mTOR inhibitors in hematologic malignancies.
Most hematologic malignancies are characterized by initial responsiveness to chemotherapeutic regimens, but many patients still die from their disease. Among the agents currently in clinical development, there is a strong rationale for evaluating rapamycin derivatives. Rapamycin was originally developed as an immunosuppressant and is approved by the US Food and Drug Administration for the treatment of kidney allograft transplant rejection. Two related compounds, RAD001 and CCI-779, are under development as cancer therapeutics. Rapamcyin binds to the immunophilin FK506-binding protein 12 and this protein/drug complex binds to and inhibits the activity of the mammalian target of rapamycin (mTOR). Among its many functions, mTOR regulates the translation of a specific subset of mRNA transcripts that encode for proteins involved in regulating the G1 to S phase transition. This review focuses on recent advances in the understanding of the mechanisms of cell growth inhibition by rapamycin, clinical trial results for the 2 agents being developed as cancer agents, and the rationale supporting the evaluation of this class of agent in hematological malignancies.
Dancey
Janet E
JE
Investigational Drug Branch, Cancer Treatment Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 6130 Executive Boulevard, Rockville, MD 20854, USA. danceyj@ctep.nci.nih.gov
D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus