Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug ‘CHOP’ regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiation – the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a ‘single hit’, in order to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not contingent on positive drug-drug interactions.

中文翻译：

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尽管存在药物拮抗作用，但超敏感反应解释了联合化疗的益处

大多数侵袭性淋巴瘤采用联合化疗治疗，通常采用多个周期的同时给药。当联合疗法具有协同（而非相加）药物相互作用时，同时给药在理论上是最佳的。我们研究了标准 4 种药物“CHOP”方案在外周 T 细胞淋巴瘤 (PTCL) 细胞系中的药效相互作用，发现 CHOP 始终表现出拮抗作用，而不是协同作用。我们使用同时​​或交错治疗的体外模型测试了交错治疗方案是否可以通过避免拮抗作用来改善肿瘤细胞杀伤。令人惊讶的是，我们观察到尽管存在拮抗的药物-药物相互作用，但通过同时给药可以最大限度地杀死肿瘤细胞。我们提出，超灵敏剂量反应（如放射学中线性二次（LQ）模型所描述的那样）可以调和这些看似矛盾的实验观察结果。 LQ 模型描述了细胞存活与剂量之间的关系，并且在放射学中已经确定了有利于大分割辐射的方案 - 施用较少的大剂量而不是多个较小的剂量。具体来说，当细胞需要DNA损伤的积累而不是“单次打击”才能死亡时，大分割治疗可能会受到青睐。通过将 LQ 模型应用于联合化疗并考虑肿瘤异质性，我们发现，即使化疗具有拮抗相互作用，同时施用多种药物也能最大限度地杀死肿瘤细胞。因此，我们的研究确定了一种新的机制，通过该机制，联合化疗可以在临床上有益，并且不依赖于积极的药物间相互作用。