Targeting the Bcl-2.
OBJECTIVE
Members of the Bcl-2 family of proteins are critical components in regulating the intrinsic apoptotic pathway. Bcl-2 protein overexpression is associated with drug resistance and poor clinical outcome in cancer patients. Preclinical and clinical evaluations demonstrate that downregulation of Bcl-2 restores the intrinsic apoptotic pathways with antitumor effects. Thus, Bcl-2 is aggressively pursued as a therapeutic target in cancer with several new drugs undergoing clinical investigations. In this manuscript, we will review clinical information on some of the novel compounds specifically designed to target the Bcl-2 gene product(s).


RESULTS
Extensive clinical evaluations using a Bcl-2-specific antisense have resulted in an overall disappointing experience. But new small molecule inhibitors of the Bcl-2 hold promise with high target affinity, ease of administration and improved toxicity profile. Early stage clinical trials of these agents are revealing promising results alone as well as in combination with existing anticancer therapeutics. Encouraging results from some of these clinical investigations are summarized in this review.


CONCLUSIONS
Downregulation of Bcl-2 and restoration of a critical apoptotic pathway in cancer cells remains an important strategy. Novel Bcl-2 inhibitors have started to deliver the therapeutic promise of this target-specific quest.
Patel
Mehul P
MP
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Masood
Aisha
A
Patel
Priya S
PS
Chanan-Khan
Asher A
AA
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2