Oxaliplatin is a widely used chemotherapeutic drug and represents the cornerstone of colorectal cancer therapy, in combination with 5-fluorouracil and folinic acid. As with many chemotherapeutic agents, its use is associated with a number of side effects, ranging from hypersensitivity reactions to haematological dyscrasias. Oxaliplatin also induces acute and chronic peripheral neuropathy. While it is likely that the haematological side effects are associated with its anti-proliferative effects and with the ability to form DNA adducts, the molecular mechanisms underlying peripheral neuropathy and hypersensitivity reactions are poorly understood, and therefore the choice of adequate supportive therapies is largely empirical. Here we show that an acute low dose oxaliplatin application on DRG neurons is able to induce an increase in intracellular calcium that is dependent on the Histamine 1 receptor (H1). Oxaliplatin-induced intracellular calcium rises are blocked by two selective H1 antagonist, as well as by U73122, a PLC inhibitor, and by 2-APB, a non-specific IP3 receptor blocker. Moreover, expression of the H1 receptor on HEK293 t cells unmasks an oxaliplatin-induced Ca2+-rise. Last, activation of H1 via either histamine or oxaliplatin activates TRPV1 receptors, a mechanism that has been associated with itch. These data, together with literature data that has shown that anti-histamine agents reduce the incidence of oxaliplatin-induced hypersensitivity, may provide a molecular mechanism of this side effect in oncological patients.

中文翻译：

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奥沙利铂通过H1组胺受体发生意外的Ca2 +动员。

奥沙利铂是一种广泛使用的化学治疗药物，是与5-氟尿嘧啶和亚叶酸组合的大肠癌治疗的基石。与许多化学治疗剂一样，其使用会引起许多副作用，从超敏反应到血液学异常。奥沙利铂还诱导急性和慢性周围神经病。虽然血液学副作用可能与其抗增殖作用以及形成DNA加合物的能力有关，但对周围神经病变和超敏反应的分子机制了解甚少，因此，选择适当的支持疗法在很大程度上是凭经验进行的。在这里，我们显示了对DRG神经元的急性低剂量奥沙利铂应用能够诱导依赖于组胺1受体（H1）的细胞内钙的增加。奥沙利铂诱导的细胞内钙升高被两种选择性的H1拮抗剂，PLC抑制剂U73122和非特异性IP3受体2-APB阻断。此外，HEK293 t细胞上H1受体的表达掩盖了奥沙利铂诱导的Ca2 +升高。最后，通过组胺或奥沙利铂激活H1会激活TRPV1受体，这是一种与瘙痒有关的机制。这些数据以及表明抗组胺药可降低奥沙利铂诱导的超敏反应发生率的文献数据，可能为肿瘤患者提供这种副作用的分子机制。