CORE--CHEMOTHERAPY
核心--化疗
基本信息
- 批准号:6237571
- 负责人:
- 金额:$ 13.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-09-01 至 1998-08-31
- 项目状态:已结题
- 来源:
- 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
项目摘要
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).
使用大肠杆菌 PNP 进行基因治疗的策略必须是
在体内得到证明。这一目标将通过以下方式实现: (1) 建立
一些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估核苷类似物,以及(3)
证明所选核苷类似物的抗癌活性
肿瘤模型并优化该活性。一、体内生长
用 PNP 基因体外转导的肿瘤(由 Dr.
UAB 的Sorscher)将被表征。体内稳定性
转导也将被确定。将要研究的肿瘤系
是人 D-54MG 神经胶质瘤、大鼠 RT-2 神经胶质瘤、鼠 MT-539M6 神经胶质瘤、鼠
B16 黑色素瘤和鼠 16/C 乳腺癌。体内生长
用报告基因体外转导的肿瘤(由
Sorscher 博士)也将进行表征以进行比较。 所有成长数据
将与未转导的亲代肿瘤系进行比较。
二、核苷类似物及其血浆药代动力学
单次 iv 或 ip 注射后即可测定相应的嘌呤
的核苷。还将确定核苷和
其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体内稳定性
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/嘌呤对将不会用于
抗肿瘤评价。三、所选用的抗癌活性
核苷类似物(腹腔注射或静脉注射)将根据 Sc 进行评估
用 PNP 基因转导的植入肿瘤系。为了比较,将
还将对用转染的肿瘤系进行评估
报告基因和非转导亲本肿瘤系。 这
将用 1 或 2 个其他转导肿瘤重复进行抗癌评估
线路组(如果有)。 详细研究以优化和表征
核苷类似物的抗癌活性(例如,途径
给药、治疗时间表、所需转导细胞的百分比
活动等)将使用最佳模型进行。抗癌
PNP 基因治疗观察到的活性将与
用标准临床药物观察相应的非转导
肿瘤(使用我们的历史数据库)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WILLIAM R WAUD其他文献
WILLIAM R WAUD的其他文献
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{{ truncateString('WILLIAM R WAUD', 18)}}的其他基金
DETAILED DRUG EVALUATION & DEVELOPMENT OF TREATMENT STRA
详细的药物评估
- 批准号:
6315176 - 财政年份:2000
- 资助金额:
$ 13.01万 - 项目类别:
DETAILED DRUG EVALUATION & DEVELOPMENT OF TREATMENT STRA
详细的药物评估
- 批准号:
6230629 - 财政年份:2000
- 资助金额:
$ 13.01万 - 项目类别:
DETAILED DRUG EVALUATION & DEVELOPMENT OF TREATMENT STRA
详细的药物评估
- 批准号:
6340287 - 财政年份:2000
- 资助金额:
$ 13.01万 - 项目类别:
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