Axelrod David E, Vedula Sudeepti, Obaniyi James
Department of Genetics and Cancer Institute of New Jersey, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854-8082, USA.
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ, 08854, USA.
Cancer Chemother Pharmacol. 2017 May;79(5):889-898. doi: 10.1007/s00280-017-3272-2. Epub 2017 Mar 25.
The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function.
A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function.
Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug.
An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.
癌症化疗的有效性受到肿瘤内异质性、自发和诱导产生的耐药突变亚克隆的出现以及正常组织在无不良副作用情况下所能承受的最大剂量的限制。本项目的目标是确定允许结肠隐窝维持的最大剂量的间歇给药方案是否能够克服这些限制，特别是通过从异质性早期结肠腺瘤中消除耐药突变体的混合物，同时维持结肠隐窝功能。
利用人体活检标本的测量数据对人类结肠隐窝细胞动力学的计算机模型进行校准。该模型能够模拟细胞毒性化疗药物的连续和间歇给药方案，以及药物对突变细胞消除和隐窝功能维持的影响。
结肠隐窝对间歇剂量的耐受能力比恒定剂量大十倍。这使得能够从异质性结肠隐窝中消除相对药物敏感和耐药的突变亚克隆的混合物。无论突变体是自发产生还是由细胞毒性药物诱导产生，都可以被消除。
在允许结肠隐窝维持的最大剂量下进行间歇给药，能够在突变亚克隆填满隐窝并形成腺瘤之前有效消除异质性混合物。
