Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents.
Highly specific signal transduction inhibitors are being developed as anti-cancer agents against an array of molecular targets, with the promise of increased selectivity and lower toxicity than classic cytotoxic chemotherapy agents. Rapamycin and its analogues are a promising class of novel therapeutics that specifically inhibit signaling from the serine-threonine kinase, mammalian target of rapamycin (mTOR). mTOR is a key intermediary in multiple mitogenic signaling pathways and plays a central role in modulating proliferation and angiogenesis in normal tissues and neoplastic processes. Rapamycin potently inhibits T-cell proliferation, and is approved for clinical use as an immuno-suppressant following kidney transplantation. Hyperactivation of mTOR signaling has been implicated in tumorigenesis, and promising pre-clinical studies in several tumor types suggest that the anti-proliferative and anti-angiogenic properties of rapamycin may be useful in cancer therapy. These studies have led to several clinical trials evaluating the safety and efficacy of rapamycin analogs in cancer therapy. The goal of this article is to review the mechanism of action of rapamycin as an anti-cancer agent, and to review the clinical experience with rapamycin and rapamycin analogs as immunosuppressive and anti-neoplastic therapeutic agents.
Rao
Ravi D
RD
Department of Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
Buckner
Jan C
JC
Sarkaria
Jann N
JN
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus