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，并且非常需要开发治疗这种疾病的改进策略。该提案的长期目标是开发和测试增加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那些。基于药代动力学理论，我们提出了利用佐剂（例如，抗药物抗体、脂质乳剂）以赋予药物分布的区域选择性改变，从而增强腹膜内（i. p.）化疗此外，基于药物动力学理论，肿瘤血流对腹膜肿瘤内药物渗透深度的限制作用，我们提出，抗血管生成剂可用于在腹膜内化疗后产生肿瘤特异性药物暴露增加。目标1中提出的工作将研究腹腔注射后抗药物抗体对抗肿瘤药物全身暴露的影响的决定因素，并将采用临床相关的人卵巢癌小鼠异种移植模型来测试抗药物抗体将增加的假设腹腔化疗的药代动力学选择性和治疗选择性。目的#2将检查脂肪乳剂对长春瑞滨（一种模型亲脂性抗癌药物）的处置、毒性和抗肿瘤作用的影响。这项工作将检验与使用外源性脂质调节药物-脂蛋白相互作用相关的假设，作为诱导药代动力学和药效学区域特异性改变的一种手段。目的#3将采用抗VEGF抗体来检验抗血管生成治疗将增加腹膜内化疗后腹膜肿瘤中药物暴露的假设。这项基于令人兴奋的初步数据的拟议工作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.