Pharmacokinetic strategies to optimize IP chemotherapy

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DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of gynecologic cancer death in the United States, and there is substantial need for the development of improved strategies to treat this disease. The long-term objectives of this proposal are to develop and test approaches for increasing the safety and efficacy of the chemotherapy of peritoneal tumors, such as those found in patients with advanced ovarian cancer. Based on pharmacokinetic theory, we have proposed "inverse targeting" strategies that utilize adjuvant agents (e.g., anti-drug antibodies, lipid emulsions) to impart regio-selective alterations in drug disposition, thereby enhancing the therapeutic selectivity of intraperitoneal (i.p.) chemotherapy. Additionally, based on pharmacokinetic theory regarding the limiting effects of tumor blood flow on the depth of drug penetration within peritoneal tumors, we have proposed that anti-angiogenic agents may be used to produce tumor-specific increases in drug exposure following i.p. chemotherapy. Work proposed in Aim #1 will investigate the determinants of anti-drug antibody effects on the systemic exposure of antineoplastics following i.p. administration, and clinically relevant murine xenograft models of human ovarian cancer will be employed to test the hypotheses that anti-drug antibodies will increase the pharmacokinetic selectivity and therapeutic selectivity of i.p. chemotherapy. Aim #2 will examine the effects of lipid emulsions on the disposition, toxicity, and anti-tumor effects of vinorelbine (a model lipophilic anti-cancer drug). This work will test hypotheses related to the use of exogenous lipid to modulate drug - lipoprotein interactions, as a means of inducing regio-specific alterations in pharmacokinetics and pharmacodynamics. Aim #3 will employ anti-VEGF antibodies to test the hypothesis that anti-angiogenic therapy will increase drug exposure in peritoneal tumors following i.p. chemotherapy. The proposed work, which builds on exciting preliminary data, will allow further development of improved strategies for the treatment of ovarian cancer.