MODULATION OF DOXORUBICIN EFFLUX IN HUMAN SOLID TUMORS

耐药是导致癌症化疗失败的主要原因， 难治性疾病 人实体瘤细胞可能本质上是 化疗后耐药或可能获得耐药。 耐药性 是多因素的，外排在耐药性中起主要作用。 用于癌症治疗的各种天然产品。 蒽环类， 阿霉素是一种重要的抗生素，用于治疗多种 人类恶性肿瘤 多柔比星的快速细胞外排已经被证实是 在耐药肿瘤细胞中得到证实。 几种相对无毒的 药物已显示在体外阻断外排并增强 化疗敏感性 维拉帕米、环孢菌素和三氟拉嗪已被 用于体内，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，丙氯拉嗪是一种有效的 人实体瘤细胞中阿霉素流出抑制剂， 对维拉帕米的外排阻断作用不敏感。 我们已经完成了一 第一阶段试验确定最大值。耐受剂量 体内的丙氯拉嗪。 从病人身上提取的细胞中 方案，显著增强阿霉素的保留， 在非小细胞肺中观察到了已证实的临床反应， 癌症和间皮瘤。 在目前的项目中，我们建议进行 在一项II期研究中， 2小时输注丙氯拉嗪。 我们还将研究标记， 肿瘤细胞和细胞系阿霉素耐药机制 在这些治疗过程中， 协议. 将收集药代动力学和药理学数据， 确定可能与外排阳性反应相关参数 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.