Pharmacokinetic strategies to optimize IP chemotherapy

描述（由申请人提供）：卵巢癌是美国妇科癌症死亡的主要原因，迫切需要发展改进的策略来治疗这种疾病。这项提议的长期目标是开发和测试提高腹膜肿瘤化疗的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“逆靶向”策略，即利用佐剂（如抗药物抗体、脂质乳剂）对药物处置进行区域选择性改变，从而提高腹腔化疗的治疗选择性。此外，基于肿瘤血流对腹膜肿瘤内药物穿透深度的限制作用的药代动力学理论，我们提出抗血管生成药物可能用于在腹腔化疗后产生肿瘤特异性的药物暴露增加。Aim #1中提出的工作将研究抗药物抗体对i.p.给药后抗肿瘤药物全身暴露的决定因素，并将采用临床相关的人类卵巢癌小鼠异种移植模型来验证抗药物抗体将增加i.p.化疗的药代动力学选择性和治疗选择性的假设。目的2将检验脂质乳剂对长春瑞滨（一种模型亲脂抗癌药物）的处置、毒性和抗肿瘤作用的影响。这项工作将测试与使用外源性脂质来调节药物-脂蛋白相互作用有关的假设，作为诱导药代动力学和药效学区域特异性改变的手段。目的3将使用抗vegf抗体来验证抗血管生成治疗将增加腹腔化疗后腹膜肿瘤药物暴露的假设。这项拟议的工作建立在令人兴奋的初步数据的基础上，将允许进一步开发卵巢癌治疗的改进策略。

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.