Obatoclax mesylate : pharmacology and potential for therapy of hematological neoplasms.
BACKGROUND
Augmentation and acceleration of apoptosis for cancer therapy are logical therapeutic strategies given the increasing body of data suggesting the dysregulation of control of cell death in many neoplasms. Apoptosis is particularly well studied in hematological neoplasms, thus these varied diseases present opportunities for pro-apoptotic drug development both as single agents and in combination with established therapies. Accordingly, several agents targeting function of anti-apoptotic Bcl-2 family members have entered clinical trials in the last decade and are discussed.


METHODS
The pan Bcl-2 family member BH3 domain mimetic obatoclax (GX15-070) is currently under clinical evaluation in solid tumors and hematological neoplasms. This agent offers the attractive property of uniformly inhibiting all of the anti-apoptotic members of the Bcl-2 protein family. Its chemistry and preclinical development and activity are reviewed. Pharmacology, pharmacodynamics, drug resistance and clinical use of this agent in leukemias and lymphomas are discussed. The prospects for obatoclax in changing clinical practice are addressed.


CONCLUSIONS
Obatoclax may not prove to have dramatic single agent activity for hematological neoplasms. It seems more likely that its activity will be manifest in combination therapy with other agents, particularly cytotoxic chemotherapies. Results of ongoing studies are awaited.
Department of Medicine, Hematology/Oncology Division, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Jamal
J
Joudeh
David
D
Claxton
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C520962:obatoclax