PREDICTIVE MODELS FOR COMBINATION CANCER CHEMOTHERAPY

描述(申请人的描述)： 这个项目的长期目标是开发一种计算机模拟 准确预测癌症剂量学的方法 靶组织联合化疗方案以达到最大限度 治疗效果好，副作用小。这项建议符合 应聘者的职业发展通过提供一个机会 结合基于生理的药代动力学/药效学 (PBPK/PD)将专业知识融入他的生物化学和 分子药理学。计算机建模方法的组合使用 动物实验将使古斯塔夫森博士能够进行更多 在药理学和医学领域的及时和创新研究 与癌症有关的毒理学。霍华德·特明奖将支持 丹尼尔·L·古斯塔夫森在实现他的长期目标时 在学术科学领域取得成功的事业。此外，这种方法还具有 将生理和疾病结合起来的潜在好处 将单个患者的状态纳入计算机建模过程中 为每个患者量身定做最佳治疗方案。 这种方法的开发在以下方面具有很大的潜力 包括临床和基础研究。拟议的研究包括： A)PBPK/PD模型；b)化学混合物的毒理学和毒理学 相互作用；以及c)使用裸体裸体的动物/人类癌症模型 小鼠人乳腺癌MX-1异种移植瘤。在这些方面的工作 单个药物和药物混合物的PBPK/PD模型将如下进行 1)建立阿霉素(DOX)的PBPK/PD模型， 环磷酰胺(CP)、甲氨蝶呤(MTX)和5-氟尿嘧啶(5-FU)， 单独和联合应用于BALB/c小鼠；2)药代动力学研究 阿昔洛韦、环磷酰胺、甲氨蝶呤和5-氟尿嘧啶的单独和联合应用 BALB/c小鼠，验证PBPK模型；3)药效学研究 阿昔洛韦、环磷酰胺、甲氨蝶呤和5-氟尿嘧啶单独或联合应用于裸鼠体内 用人MX-1乳腺肿瘤移植瘤，验证PD模型，并 评价疗效；4)建立DOX、CP、MTX的PBPK/PD模型 和5-FU，单独和组合，基于文献在人类中 来自BALB/c小鼠PBPK/PD模型的信息和种间比例； 5)利用文献资料验证人体模型。

DESCRIPTION (Applicant's Description): The long-term goal of this project is to develop a computer modeling approach for the accurate prediction of dosimetry for cancer chemotherapy combination protocols in target tissues to achieve maximal therapeutic efficacy with minimal side effects. This proposal fits into the candidate's career development by providing an opportunity to incorporate physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling expertise into his background of biochemical and molecular pharmacology. The combined use of computer modeling approaches and animal experimentation will allow Dr. Gustafson to conduct more timely and innovative research in the fields of pharmacology and toxicology in relation to cancer. A Howard Temin Award would support Daniel L. Gustafson in the achievement of his long-term goal of having a successful career in academic science. Furthermore, this approach has the potential benefit of incorporating the physiological and disease states of individual patients into the computer modeling process for the "custom design" of the best therapeutic regimen for each patient. Development of this type of approach has a great deal of potential in both clinical and basic research. The proposed research integrates: a) PBPK/PD modeling; b) toxicology of chemical mixtures and toxicologic interactions; and c) animal/human models of cancer using athymic "nude" mice with human MX-1 mammary tumor xenografts. The work on these PBPK/PD models for individual drugs and drug mixtures will proceed as follows: 1) build PBPK/PD models for doxorubicin (DOX), cyclophosphamide (CP), methotrexate (MTX) and 5-fluorouracil (5-FU), singly and in combination, in BALB/c mice; 2) study pharmacokinetics thoroughly on DOX, CP, MTX and 5-FU, singly and in combination, in BALB/c mice and validate the PBPK models; 3) study pharmacodynamics of DOX, CP, MTX and 5-FU, singly and in combination, in athymic "nude" mice with human MX-1 mammary tumor xenografts, validate the PD models, and evaluate therapeutic efficacy; 4) build PBPK/PD models for DOX, CP, MTX and 5-FU, singly and in combination, in humans based on literature information and interspecies scaling from BALB/c mouse PBPK/PD models; and 5) validate human models using literature information.