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首页> 外文期刊>Cell cycle >Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies
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Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

机译：新型I期研究结合G1期，S期和G2 / M期细胞周期抑制剂治疗晚期恶性肿瘤

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PURPOSE: Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells - G(1), S, and G(2)/M.METHODS: Temsirolimus (G(1) inhibitor), topotecan (S inhibitor), and bortezomib (G(2)/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15mg/kg IV D1, 8, 15; topotecan 2.8mg/m(2) IV D1, 8; and bortezomib 0.9mg/m(2) IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G(2)/M and S phases to G(1) phase and the quiescent G(0) phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9).CONCLUSION: Combining drugs with inhibitory activity of G(1) phase, S phase, and G(2)/M phase is safe and warrants further evaluation.
机译：目的：癌症是异常细胞增殖的一种表现，细胞周期是肿瘤学中最成功的药物靶标之一。没有以前的研究报告同时针对由增殖细胞组成的3个主要细胞周期阶段-G（1），S和G（2）/ M方法：替罗罗莫司（G（1）抑制剂），拓扑替康（S抑制剂）和硼替佐米（G（2）/ M抑制剂）联合应用3 + 3剂量递增方案对晚期恶性肿瘤患者进行评估，以评估该细胞周期靶向方法的安全性并确定最大耐受剂量（主要终点） 。使用一种计算机模拟的药效学模型，其中使用了每种药物对细胞周期的确定作用，以验证方案并指导给药方案。结果：招募了62名受试者。最常见的不良事件和剂量限制性毒性是血细胞减少症，与采用的细胞周期靶向方法一致。持有研究药物后，所有血细胞减少症均恢复为基线值。最大耐受剂量为西罗莫司15 mg / kg IV D1，8，15;托泊替康2.8mg / m（2）IV D1，8;和硼替佐米0.9mg / m（2）IV D1、4、8、11的21天周期。计算机模拟表明该方案诱导细胞群体从G（2）/ M和S期转移到G（1）期和静态G（0）期。 18％的受试者（11/62）达到部分缓解（n = 2，卵巢浆液性甲状腺和甲状腺乳头状瘤）或稳定的疾病> 6个月（n = 9）。结论：联合使用具有G（1）期抑制活性的药物， S期和G（2）/ M期是安全的，值得进一步评估。

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