Jain Rajul K, Hong David S, Naing Aung, Wheler Jennifer, Helgason Thorunn, Shi Nai-Yi, Gad Yash, Kurzrock Razelle
a Department of Investigational Cancer Therapeutics (Phase I Program) ; MD Anderson Cancer Center ; Houston , TX USA.
b SimVivo ; Houston , TX USA.
Cell Cycle. 2015;14(21):3434-40. doi: 10.1080/15384101.2015.1090065.
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--G1, S, and G2/M.
Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/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.
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 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m(2) IV D1, 8; and bortezomib 0.6 mg/m2 IV D1, 4, 8, 11 [DOSAGE ERROR CORRECTED] of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 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).
Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation.
癌症是细胞异常增殖的一种表现，而细胞周期是肿瘤学中最成功的药物作用靶点之一。此前尚无研究报道同时靶向增殖细胞所处的3个主要细胞周期阶段——G1期、S期和G2/M期。
采用3+3剂量递增方案，将替西罗莫司（G1期抑制剂）、拓扑替康（S期抑制剂）和硼替佐米（G2/M期抑制剂）联合应用于晚期恶性肿瘤患者，以评估这种细胞周期靶向治疗方法的安全性并确定最大耐受剂量（主要终点）。使用基于这些药物对细胞周期既定作用的计算机药效学模型来验证该方案并指导给药方案。
共纳入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，这与所采用的细胞周期靶向治疗方法一致。在暂停研究药物给药后，所有血细胞减少均恢复至基线值。21天周期的最大耐受剂量为替西罗莫司15mg/kg静脉注射，第1、8、15天；拓扑替康2.8mg/m²静脉注射，第1、8天；硼替佐米0.6mg/m²静脉注射，第1、4、8、11天[剂量错误已纠正]。计算机模拟表明，该方案可诱导细胞群体从G2/M期和S期向G1期及静止的G0期转变。18%的受试者（11/62）达到部分缓解（n = 2，浆液性卵巢癌和乳头状甲状腺癌）或疾病稳定>6个月（n = 9）。
联合使用具有G1期、S期和G2/M期抑制活性的药物是安全的，值得进一步评估。
