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外観
白色～わずかにうすい褐色、結晶～粉末
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溶解性
エタノール(99.5)に溶けやすく、水にほとんど溶けない。
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用途
mTOR 阻害剤で、乳がん細胞株において腫瘍の成長を阻害します（IC50=1.6 nmol/l（SKBr3），4.3
nmol/l（BT474））。
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効能
抗悪性腫瘍薬, mTOR阻害薬
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商品名
トーリセル (ファイザー)
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説明
While renal cell carcinoma (RCC) accounts for only 2 3% of all cancers, the 5-year survival rate for advanced RCC disease is only 5 10%, with approximately 13,000 deaths occurring annually (US statistics only). Immunotherapeutic cytokine options, such as IFN-αand IL-2, have traditionally been frontline treatments, but these agents are not efficacious in all patients and can cause serious side effects. In addition, bevacizumab, a monoclonal antibody against VEGF, has also demonstrated prolongation of PFS. The newest entry for this indication focuses on targets that are downstream from VEGF. Temsirolimus is an inhibitor of the serine/threonine kinase mTOR, which is the mammalian target of rapamycin. mTOR has been implicated in cell replication through control of the cell cycle translation of specific mRNAs. Inhibition of mTOR prevents phosphorylation of the 4E binding protein-1 and the 40S ribosomal protein S6 kinase that are responsible for cell cycle protein translation initiation; cell cycle arrest occurs as the result of termination of cell division from the G1 to the S phase. Disruption of mTOR signaling also has antiangiogenic effects that could be deemed essential in combating RCC, which is driven by unregulated angiogenesis. Temsirolimus is the 2,2-bis(hydroxymethyl)propionate ester of rapamycin (sirolimus), a macrolide fungicide isolated from the bacteria Streptomyces hygroscopicus. Similar to its parent sirolimus, temsirolimus interacts with mTOR through its complex with FK-506 binding protein 12.
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化学的特性
White Solid
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使用
Temsirolimus, a cell cycle inhibitor developed by Wyeth
for the treatment of renal cell carcinoma, was launched in the
US in 2007. Temsirolimus works by inhibiting mTOR
(mammalian target of rapamycin)-driven cell proliferation. Temsirolimus is also being developed for the treatment
of mantle cell lymphoma (PhIII) and also as mono- or combination
therapy for the treatment of ovarian and endometrium
cancer (PhII). Additionally, temsirolimus is being
evaluated for the treatment of several other types of cancer
as well as multiple sclerosis and rheumatoid arthritis.
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一般的な説明
Temsirolimus is an esterified derivative of rapamycinand in a similar manner binds initially to the proteinFKBP-12(FK506-binding protein).This complexthen acts to inhibit the mammalian target of rapamycin(mTOR), a serine-threonine kinase that plays a crucial rolein cell division. It is somewhat unique in its method of kinaseinhibition, because it actually binds to an allostericmodulator of the kinase rather than just binding to theATP-binding site like most other kinase inhibitors.Temsirolimus is available as a 25-mg/mL injection forIV administration in the treatment of advanced RCC. Theagent is extensively metabolized and undergoes rapid hydrolysisof the ester function to give rapamycin that retainsactivity.Additional metabolism is mediated primarilyby CYP3A4 to give several hydroxylated and demethylatedmetabolites that are inactive. The agent and metabolites areeliminated primarily in the feces with half-lives of 17 and55 hours for temsirolimus and rapamycin, respectively.This agent, like rapamycin, possesses immunosuppressantproperties and there is an increased risk of infection.The most serious side effects are interstitial lung disease,perforation of the bowel, and acute renal failure althoughthese occur only rarely. The most commonly seen side effects are rash, weakness, mucositis, nausea, edema, andanorexia.
