CORE--CHEMOTHERAPY

核心--化疗

• 批准号: 6103078
• 负责人: WILLIAM R WAUD
• 金额: $ 13.51万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103078
• 关键词: antineoplastics; biomedical facility; cooperative study; disease /disorder model; dosage; drug administration routes; drug screening /evaluation; drug tolerance; glioma; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; neoplasm /cancer transplantation; neoplastic growth; nucleoside analog; pharmacokinetics; prodrugs; purine analog; purine nucleosides; tissue /cell culture

It is essential that the strategy for gene therapy using E. coli PNP be demonstrated in vivo. This goal will be accomplished by (1) establishing a few appropriate in vivo tumor models, (2) selecting appropriate nucleoside analogs by toxicity and pharmacokinetic evaluations, and (3) demonstrating anticancer activity of selected nucleoside analogs in the tumor models and optimizing this activity. First, the in vivo growth of tumors transduced in vitro with the PNP gene (to be supplied by Dr. Sorscher of UAB) will be characterized. The in vivo stability of the transduction will also be determined. The tumor lines that will be studied are human D-54MG glioma, rat RT-2 glioma, murine MT-539M6 glioma, murine B16 melanoma, and murine 16/C mammary adenocarcinoma. The in vivo growth of the tumors transduced in vitro with a reporter gene (to be supplied by Dr. Sorscher) will also be characterized for comparison. All growth data will be compared with that for the nontransduced parental tumor line. Second, the plasma pharmacokinetics of a nucleoside analog and its corresponding purine will be determined after a single iv or ip injection of the nucleoside. An MTD will be also determined for the nucleoside and its purine using an appropriate treatment regimen, which will depend on the plasma pharmacokinetics of the nucleoside and the in vivo stability of the transduced PNP gene. If a nucleoside analog and its purine are found to have similar MTDs, then this nucleoside/purine pair will not be used in antitumor evaluations. Third, the anticancer activity of the selected nucleoside analog (administered ip or iv) will be evaluated against a Sc implanted tumor line transduced with the PNP gene. For comparison, the evaluation will also be conducted with the tumor line transduced with a reporter gene and with the nontransduced parental tumor line. The anticancer evaluations will be repeated with l or 2 other transduced tumor line sets if available. Detailed studies to optimize and characterize the anticancer activity of the nucleoside analog (e.g., route of administration, treatment schedule, percent of transduced cells required for activity, etc.) will be conducted using the best model. The anticancer activity observed with the PNP gene therapy will be compared with that observed with standard clinical agents for the corresponding nontransduced tumor (using our historical data base).

因此，利用大肠杆菌进行基因治疗的策略是必要的。大肠杆菌PNP be 在活体中证明。这一目标将通过以下方式实现：（1）建立 几种合适的体内肿瘤模型，（2）选择合适的 通过毒性和药代动力学评价的核苷类似物，和（3） 证明了所选核苷类似物的抗癌活性， 肿瘤模型和优化这种活性。首先，体内生长 体外用PNP基因转导的肿瘤（由Dr. UAB的Sorscher）将被表征。的体内稳定性 还将确定转导。将要研究的肿瘤细胞系 是人D-54 MG神经胶质瘤、大鼠RT-2神经胶质瘤、鼠MT-539 M6神经胶质瘤、鼠MT-539 M6神经胶质瘤、 B16黑色素瘤和鼠16/C乳腺癌。体内生长 在体外用报告基因转导的肿瘤（由 博士Sorscher）也将被表征用于比较。 所有增长数据 将与未转导的亲本肿瘤系进行比较。 第二，核苷类似物的血浆药代动力学及其 在单次IV或IP注射后将测定相应的嘌呤 的核苷。还将确定核苷的MTD， 它的嘌呤使用适当的治疗方案，这将取决于 核苷的血浆药代动力学和 转导的PNP基因。如果发现核苷类似物及其嘌呤 具有相似的MTD，则该核苷/嘌呤对将不用于 抗肿瘤评价。第三，选择的抗癌活性 核苷类似物（ip或iv给药）将根据SC进行评估 用PNP基因转导的移植肿瘤系。作为比较， 还将用转导了抗肿瘤药物的肿瘤细胞系进行评估。 报告基因和未转导的亲本肿瘤系。 的 将用1或2个其它转导的肿瘤重复抗癌评价 行集（如果可用）。 详细的研究，以优化和表征 核苷类似物的抗癌活性（例如，途径 给药、治疗方案、所需转导细胞的百分比 活动等）将使用最佳模式进行。抗癌 用PNP基因治疗观察到的活性将与 对于相应的非转导的 肿瘤（使用我们的历史数据库）。