The overall objective of this proposal is to develop new therapeutic regimens for treatment of breast, ovarian, and non-small cell lung carcinomas, based on performance of rationally designed, phase II trials of topoisomerase I inhibitors as single agents, in combination regimens, and in dose-intensive regimens. The program brings together a strong, interactive team of biochemists, pharmacologists, preclinical and clinical investigators to design, implement, and conduct pharmacokinetic and pharmacodynamic guided phase II trials to optimize the use of topoisomerase I directed agents. Microenzymatic assays of topoisomerase I and Il activities and susceptibility to camptothecin analogs will be performed on CT- or bronchoscopic-guided biopsy specimens obtained from tumors of patients participating in these studies. Intensive pharmacology monitoring .will be performed. Pharmacokinetic and pharmacodynamic parameters-will serve as the basis for developing phase II trials involving topoisomerase I inhibitors and other selected agents including cisplatin and/or alkylating agents in non-small cell lung and ovarian cancer; adriamycin and/or alkylating agents in breast cancer. Dose intensification studies of the topoisomerase I inhibitors alone and in combination regimens will be performed using hematopoietic stem cell support. Topoisomerase I inhibitors to be studied in these protocols will include topotecan, CPT-11 and 9-aminocamptothecin. The identification, design, and prioritization of phase II studies will be based on results of biochemical analysis, preclinical models, and/or phase I trials conducted at the CWRU/Ireland Cancer Center and developed in collaboration with staff of the Cancer Therapy Evaluation and Development Program of the National Cancer Institute.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01CA063200-04S4
Application #
6288474
Study Section
Special Emphasis Panel (SRC (62))
Program Officer
Arbuck, Susan
Project Start
1994-06-03
Project End
2001-03-31
Budget Start
1997-05-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$327,077
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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