MTOR inhibitors

Although novel mTOR inhibitors are in development, to date, only the mTORCl-specific inhibitor rapamycin (and closely related derivatives that improve... 

Faivre, S., Kroemer, G., and Raymond, E. (2006). Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5, 671-688. 

Cao, P. Maira, SM., Garcia-Echeverria, C. and Hedley, DW. (2009) Br. J. Cancer, Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xengrafts. 100, 1267-1276. 

Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers. The PDA has recently approved everolimus for organ rejection prophylaxis on April 22, 2010. A Phase II trial reports it is effective in the treatment of subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis. In Oct 2010, the PDA approved its use in SEGA unsuitable for surgery. As of Oct 2010 Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma, pancreatic neuroendocrine tumors (NET), and lymphoma. ... 

Elit L. (2006) Drug evaluation AP-23573 — an mTOR inhibitor for the treatment of cancer. IDrugs 9 636-644. 

Mita M, Sankhala K, Abdel-Karim I, Mita A, Giles E. (2008) Deforolimus (AP23573) a novel mTOR inhibitor in clinical development. Expert Opin Inv Drugs 17 1947-1954. 

Temsirolimus (Torisel Kit) [mTOR Inhibitor] Uses Advanced RCC Action mTOR inhibitor Dose 25 mg IV over 30-60 min x 1 wk continue until tox or progression pre med w/ 25-50 mg Benadryl 30 min before Caution [D, -] w/ CYP3A4 inhib/inducers (Table VI-8), avoid grapefruit juice, vaccines, immediately postop Contra None Disp IV SE Hypersensitivity Rxn, rash, asthenia, mucositis, N, edema, anorexia, poor wound healing, bowel perfusion EMS May T glucose OD May cause NA, abd pain, HA, confusion, melana, and Szs symptomatic and supportive... 

Everolimus is a derivative of rapamycin (siro-limus), and works similarly to rapamycin as an mTOR inhibitor. It is used as an immunosuppressant to prevent rejection of organ transplants. 

Forrest, M. L., C.-W. Won, A. W. Malick, and G. S. Kwon. 200l8i vitro release of the mTOR inhibitor rapamycin from polyethylene glycol)- boly(8-caprolactone) micelled. Control. Rel.110 370-377. 

Costa LJ. Aspects of mTOR biology and the use of mTOR inhibitors in non-Hodgkin s lymphoma. Cancer Treat. Rev. 2007 33 78-84. 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

Other manifestations of mTOR inhibitor renal effects are delayed recovery from ischemic renal injury. In rats not on cyclosporine, siroiimus impairs recovery from acute renal ischemia [785]. Human series describe delayed recovery from post-transplant ischemic injury, and worsening function in glomerulonephritis in the presence of siroiimus [786-787]. Few studies have tested TAC and everoiimus for similar changes [788]. 

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