PREDICTIVE MODELS FOR COMBINATION CANCER CHEMOTHERAPY

描述（申请人描述）： 这个项目的长期目标是开发一个计算机模型 癌症剂量学准确预测的方法 在靶组织中的化疗组合方案， 副作用最小的治疗效果。 该提案符合 候选人的职业发展，提供机会， 结合基于生理学药代动力学/药效学 (PBPK/PD）建模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 动物实验可以让古斯塔夫森博士 及时和创新的研究领域的药理学和 与癌症有关的毒理学。 霍华德·泰明奖将支持 丹尼尔湖古斯塔夫森在实现他的长期目标， 在学术科学领域取得成功此外，这种方法 结合生理和疾病的潜在益处 将个体患者的状态纳入计算机建模过程， 为每位患者“定制”最佳治疗方案。 这种方法的发展在以下方面具有很大的潜力： 临床和基础研究。 拟议的研究包括： a）PBPK/PD建模; B）化学混合物的毒理学和毒理学 相互作用;和c）使用无胸腺“裸”细胞的动物/人癌症模型 人MX-1乳腺肿瘤异种移植物的小鼠。 在这些方面的工作 单个药物和药物混合物的PBPK/PD模型将继续进行， 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）， 在BALB/c小鼠中单独和组合; 2）研究药代动力学 彻底对DOX，CP，MTX和5-FU，单独和联合， BALB/c小鼠进行PBPK模型的验证; 3）药效学研究 DOX、CP、MTX和5-FU，单独和联合，在无胸腺“裸”小鼠中 人MX-1乳腺肿瘤异种移植物，验证PD模型，以及 建立DOX、CP、MTX的PBPK/PD模型 和5-FU，单药和联合给药，基于文献 来自BALB/c小鼠PBPK/PD模型的信息和种间缩放; 以及5）使用文献信息验证人体模型。

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.