Bcl-2 Antisense Therapy in Multiple Myeloma
November 04, 2004
Most malignant plasma cells overexpress Bcl-2, which contributesto resistance against apoptosis induced by dexamethasone and otheranticancer agents. Oblimersen sodium (Genasense, previously knownas G3139), an antisense oligonucleotide that specifically binds to bcl-2messenger RNA, decreases production of Bcl-2 protein in both humanmyeloma cell lines, as well as in ex vivo purified myeloma cells, andenhances the cytotoxicity of dexamethasone and doxorubicin. Combiningoblimersen with other anticancer agents represents a therapyenhancingstrategy to reverse the multidrug resistance seen in multiplemyeloma (MM). Phase II trials are evaluating the potential role ofoblimersen in reversing resistance to standard therapies. Preliminaryresults from these trials in patients with refractory or relapsed MMindicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone isactive and well tolerated and that oblimersen may help overcome chemotherapyresistance and restore sensitivity to MM cells. A randomizedphase III clinical trial comparing dexamethasone plus oblimersenwith dexamethasone alone in patients with relapsed or refractory myelomahas completed enrollment, with results expected to be availablein 2004. Future studies will focus on the role of oblimersen in combinationwith novel biologic agents such as bortezomib (Velcade).