Temsirolimus.
Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.
Ma
Wen W
WW
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland 21231-1000, USA.
Jimeno
Antonio
A
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D016503:Drug Delivery Systems; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus