MODULATION OF DOXORUBICIN EFFLUX IN HUMAN SOLID TUMORS

耐药是癌症化疗失败的主要原因

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.