Bcl-2 antisense therapy in multiple myeloma.
Most malignant plasma cells overexpress Bcl-2, which contributes to resistance against apoptosis induced by dexamethasone and other anticancer agents. Oblimersen sodium (Genasense, previously known as G3139), an antisense oligonucleotide that specifically binds to bcl-2 messenger RNA, decreases production of Bcl-2 protein in both human myeloma cell lines, as well as in ex vivo purified myeloma cells, and enhances the cytotoxicity of dexamethasone and doxorubicin. Combining oblimersen with other anticancer agents represents a therapy-enhancing strategy to reverse the multidrug resistance seen in multiple myeloma (MM). Phase II trials are evaluating the potential role of oblimersen in reversing resistance to standard therapies. Preliminary results from these trials in patients with refractory or relapsed MM indicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone is active and well tolerated and that oblimersen may help overcome chemotherapy resistance and restore sensitivity to MM cells. A randomized phase III clinical trial comparing dexamethasone plus oblimersen with dexamethasone alone in patients with relapsed or refractory myeloma has completed enrollment, with results expected to be available in 2004. Future studies will focus on the role of oblimersen in combination with novel biologic agents such as bortezomib (Velcade).
Chanan-Khan
Asher A
AA
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. asher.chanan-khan@roswellpark.org
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013873:Thionucleotides; D003907:Dexamethasone; D004317:Doxorubicin; C408162:oblimersen