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Blood, 15 July 2005, Vol. 106, No. 2, pp. 395. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vacca, A. Search for Related Content PubMed Articles by Vacca, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Yasui et al, page 706 New aspects of myeloma management Angelo Vacca UNIVERSITY OF BARI MEDICAL SCHOOL SDX-101, the etodolac R-enantiomer, is an anti-inflammatory drug with a cytotoxic effect on multiple myeloma cells but not on normal peripheral blood mononuclear cells. The antiproliferative activity of nonsteroidal anti-inflammatory drugs and their potential use as antitumor agents are under scrutiny.1 A starting point is the demonstration that these drugs have some effects on cancer cells. View larger version (28K): [in this window] [in a new window]   SDX-101 induces growth inhibition in MM cell lines. See the complete figure in the article beginning on page 706.   In this issue of Blood, Yasui and colleagues provide the first evidence of the cytotoxic effect of SDX-101, the R-enantiomer of etodolac, in different multiple myeloma (MM) cell lines. The authors illustrate SDX-101's antitumor activity against both drug-sensitive and -resistant MM cells and against primary patient MM cells within the bone marrow environment. It is important to bear in mind that these effects were obtained with concentrations without cytotoxicity on normal peripheral blood mononuclear cells and at clinically achievable plasma levels. Some MM cells were resistant to doxorubicin, dexamethasone, and bortezomib and were hence highly hypermutated. The cytotoxic effect is mediated via caspase-8/-9/-3 activation and apoptosis. In addition, SDX-101 induced down-regulation of cyclin D1 expression in MM cells, resulting in an apoptotic population, as shown by cell-cycle analysis. As they have previously shown that novel chemotherapeutic agents augment the cytotoxicity of dexamethasone,2 Yasui and colleagues now demonstrate that the combination of SDX-101 plus dexamethasone is highly synergistic. It has been well established that myeloid cell leukemia-1 (Mcl-1) plays an important role in proliferation and inhibition of apoptosis, as well as in the induction of drug resistance3: the results obtained by Yasui and colleagues thus strongly suggest that up-regulation of the proapoptotic variant Mcl-1S and inhibition of the antiapoptotic variant Mcl-1L are the principal events in the apoptotic activity of SDX-101. It has previously been reported that the bone marrow microenvironment plays an important role in the pathogenesis of MM.4,5 Yasui and colleagues demonstrate that SDX-101 ablates the growth stimulatory effect of this microenvironment on MM cells. It is interesting to note that SDX-101 lacks cyclooxygenase(COX) inhibitory activity and hence the related side effects and that it is approved for treatment of degenerative joint diseases and rheumatoid arthritis. Results as a whole provide the preclinical framework for clinical trials of SDX-101 alone or in combination with dexamethasone to improve patient outcome in MM. The study is an important contribution to MM research. References Jacobs EJ, Thun MJ, Connell CJ, et al. Aspirin and other nonsteroidal anti-inflammatory drugs and breast cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev. 2005;14: 261-264.[Abstract/Free Full Text] Hideshima T, Chauhan D, Hayashi T, et al. Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. Cancer Res. 2003;63: 8428-8436.[Abstract/Free Full Text] Iglesias-Serret D, Pique M, Gil J, Pons G, Lopez JM. Transcriptional and translational control of Mcl-1 during apoptosis. Arch Biochem Biophys. 2003;417: 141-152.[CrossRef][Medline] [Order article via Infotrieve] Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005;105: 1383-1395.[Abstract/Free Full Text] Vacca A, Ria R, Semeraro F, et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood. 2003;102: 3340-3348.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma Hiroshi Yasui, Teru Hideshima, Makoto Hamasaki, Aldo M. Roccaro, Norihiko Shiraishi, Shaji Kumar, Pierfrancesco Tassone, Kenji Ishitsuka, Noopur Raje, Yu-Tzu Tai, Klaus Podar, Dharminder Chauhan, Lorenzo M. Leoni, Sarath Kanekal, Gary Elliott, Nikhil C. Munshi, and Kenneth C. Anderson Blood 2005 106: 706-712. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vacca, A. Search for Related Content PubMed Articles by Vacca, A. 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