Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy.
Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy.
复制标题
用于成人和儿童癌症治疗的细胞周期抑制剂化疗的开发。
DOI：
10.1158/0008-5472.can-17-2782
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发表时间：
2018-01-15
期刊：
影响因子：
11.2
通讯作者：
Sampson VB
中科院分区：
文献类型：
--
作者：
Mills CC;Kolb EA;Sampson VB
抑制细胞周期进程的药物的临床前和临床开发使人们了解了在癌症患者中靶向各种细胞周期调节剂的可行性。靶向参与细胞周期进程的关键蛋白（包括细胞周期蛋白依赖性激酶（CDK）和检查点激酶）的小分子抑制剂可诱导肿瘤细胞的细胞周期阻滞和凋亡。早期I期研究表明，靶向抑制剂可以安全地用于成人和儿童癌症患者，但这些药物作为单一药物通常显示出有限的临床益处。在这篇综述中，我们讨论了支持细胞周期抑制与化疗药物的双重组合策略的生物学机制，这些策略有望为癌症患者实现合理的靶向治疗。评价这些组合策略的基本原理是DNA损伤使肿瘤对不可逆的细胞周期阻滞疗法高度响应。预计这种方法将产生强度较低的治疗，并最大限度地提高单个药物对实体瘤和血液恶性肿瘤的疗效。
Preclinical and clinical development of agents that inhibit cell cycle progression have brought an understanding of the feasibility of targeting various cell-cycle regulators in patients with cancer. Small molecule inhibitors targeting key proteins that participate in cell cycle progression including the cyclin-dependent kinases (CDKs) and checkpoint kinases induce cell cycle arrest and apoptosis in neoplastic cells. Early phase I studies demonstrate targeted inhibitors can be administered safely in adult and pediatric cancer patients, but these agents generally show limited clinical benefits as single-agents. In this review, we discuss biological mechanisms that support dual combination strategies of cell cycle inhibition with chemotherapeutic agents that are anticipated to achieve rationally targeted therapies for cancer patients. The rationale for evaluating these combination strategies is that DNA damage renders tumors highly responsive to irreversible cell cycle arrest therapy. This approach is predicted to generate less intensive therapies and maximize the efficacy of individual agents against solid tumors and hematological malignancies.