The purpose of this proposal is to study the clinical significance of multidrug resistance in breast and ovarian carcinomas, lymphomas, and Hodgkin's disease. These tumors were chosen because: (1) they are moderately curable in patients with minimal disease (breast and ovarian cancers) and in advanced stages (lymphomas and Hodgkin's disease); and (2) we have shown significantly increased mdr1 gene expression in patients with these cancers who have failed chemotherapy, suggesting that this mechanism may be responsible for the resistance and that its reversal may result in clinical remission of tumors. A series of Phase I and II clinical trials are proposed to modulate mdr1 expression in these cancers. Important features of these trials are: (1) Serial sampling of tumors by fine needle aspiration, with assessment of mdr1 expression by both immunocytochemistry for P-glycoprotein and RNA- directed polymerase chain reaction (PCR). (2) Detailed pharmacokinetic studies to determine the effects of the modulating agent upon the disposition and effective dose exposure (plasma area under the curve) of the cytotoxic drug. (3) Patients will serve as their own controls with pharmacokinetic studies both with and without the modulating drug. (4) Monitoring of the level of the modulating agent in all patients to determine whether adequate levels of free drug have been achieved. (5) The combination of etoposide and cyclosporine will be used in the first set of protocols. If cyclosporine plus etoposide produce remissions in at least 20% of refractory patients, a second generation of studies will add doxorubicin and vinblastine to this combination. If cyclosporine is unsuccessful we will study cefoperazone, an antibiotic which we have shown to be an effective modulator in preclinical experiments. The second aspect of the proposal concerns retrospective studies of mdr1 expression in these tumors, for which extensive data bases of clinical characteristics and outcome and other pathological correlations are available at Stanford. Expression of mdr1 will be determined in stored frozen tissues by immunochemistry and PCR, and in paraffin-embedded fixed tissues by immunochemistry. Results will be analyzed by multivariate analysis in comparison to other known and potential factors for prognostic importance in tumor response to chemotherapy and patient survival. This proposal represents an integrated effort by a team of medical oncologists and pathologists at Stanford University School of Medicine to further understand and reverse the function of the multidrug resistance gene in these cancers, with the long-term goal of increasing their curability.

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National Cancer Institute (NCI)
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