Platinum-based compounds remain a well-established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type-specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug-induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss. Formation and persistence of platination products in the DNA of individual nuclei were measured in drug-exposed cell lines, in primary human tumor cells and in tissue sections using an immunocytochemical method. Using a mouse model of CP-induced toxicity, the antihistaminic drug diphenhydramine (DIPH) and two methylated derivatives decreased DNA platination in normal tissues and also ameliorated nephrotoxicity, ototoxicity, and neurotoxicity. In addition, DIPH sensitized multiple cancer cell types, particularly ovarian cancer cells, to CP by increasing intracellular uptake, DNA platination, and/or apoptosis in cell lines and in patient-derived primary tumor cells. Mechanistically, DIPH diminished transport capacity of CP efflux pumps MRP2, MRP3, and MRP5 particularly in its C2+C6 bimethylated form. Overall, we demonstrate that DIPH reduces side effects of platinum-based chemotherapy and simultaneously inhibits key mechanisms of platinum resistance. We propose that measuring DNA platination after ex vivo exposure may predict the responsiveness of individual tumors to DIPH-like modulators.

中文翻译：

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苯海拉明通过同时使肿瘤细胞敏感并保护正常细胞，增加了铂类药物的治疗范围。

尽管基于铂的化合物的不良反应大大限制了药物的治疗范围，但它们仍然是用于癌症治疗的公认的化学疗法。细胞类型特异性毒性和肿瘤的临床反应性都与改变药物进入和输出的机制有关。我们寻求通过增加恶性细胞中药物诱导的DNA损伤水平并同时保护正常组织免于累积此类损伤和功能丧失来提高顺铂（CP）功效的药理剂。使用免疫细胞化学方法，在暴露于药物的细胞系，原代人肿瘤细胞和组织切片中，测量了单个核DNA中电镀产物的形成和持久性。使用CP诱发毒性的小鼠模型，抗组胺药苯海拉明（DIPH）和两种甲基化衍生物可减少正常组织中的DNA平台化，并改善肾毒性，耳毒性和神经毒性。另外，DIPH通过增加细胞系和患者来源的原发性肿瘤细胞中的细胞内摄取，DNA平台化和/或凋亡，使多种癌细胞类型，特别是卵巢癌细胞对CP敏感。从机理上讲，DIPH降低了CP外排泵MRP2，MRP3和MRP5的运输能力，特别是C2 + C6甲基化形式。总体而言，我们证明DIPH减少了铂类化学疗法的副作用，同时抑制了铂耐药性的关键机制。我们建议，在离体暴露后测量DNA平台化可以预测单个肿瘤对DIPH样调节剂的反应性。