|
|
 Previous Article | Table of Contents | Next Article 
Modulation of nitrosourea resistance in myeloid leukemias
SL Gerson and JE Trey
Department of Medicine, University Hospitals of Cleveland, Case Western
Reserve University School of Medicine, OH 44106.
Drug resistance in myeloid leukemias may be mediated by an increased
capacity to repair chemotherapy-induced DNA damage. Some tumor cell lines
that are resistant to nitrosoureas contain the DNA repair protein
O6-alkylguanine-DNA alkyltransferase (alkyltransferase). This protects
cells by removing cytotoxic, nitrosourea-induced O6-alkylguanine adducts.
We measured the level of alkyltransferase activity in myeloid leukemic
cells freshly obtained from patients to determine whether the
alkyltransferase was an important factor in nitrosourea resistance in these
cells and whether inactivation of this protein could sensitize leukemic
cells to nitrosoureas. Myeloid leukemic cells from patients with acute
nonlymphocytic leukemia and chronic myelogenous leukemia had higher levels
of alkyltransferase than did myeloid precursors from normal donors (P less
than .01). This difference did not appear to be due to the state of
differentiation of the leukemic or normal cells. To show that this repair
protein mediated nitrosourea resistance in leukemic cells, cells were
treated with the modified base O6- methylguanine to selectively and
irreversibly inactivate the alkyltransferase and then exposed to 1,3-bis
(2-chloroethyl)-1- nitrosourea (BCNU). An 18-hour incubation in 0.5 mmol/L
O6- methylguanine caused an 87% +/- 3.6% decrease in alkyltransferase
activity in leukemic cells and a 73% +/- 8.6% decrease in normal myeloid
precursors. After treatment with O6-methylguanine, clonogenic leukemic
cells from ten different donors became much more sensitive to BCNU, with a
decrease in the dose needed to reduce colony survival by 50% (LD50) of 6.3
+/- 1.4-fold. A lesser effect was seen on CFU-GM, BFU- E, and CFU-GEM where
the LD50 decreased two- to threefold. These studies show that nitrosourea
resistance in myeloid leukemic cells can be abrogated by inactivation of
the DNA repair protein O6-alkylguanine- DNA alkyltransferase. This method
of biochemical modulation of DNA repair will sensitize leukemic cells to
nitrosoureas in vitro and has the potential of increasing the therapeutic
index of nitrosoureas in this disease.
Volume 71,
Issue 5,
pp. 1487-1494,
05/01/1988
Copyright © 1988 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. Pigneux, V. Perreau, E. Jourdan, N. Vey, N. Dastugue, F. Huguet, J.-J. Sotto, L. R. Salmi, N. Ifrah, and J. Reiffers
Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results
Haematologica,
October 1, 2007;
92(10):
1327 - 1334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Giles, S. Verstovsek, D. Thomas, S. Gerson, J. Cortes, S. Faderl, A. Ferrajoli, F. Ravandi, S. Kornblau, G. Garcia-Manero, et al.
Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia
Clin. Cancer Res.,
November 1, 2005;
11(21):
7817 - 7824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Giles, D. Thomas, G. Garcia-Manero, S. Faderl, J. Cortes, S. Verstovsek, A. Ferrajoli, S. Jeha, M. Beran, C. Koller, et al.
A Phase I and Pharmacokinetic Study of VNP40101M, a Novel Sulfonylhydrazine Alkylating Agent, in Patients with Refractory Leukemia
Clin. Cancer Res.,
May 1, 2004;
10(9):
2908 - 2917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-Y. Tserng, S. T. Ingalls, E. M. Boczko, T. P. Spiro, X. Li, S. Majka, S. L. Gerson, J. K. V. Willson, and C. L. Hoppel
Pharmacokinetics of O6-Benzylguanine (NSC637037) and Its Metabolite, 8-Oxo-O6-Benzylguanine
J. Clin. Pharmacol.,
August 1, 2003;
43(8):
881 - 893.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Gerson
Clinical Relevance of MGMT in the Treatment of Cancer
J. Clin. Oncol.,
May 1, 2002;
20(9):
2388 - 2399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dowlati, J. Haaga, S. C. Remick, T. P. Spiro, S. L. Gerson, L. Liu, S. J. Berger, N. A. Berger, and J. K. V. Willson
Sequential Tumor Biopsies in Early Phase Clinical Trials of Anticancer Agents for Pharmacodynamic Evaluation
Clin. Cancer Res.,
October 1, 2001;
7(10):
2971 - 2976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. P. Spiro, L. Liu, S. Majka, J. Haaga, J. K. V. Willson, and S. L. Gerson
Temozolomide: The Effect of Once- and Twice-a-Day Dosing on Tumor Tissue Levels of the DNA Repair Protein O6-Alkylguanine-DNA-Alkyltransferase
Clin. Cancer Res.,
August 1, 2001;
7(8):
2309 - 2317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. P. Spiro, S. L. Gerson, L. Liu, S. Majka, J. Haaga, C. L. Hoppel, S. T. Ingalls, J. M. Pluda, and J. K. V. Willson
O6-Benzylguanine: A Clinical Trial Establishing the Biochemical Modulatory Dose in Tumor Tissue for Alkyltransferase-directed DNA Repair
Cancer Res.,
May 1, 1999;
59(10):
2402 - 2410.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Gerson, J. Schupp, L. Liu, A. E. Pegg, and S. Srinivasen
Leukocyte O6-Alkylguanine-DNA Alkyltransferase from Human Donors Is Uniformly Sensitive to O6-Benzylguanine
Clin. Cancer Res.,
March 1, 1999;
5(3):
521 - 524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Evans, J. Lord, P. Owen-Lynch, G Johnson, C Dive, and A. Whetton
Suppression of apoptosis by v-ABL protein tyrosine kinase is associated with nuclear translocation and activation of protein kinase C in an interleukin-3-dependent haemopoietic cell line
J. Cell Sci.,
January 7, 1995;
108(7):
2591 - 2598.
[Abstract]
[PDF]
|
|
|
|
|
