MODULATION OF DOXORUBICIN EFFLUX IN HUMAN SOLID TUMORS

耐药性是中国癌症化疗失败的主要原因 难治性疾病。人类实体瘤细胞可能在本质上 耐药或可能在化疗后获得抗药性。抗药性 是不是多因素和外流在抗药性中起主要作用 用于癌症治疗的各种天然产品。蒽环类药物， 阿霉素是一种重要的抗生素，用于治疗各种 人类的恶性肿瘤。阿霉素的快速细胞外排已经被 在耐药肿瘤细胞中表现出来。几种相对无毒的 药物已被证明能在体外阻断外排并增强 对化学药物敏感。维拉帕米、环孢菌素和三氟拉嗪 在体内使用，目的是增强药物保留和临床 难治性肿瘤的反应。 我们早期的研究表明，丙氯哌嗪是一种有效的 阿霉素外排抑制剂在人实体瘤细胞中的外排 对维拉帕米的外排阻断作用不敏感。我们已经完成了一个 第一阶段试验，以确定最大值。耐受量 异丙哌嗪在体内。在从病人身上提取的细胞中 方案，显著提高了阿霉素的保留率 在非小细胞肺癌中表现出和临床反应。 癌症和间皮瘤。在目前的项目中，我们建议进行 进行一项II期研究，联合应用阿霉素 丙氯哌嗪2小时静脉滴注。我们还将学习记分器和 肿瘤细胞和细胞系对阿霉素耐药机制的研究 在治疗过程中从患者那里建立起来的 协议。将收集药代动力学和药理学数据以 确定可能与外排阳性反应相关的参数 阻挡。

Drug resistance is a major cause for failure of cancer chemotherapy in refractory disease. Human solid tumor cells may be intrinsically resistant or may acquire resistance after chemotherapy. Drug resistance is multifactorial and efflux plays a major part in resistance to a variety of natural products used in cancer treatment. Anthracycline, doxorubicin is an important antibiotic used in treatment of a variety of human malignancies. Rapid cellular efflux of doxorubicin has been demonstrated in drug resistant tumor cells. Several relatively non-toxic drugs have been shown to block efflux in vitro and enhance chemosensitivity. Verapamil, cyclosporin and trifluoperazine have been used in vivo with the intent to enhance drug retention and clinical response of refractory tumors. Our earlier studies have shown that prochlorperazine is a potent inhibitor of doxorubicin efflux in human solid tumor cells which are insensitive to efflux blocking action of verapamil. We have completed a phase I trial to determine the maximum. tolerated dose of prochlorperazine in vivo. In cells retrieved from patients on this protocol, significantly enhanced retention of doxorubicin was demonstrated and clinical responses were seen in no-small cell lung cancer and mesotheliomas. In the current project, we proposed to carry out a phase II study combining administration of doxorubicin followed by 2 hr infusion of prochlorperazine. We will also study markers and mechanisms of doxorubicin resistance in tumor cells and cell lines established from patients during the course of therapy on these protocols. Pharmacokinetic and pharmacological data will be collected to identify parameters which may correlate with positive response to efflux blocking.