Pharmacokinetic strategies to optimize IP chemotherapy

描述(申请人提供)：卵巢癌是美国妇科癌症死亡的主要原因，有大量需要制定改进的策略来治疗这种疾病。这项建议的长期目标是开发和测试提高腹膜肿瘤化疗安全性和有效性的方法，例如在晚期卵巢癌患者中发现的方法。基于药代动力学理论，我们提出了利用辅助剂(如抗药物抗体、脂肪乳剂)在药物处置中进行区域选择性改变的“反向靶向”策略，从而提高了腹膜内药物治疗的选择性。化疗。此外，基于肿瘤血流对药物在腹膜肿瘤内渗透深度的限制作用的药代动力学理论，我们提出可以使用抗血管生成剂来产生肿瘤特异性增加的药物暴露。化疗。在Aim#1中提出的工作将调查抗药抗体对ip后全身暴露的抗肿瘤药物的影响的决定因素。给药和临床相关的人卵巢癌小鼠异种移植模型将被用来检验抗药抗体将增加I.P.的药代动力学选择性和治疗选择性的假设。化疗。目的#2研究脂肪乳剂对长春瑞滨(一种典型的亲脂性抗癌药物)的处置、毒性和抗肿瘤作用的影响。这项工作将测试有关使用外源性脂质来调节药物-脂蛋白相互作用的假设，作为诱导药代动力学和药效学中区域特异性改变的一种手段。目的#3将使用抗血管内皮生长因子抗体来验证抗血管生成治疗将增加腹膜肿瘤在腹腔注射后的药物暴露的假设。化疗。这项拟议的工作建立在令人兴奋的初步数据基础上，将允许进一步开发改进的卵巢癌治疗策略。

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.