Clin Cancer Res：柚子汁有助抗癌药物更好发挥作用

近日，芝加哥医学大学科学家发现一天八盎司葡萄柚汁可以减缓身体对西罗莫司的代谢。在8月Clinical Cancer Research杂志上刊登的一项临床试验研究数据显示，癌症患者每天喝一杯柚子汁能达到服用抗癌药物类似的好处。柚子汁也可以帮助患者避免因服用高剂量的药物所带来的副作用，同时也可减少用药成本。

他们观察到，喝八盎司柚子汁的患者西罗莫司代谢水平提高了350％，而每天服用减慢新陈代谢的一种药物酮康唑的患者，西罗莫司代谢水平提高了500％。

葡萄柚汁可以抑制肠道中的酶，这打破西罗莫司和其他一些药物的吸收。这一效果仅仅在使用葡萄柚汁开始的几个小时内，研究人员指出葡萄柚汁的功效会逐天慢慢消失。葡萄柚汁以及具有类似机制的药物可显著增加许多药物的血药浓度，但长期以来一直被认为过量是危害的，相反，这项最新研究发现葡萄柚汁可以通过某种途径增加西罗莫司的可用性和有效性。

编译自：Grapefruit Juice Helps Anti-Cancer Drug Work Better

doi:10.1158/1078-0432.CCR-12-0110
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Phase I Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients

Ezra E.W. Cohen1,5, Kehua Wu1, Christine Hartford2, Masha Kocherginsky3, et al.

Purpose: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.

Experimental Design: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.

Results: Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.

Conclusion: Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.