, et al. Barcelonic acid A, a new farnesyl-protein transferase inhibitor from Phoma species. J Nat Prod. 1995;58:986-991[Medline] [Order article via Infotrieve]. 158. Van der Pyl D, Cans P, Debernard JJ, et al. RPR113228, a novel farnesyl-protein transferase inhibitor produced by Chrysosporium lobatum. J Antibiot (Tokyo). 1995;48:736-737[Medline] [Order article via Infotrieve]. 159. Silverman KC, Cascales C, Genilloud O, et al. Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase. Appl Microbiol Biotechnol. 1995;43:610-616[Medline] [Order article via Infotrieve]. 160. Silverman KC, Jayasuriya H, Cascales C, et al. Oreganic acid, a potent inhibitor of Ras farnesyl-protein transferase. Biochem Biophys Res Commun. 1997;232:478-481[Medline] [Order article via Infotrieve]. 161. Sturm S, Gil RR, Chai HB, et al. Lupane derivatives from Lophopetalum wallichi with farnesyl protein transferase inhibitory activity. J Nat Prod. 1996;59:658-663[Medline] [Order article via Infotrieve]. 162. Sekizawa R, Iinuma H, Naganawa H, et al. Isolation of novel saquayamycins as inhibitors of farnesyl-protein transferase. J Antibiot (Tokyo). 1996;49:487-490[Medline] [Order article via Infotrieve]. 163. Tsuda M, Muraoka Y, Takeuchi T, Sekizawa R, Umezawa K. Stereospecific synthesis of a novel farnesyl protein transferase inhibitor, valinoctin and its analogues. J Antibiot (Tokyo). 1996;49:1031-1035[Medline] [Order article via Infotrieve]. 164. Lee S, Park S, Oh JW, Yang C. Natural inhibitors for protein prenyltransferase. Planta Med. 1998;64:303-308[Medline] [Order article via Infotrieve].
165.
Gibbs JB, Pompliano DL, Mosser SD, et al.
Selective inhibition of farnesyl-protein transferase blocks ras processing in vivo.
J Biol Chem.
1993;268:7617-7620
166.
James GL, Brown MS, Cobb MH, Goldstein JL.
Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells.
J Biol Chem.
1994;269:27705-27714
167.
James G, Goldstein JL, Brown MS.
Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells.
Proc Natl Acad Sci U S A.
1996;93:4454-4458 168. Sun J, Qian Y, Hamilton AD, Sebti SM. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene. 1998;16:1467-1473[Medline] [Order article via Infotrieve].
169.
Whyte DB, Kirschmeier P, Hockenberry TN, et al.
K-Ras and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors.
J Biol Chem.
1997;272:14459-14464
170.
Zhang FL, Kirschmeier P, Carr D, et al.
Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I.
J Biol Chem.
1997;272:10232-10239
171.
Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM.
Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo.
J Biol Chem.
1997;272:14093-14097 172. Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SD. Inhibition of the prenylation of K-RAS, but not H- or N-RAS is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene. 1997;15:1283-1288[Medline] [Order article via Infotrieve].
173.
Lerner EC, Qian Y, Hamilton AD, Sebti SM.
Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor.
J Biol Chem.
1995;270:26770-26773 174. Lebowitz PF, Davide JP, Prendergast GC. Evidence that farnesyltransferase inhibitors suppress Ras transformation by interfering with Rho activity. Mol Cell Biol. 1995;15:66136622. 175. Lebowitz PF, Prendergast GC. Non-Ras targets of farnesyltransferase inhibitors: focus on Rho. Oncogene. 1998;17:1439-1445[Medline] [Order article via Infotrieve].
176.
Booden MA, Baker TL, Solski PA, Der CJ, Punke SG, Buss JE.
A non-farnesylated Ha-Ras protein can be palmitoylated and trigger potent differentiation and transformation.
J Biol Chem.
1999;274:1423-1431 177. Cox AD, Der CJ. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta. 1997;1333:F51-F71[Medline] [Order article via Infotrieve].
178.
Du W, Lebowitz PF, Prendergast GC.
Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB.
Mol Cell Biol.
1999;19:1831-1840 179. Adamson P, Marshall CJ, Hall A, Tilbrook PA. Post-translational modifications of p21rho proteins. J Biol Chem. 1992;267:2003320038.
180.
Sepp-Lorenzino L, Rosen N.
A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells.
J Biol Chem.
1998;273:20243-20251 181. Hung WC, Chuang LY. Involvement of caspase family proteases in FPT inhibitor II-induced apoptosis in human ovarian cancer cells. Int J Cancer. 1998;12:1339-1342. 182. Hung WC, Chuang LY. The farnesyltransferase inhibitor, FPT inhibitor III upregulates Bax and Bcl-xs expression and induces apoptosis in human ovarian cancer cells. Int J Oncol. 1998;12:137-140[Medline] [Order article via Infotrieve].
183.
Norgaard P, Law B, Joseph H, et al.
Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis.
Clin Cancer Res.
1999;5:35-42
184.
Moasser MM, Sepp-Lorenzino L, Kohl NE, Oliff A, Balog A, Su DS.
Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones.
Proc Natl Acad Sci U S A.
1998;95:1369-1374 185. DeSolms SJ, Giuliani EA, Graham SL, et al. N-Arylalkyl pseudopeptide inhibitors of farnesyltransferase. J Med Chem. 1998;41:2651-2656[Medline] [Order article via Infotrieve]. 186. McNamara DJ, Dobrusin E, Leonard DM, et al. C-terminal modifications of histidyl-N-benzylglycinamides to give improved inhibition of Ras farnesyltransferase, cellular activity, and anticancer activity in mice. J Med Chem. 1997;40:3319-3322[Medline] [Order article via Infotrieve]. 187. Leftheris K, Kline T, Vite GD, et al. Development of potent inhibitors of Ras farnesyltransferase possessing cellular and in vivo activity. J Med Chem. 1996;39:224-236[Medline] [Order article via Infotrieve].
188.
Jansen B, Schlagbauer-Wadl H, Kahr H, et al.
Novel Ras antagonist blocks human melanoma growth.
Proc Natl Acad Sci U S A.
1999;96:14019-14024
189.
Brown MS, Goldstein JL, Paris KJ, Burnier JP, Marsters JC Jr.
Tetrapeptide inhibitors of protein farnesyltransferase: amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation.
Proc Natl Acad Sci U S A.
1992;89:8313-8316
190.
Mahgoub N, Taylor BR, Gratiot M, et al.
In vitro and in vivo effects of a farnesyltransferase inhibitor on NF-1-deficient hematopoietic cells.
Blood.
1999;94:2469-2476 191. Ito T, Kawata S, Tamura S, et al. Suppression of human pancreatic cancer growth in BALB/c nude mice by manumycin, a farnesyl:protein transferase inhibitor. Jpn J Cancer Res. 1996;87:113-116[Medline] [Order article via Infotrieve].
192.
Liu M, Bryant MS, Chen J, et al.
Antitumor activity of SCH66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and Wap-ras transgenic mice.
Cancer Res.
1998;58:4947-4956
193.
Prendergast GC, Davide JP, Lebowitz PF, Wechsler-Reya R, Kohl NE.
Resistance of a variant ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibitors.
Cancer Res.
1996;56:2626-2632
194.
Del Villar K, Urano J, Guo L, Tamanoi F.
A mutant form of human protein farnesyltransferase exhibits increased resistance to farnesyltransferase inhibitors.
J Biol Chem.
1999;274:27010-27017 195. Qian Y, Vogt A, Vasudevan A, Sebti SM, Hamilton AD. Selective inhibition of type-I geranylgeranyltransferase in vitro and in whole cells by CAAL peptidomimetics. Bioorg Med Chem. 1998;6:293-299[Medline] [Order article via Infotrieve]. 196. Vogt A, Qian Y, McGuire TF, Hamilton AD, Sebti SM. Protein geranylgeranylation, not farnesylation, is required for the G1 to S phase transition in mouse fibroblasts. Oncogene. 1996;13:1991-1999[Medline] [Order article via Infotrieve].
197.
McGuire TF, Qian Y, Vogt A, Hamilton AD, Sebti SM.
Platelet-derived growth factor receptor tyrosine phosphorylation requires protein geranylgeranylation but not farnesylation.
J Biol Chem.
1996;271:27402-27407
198.
Miquel K, Pradines A, Sun J, et al.
GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells.
Cancer Res.
1997;57:1846-1850
199.
Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM.
The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner.
J Biol Chem.
1997;272:27224-27229
200.
Lantry LE, Zhang Z, Yao R, et al.
Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Carcinogenesis.
2000;21:113-116
201.
Volker C, Miller RA, McCleary WR, et al.
Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction.
J Biol Chem.
1991;266:21515-21522
202.
Marciano D, Ben-Baruch G, Marom M, Egozi Y, Haklai R, Kloog Y.
Farnesyl derivatives of rigid carboxylic acids
203.
Marom M, Haklai R, Ben-Baruch G, Marciano D, Egozi Y, Kloog Y.
Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid.
J Biol Chem.
1995;270:22263-22270 204. Gana-Weisz M, Haklai R, Marciano D, Egozi Y, Ben-Baruch G, Kloog Y. The Ras antagonist S-farnesylthiosalicylic acid induces inhibition of MAPK activation. Biochem Biophys Res Commun. 1997;239:900-904[Medline] [Order article via Infotrieve]. 205. Haklai R, Weisz MG, Elad G, et al. Dislodgment and accelerated degradation of Ras. Biochemistry. 1998;37:1306-1314[Medline] [Order article via Infotrieve]. 206. Perez-Sala D, Gilbert BA, Rando RR, Canada FJ. Analogs of farnesylcysteine induce apoptosis in HL-60 cells. FEBS Lett. 1998;426:319-324[Medline] [Order article via Infotrieve]. 207. Aharonson Z, Gana-Weisz M, Varsano T, Haklai R, Marciano D, Kloog Y. Stringent structural requirements for anti-Ras activity of S-prenyl analogues. Biochim Biophys Acta. 1998;1406:40-50[Medline] [Order article via Infotrieve]. 208. Kadam S, McAlpine JB. Dorrigocins: novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. III. Biological properties and mechanism of action. J Antibiot (Tokyo). 1994;47:875-880[Medline] [Order article via Infotrieve]. 209. Chen Y. Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease. Ann N Y Acad Sci. 1999;886:103-108[Medline] [Order article via Infotrieve].
210.
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AD.
PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.
J Biol Chem.
1995;270:27489-27494
211.
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR.
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Proc Natl Acad Sci U S A.
1995;92:7686-7689
212.
DeSilva DR, Jones EA, Favata MF, et al.
Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy.
J Immunol.
1998;160:4175-4181
213.
Favata MF, Horiuchi KJ, Manos EJ, et al.
Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
J Biol Chem.
1998;273:18623-18632 214. Williams DH, Wilkinson SE, Purton T, Lamont A, Flotow H, Murray EJ. Ro 09-2210 exhibits potent anti-proliferative effects on activated T-cells by selectively blocking MKK activity. Biochemistry. 1998;37:9579-9585[Medline] [Order article via Infotrieve].
215.
Cox LY, Motz J, Troll W, Garte SJ.
Antipain-induced suppression of oncogene expression in H-ras-transformed NIH3T3 cells.
Cancer Res.
1991;51:4810-4814
216.
Itoh O, Kuroiwa S, Atsumi S, Umezawa K, Takeuchi T, Mar M.
Induction by guanosine analogue oxanosine of reversion toward the normal phenotype of K-ras transformed rat kidney cells.
Cancer Res.
1989;49:996-1000 217. Shindo-Okado N, Makabe O, Nagahara H, Nishimura S. Permanent conversion of mouse and human cells transformed by activated ras or raf genes to apparently normal cells by treatment with the antibiotic azatyrosine. Mol Carcinog. 1989;2:159-167[Medline] [Order article via Infotrieve].
218.
Kumar CC, Prorock-Rogers C, Kelly J, et al.
SCH51344 inhibits ras transformation by a novel mechanism.
Cancer Res.
1995;55:5106-5117 219. Walsh AB, Dhanasekaran M, Bar-Sagi D, Kumar CC. SCH51344-induced reversal of Ras-transformation is accompanied by the specific inhibition of the Ras and Rac-dependent cell morphology pathway. Oncogene. 1997;15:2553-2560[Medline] [Order article via Infotrieve].
220.
Giardiello FM, Hamilton SR, Krush AJ, et al.
Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.
N Engl J Med.
1993;328:1313-1316 221. Verhuel HM, Panigrahy D, Yuan J, D'Amato RJ. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer. 1999;79:114-118[Medline] [Order article via Infotrieve]. 222. Herrmann C, Block C, Geisen C, et al. Sulindac sulfide inhibits Ras signaling. Oncogene. 1998;17:1769-1776[Medline] [Order article via Infotrieve]. 223. Schulte TW, Blagosklonny MV, Romanova L, et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signaling pathway. Mol Cell Biol. 1996;16:5839-5845[Abstract]. 224. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an HSP90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell. 1997;89:239-250[Medline] [Order article via Infotrieve]. 225. Koera K, Nakamura K, Nakao K, et al. K-ras is essential for the development of the mouse embryo. Oncogene. 1997;15:1151-1159[Medline] [Order article via Infotrieve].
226.
Johnson L, Greenbaum D, Cichowski K, et al.
K-ras is an essential gene in the mouse with partial functional overlap with N-ras.
Genes Dev.
1997;11:2468-2481
227.
Umanoff H, Edelmann W, Pellicer A, Kucherlapati R.
The murine N-ras gene is not essential for growth and development.
Proc Natl Acad Sci U S A.
1995;92:1709-1713 228. Casey S, Dautry F. Inactivation of the murine N-ras gene by gene targeting. Oncogene. 1992;12:2525-2528.
229.
Qiu RG, Chen J, McCormick F, Symons M.
A role for Rho in Ras transformation.
Proc Natl Acad Sci U S A.
1995;92:11781-11785 230. Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ. Activation of Rac1, RhoA and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995;15:6443-6453[Abstract]. 231. Khosravi-Far R, White MA, Westwick JK, et al. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol. 1996;16:3923-3933[Abstract].
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M. Raponi, J. E. Lancet, H. Fan, L. Dossey, G. Lee, I. Gojo, E. J. Feldman, J. Gotlib, L. E. Morris, P. L. Greenberg, et al. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia Blood, March 1, 2008; 111(5): 2589 - 2596. [Abstract] [Full Text] [PDF] |
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J.-L. Harousseau, J. E. Lancet, J. Reiffers, B. Lowenberg, X. Thomas, F. Huguet, P. Fenaux, S. Zhang, W. Rackoff, P. De Porre, et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia Blood, June 15, 2007; 109(12): 5151 - 5156. [Abstract] [Full Text] [PDF] |
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P. Fenaux, A. Raza, G. J. Mufti, C. Aul, U. Germing, H. Kantarjian, L. Cripe, R. Kerstens, P. De Porre, and R. Kurzrock A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome Blood, May 15, 2007; 109(10): 4158 - 4163. [Abstract] [Full Text] [PDF] |
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Y. Dai, P. Khanna, S. Chen, X.-Y. Pei, P. Dent, and S. Grant Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation Blood, May 15, 2007; 109(10): 4415 - 4423. [Abstract] [Full Text] [PDF] |
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M. Raponi, J.-L. Harousseau, J. E. Lancet, B. Lowenberg, R. Stone, Y. Zhang, W. Rackoff, Y. Wang, and D. Atkins Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia Clin. Cancer Res., April 1, 2007; 13(7): 2254 - 2260. [Abstract] [Full Text] [PDF] |
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C. Parikh, R. Subrahmanyam, and R. Ren Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice Blood, October 1, 2006; 108(7): 2349 - 2357. [Abstract] [Full Text] [PDF] |
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S. M. Kornblau, M. Womble, Y. H. Qiu, C. E. Jackson, W. Chen, M. Konopleva, E. H. Estey, and M. Andreeff Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia Blood, October 1, 2006; 108(7): 2358 - 2365. [Abstract] [Full Text] [PDF] |
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C. Arana-Yi, A. Quintas-Cardama, F. Giles, D. Thomas, A. Carrasco-Yalan, J. Cortes, H. Kantarjian, and S. Verstovsek Advances in the Therapy of Chronic Idiopathic Myelofibrosis Oncologist, September 1, 2006; 11(8): 929 - 943. [Abstract] [Full Text] [PDF] |
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J. Milan, C. Charalambous, R. Elhag, T. C. Chen, W. Li, S. Guan, F. M. Hofman, and R. Zidovetzki Multiple signaling pathways are involved in endothelin-1-induced brain endothelial cell migration Am J Physiol Cell Physiol, July 1, 2006; 291(1): C155 - C164. [Abstract] [Full Text] [PDF] |
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S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295. [Abstract] [Full Text] [PDF] |
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M. S. Tallman, D. G. Gilliland, and J. M. Rowe Drug therapy for acute myeloid leukemia Blood, August 15, 2005; 106(4): 1154 - 1163. [Abstract] [Full Text] [PDF] |
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M. Gomez-Benito, I. Marzo, A. Anel, and J. Naval Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination Mol. Pharmacol., June 1, 2005; 67(6): 1991 - 1998. [Abstract] [Full Text] [PDF] |
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J. Cortes, S. Faderl, E. Estey, R. Kurzrock, D. Thomas, M. Beran, G. Garcia-Manero, A. Ferrajoli, F. Giles, C. Koller, et al. Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes J. Clin. Oncol., April 20, 2005; 23(12): 2805 - 2812. [Abstract] [Full Text] [PDF] |
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C. Dorrell, K. Takenaka, M. D. Minden, R. G. Hawley, and J. E. Dick Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition Mol. Cell. Biol., August 15, 2004; 24(16): 6993 - 7002. [Abstract] [Full Text] [PDF] |
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D. E. Spaner Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells J. Leukoc. Biol., August 1, 2004; 76(2): 338 - 351. [Abstract] [Full Text] [PDF] |
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M. Yamaguchi, C. Zhou, A. Nanda, and J. H. Zhang Ras Protein Contributes to Cerebral Vasospasm in a Canine Double-Hemorrhage Model Stroke, July 1, 2004; 35(7): 1750 - 1755. [Abstract] [Full Text] [PDF] |
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H. J. Mackay, R. Hoekstra, F. A. L. M. Eskens, W. J. Loos, D. Crawford, M. Voi, A. Van Vreckem, T. R. J. Evans, and J. Verweij A Phase I Pharmacokinetic and Pharmacodynamic Study of the Farnesyl Transferase Inhibitor BMS-214662 in Combination with Cisplatin in Patients with Advanced Solid Tumors Clin. Cancer Res., April 15, 2004; 10(8): 2636 - 2644. [Abstract] [Full Text] [PDF] |
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A. F. List, J. Vardiman, J.-P. J. Issa, and T. M. DeWitte Myelodysplastic Syndromes Hematology, January 1, 2004; 2004(1): 297 - 317. [Abstract] [Full Text] [PDF] |
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R. Kurzrock, H. M. Kantarjian, J. E. Cortes, N. Singhania, D. A. Thomas, E. F. Wilson, J. J. Wright, E. J. Freireich, M. Talpaz, and S. M. Sebti Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting Blood, December 15, 2003; 102(13): 4527 - 4534. [Abstract] [Full Text] [PDF] |
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N. W. C. J. van de Donk, D. Schotte, M. M. J. Kamphuis, A. M. W. van Marion, B. van Kessel, A. C. Bloem, and H. M. Lokhorst Protein Geranylgeranylation Is Critical for the Regulation of Survival and Proliferation of Lymphoma Tumor Cells Clin. Cancer Res., November 15, 2003; 9(15): 5735 - 5748. [Abstract] [Full Text] [PDF] |
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N. Ochiai, R. Uchida, S.-i. Fuchida, A. Okano, M. Okamoto, E. Ashihara, T. Inaba, N. Fujita, H. Matsubara, and C. Shimazaki Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro Blood, November 1, 2003; 102(9): 3349 - 3353. [Abstract] [Full Text] [PDF] |
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N. W. C. J. van de Donk, M. M. J. Kamphuis, B. van Kessel, H. M. Lokhorst, and A. C. Bloem Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels Blood, November 1, 2003; 102(9): 3354 - 3362. [Abstract] [Full Text] [PDF] |
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S. S. Clark, L. Zhong, D. Filiault, S. Perman, Z. Ren, M. Gould, and X. Yang Anti-Leukemia Effect of Perillyl Alcohol in Bcr/Abl-Transformed Cells Indirectly Inhibits Signaling through Mek in a Ras- and Raf-Independent Fashion Clin. Cancer Res., October 1, 2003; 9(12): 4494 - 4504. [Abstract] [Full Text] [PDF] |
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C. Selleri, J. P. Maciejewski, N. Montuori, P. Ricci, V. Visconte, B. Serio, L. Luciano, and B. Rotoli Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Blood, August 15, 2003; 102(4): 1490 - 1498. [Abstract] [Full Text] [PDF] |
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A. A. Adjei, G. A. Croghan, C. Erlichman, R. S. Marks, J. M. Reid, J. A. Sloan, H. C. Pitot, S. R. Alberts, R. M. Goldberg, L. J. Hanson, et al. A Phase I Trial of the Farnesyl Protein Transferase Inhibitor R115777 in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer Clin. Cancer Res., July 1, 2003; 9(7): 2520 - 2526. [Abstract] [Full Text] [PDF] |
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L. C. Platanias Map kinase signaling pathways and hematologic malignancies Blood, June 15, 2003; 101(12): 4667 - 4679. [Abstract] [Full Text] [PDF] |
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T. L. Baker, H. Zheng, J. Walker, J. L. Coloff, and J. E. Buss Distinct Rates of Palmitate Turnover on Membrane-bound Cellular and Oncogenic H-Ras J. Biol. Chem., May 23, 2003; 278(21): 19292 - 19300. [Abstract] [Full Text] [PDF] |
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A. A. Adjei, A. Mauer, L. Bruzek, R. S. Marks, S. Hillman, S. Geyer, L. J. Hanson, J. J. Wright, C. Erlichman, S. H. Kaufmann, et al. Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1760 - 1766. [Abstract] [Full Text] [PDF] |
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A. Nakajima, T. Tauchi, M. Sumi, W. R. Bishop, and K. Ohyashiki Efficacy of SCH66336, a Farnesyl Transferase Inhibitor, in Conjunction with Imatinib against BCR-ABL-positive Cells Mol. Cancer Ther., March 1, 2003; 2(3): 219 - 224. [Abstract] [Full Text] [PDF] |
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J. Cortes, M. Albitar, D. Thomas, F. Giles, R. Kurzrock, A. Thibault, W. Rackoff, C. Koller, S. O'Brien, G. Garcia-Manero, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies Blood, March 1, 2003; 101(5): 1692 - 1697. [Abstract] [Full Text] [PDF] |
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G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF] |
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C. Bezombes, A. de Thonel, A. Apostolou, T. Louat, J.-P. Jaffrezou, G. Laurent, and A. Quillet-Mary Overexpression of Protein Kinase Czeta Confers Protection Against Antileukemic Drugs by Inhibiting the Redox-Dependent Sphingomyelinase Activation Mol. Pharmacol., December 1, 2002; 62(6): 1446 - 1455. [Abstract] [Full Text] [PDF] |
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M. Chatterjee, D. Honemann, S. Lentzsch, K. Bommert, C. Sers, P. Herrmann, S. Mathas, B. Dorken, and R. C. Bargou In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway Blood, October 16, 2002; 100(9): 3311 - 3318. [Abstract] [Full Text] [PDF] |
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G. K. Dy and A. A. Adjei Novel Targets for Lung Cancer Therapy: Part I J. Clin. Oncol., June 15, 2002; 20(12): 2881 - 2894. [Abstract] [Full Text] [PDF] |
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J. George, A. Afek, P. Keren, I. Herz, I. Goldberg, R. Haklai, Y. Kloog, and G. Keren Functional Inhibition of Ras by S-trans,trans-Farnesyl Thiosalicylic Acid Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice Circulation, May 21, 2002; 105(20): 2416 - 2422. [Abstract] [Full Text] [PDF] |
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P. O. Iversen, P. D. Emanuel, and M. Sioud Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth Blood, May 13, 2002; 99(11): 4147 - 4153. [Abstract] [Full Text] [PDF] |
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A. F. List New Approaches to the Treatment of Myelodysplasia Oncologist, April 1, 2002; 7(90001): 39 - 49. [Abstract] [Full Text] [PDF] |
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P. Russo, C. Ottoboni, D. Malacarne, A. Crippa, J.-F. Riou, and P. M. O'Connor Nonpeptidomimetic Farnesyltransferase Inhibitor RPR-115135 Increases Cytotoxicity of 5-Fluorouracil: Role of p53 J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 220 - 226. [Abstract] [Full Text] [PDF] |
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J. E. Karp, J. E. Lancet, S. H. Kaufmann, D. W. End, J. J. Wright, K. Bol, I. Horak, M. L. Tidwell, J. Liesveld, T. J. Kottke, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial Blood, June 1, 2001; 97(11): 3361 - 3369. [Abstract] [Full Text] [PDF] |
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A. A. Adjei, J. N. Davis, L. M. Bruzek, C. Erlichman, and S. H. Kaufmann Synergy of the Protein Farnesyltransferase Inhibitor SCH66336 and Cisplatin in Human Cancer Cell Lines Clin. Cancer Res., May 1, 2001; 7(5): 1438 - 1445. [Abstract] [Full Text] |
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M. A. Morgan, O. Dolp, and C. W. M. Reuter Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling Blood, March 15, 2001; 97(6): 1823 - 1834. [Abstract] [Full Text] [PDF] |
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D. G. Peters, R. R. Hoover, M. J. Gerlach, E. Y. Koh, H. Zhang, K. Choe, P. Kirschmeier, W. R. Bishop, and G. Q. Daley Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia Blood, March 1, 2001; 97(5): 1404 - 1412. [Abstract] [Full Text] [PDF] |
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B. J. Druker, C. L. Sawyers, R. Capdeville, J. M. Ford, M. Baccarani, and J. M. Goldman Chronic Myelogenous Leukemia Hematology, January 1, 2001; 2001(1): 87 - 112. [Abstract] [Full Text] [PDF] |
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