肿瘤化疗耐药的研究：一项多尺度计算研究
Investigating the development of chemotherapeutic drug resistance in cancer: A multiscale computational study
摘要：
化疗是用于治疗人类癌症的最重要的治疗选择之一，无论是单独使用还是与放射治疗和手术联合使用。最近的研究表明，在许多人类恶性肿瘤中，肿瘤内异质性在驱动化疗耐药性方面具有重要作用。多种因素，包括内部细胞周期动力学和外部微循环导致肿瘤内异质性。在本文中，我们提出了一个混合的，多尺度的，基于个人的数学模型，将内部细胞周期动力学和氧浓度的变化，研究交付的影响，几种不同的化疗药物对异质亚群的癌细胞与不同的细胞周期动力学。多尺度模型的计算模拟结果与现有的实验数据吻合良好，并支持这一假设，即在不断增长的肿瘤块内的肿瘤细胞的慢循环亚群可以诱导对化疗的耐药性，因此使用常规化疗实际上可能导致出现占主导地位的，耐治疗的，慢循环的肿瘤细胞亚群。我们的结果表明，这种化疗耐药性的出现主要是由于所施用的药物不能靶向所有癌细胞，而不管它们所处的细胞周期阶段如何，即大多数化疗药物靶向细胞周期的特定阶段中的细胞，因此总是避开一些不在靶向细胞周期阶段中的癌细胞。结果还表明，这种细胞周期介导的耐药性可以通过使用多剂量的细胞周期，阶段特异性化疗来克服，这些化疗针对所有阶段的细胞及其适当的测序和调度。
英文摘要：
Chemotherapy is one of the most important therapeutic options used to treat human cancers, either alone or in combination with radiation therapy and surgery. Recent studies have indicated that intra-tumoural heterogeneity has a significant role in driving resistance to chemotherapy in many human malignancies. Multiple factors including the internal cell-cycle dynamics and the external microenvironement contribute to the intra-tumoural heterogeneity. In this paper we present a hybrid, multiscale, individual-based mathematical model, incorporating internal cell-cycle dynamics and changes in oxygen concentration, to study the effects of delivery of several different chemotherapeutic drugs on the heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics. The computational simulation results from the multiscale model are in good agreement with available experimental data and support the hypothesis that slow-cycling sub-populations of tumour cells within a growing tumour mass can induce drug resistance to chemotherapy and thus the use of conventional chemotherapy may actually result in the emergence of dominant, therapy-resistant, slow-cycling subpopulations of tumour cells. Our results indicate that the appearance of this chemotherapeutic resistance is mainly due to the inability of the administered drug to target all cancer cells irrespective of the stage in the cell-cycle they are in i.e. most chemotherapeutic drugs target cells in a particular phase/phases of the cell-cycle, and hence always spare some cancer cells that are not in the targeted cell-cycle phase/phases. The results also suggest that this cell-cycle-mediated drug resistance may be overcome by using multiple doses of cell-cycle, phase-specific chemotherapy that targets cells in all phases and its appropriate sequencing and scheduling.
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