PROGRAM 4 - TUMOR BIOLOGY is part of the Project entitled: 'DNA Topoisomerase I-Targeted Therapy of Colon Cancer'. Highly active topoisomerase I inhibitors, identified in Program 2 and 3 and synthesized in adequate quantities by Program 1, will be tested using the xenograft system. The highest priority has been given to advanced studies of camptothecin analogs with unprecedented efficacy against colon cancer xenografts (See Overall Research Plan, Preliminary Studies). Every effort will be made to bring these analogs to early clinical trials. Our approach follows several steps: 1. Each compound received for evaluation will be tested for acute and chronic toxicity in nude mice. 2. Initial testing of a new analog, active in in-vitro screens, will be done on two xenograft tumor lines, and the advanced drug studies on two additional lines. The overall toxicity, as well as intestinal, bone marrow and urinary bladder toxicities will be monitored. The endpoints include tumor growth prevention, delay in growth, tumor regression/regrowth. 3. The treatment of artificial liver, lung, or brain metastases and cecal implants will be part of the advanced drug testing. The data will be evaluated and their statistical significance established. 4. Attempts will be made to identify tumors with de-novo resistance and develop one or several human colonic tumor lines with acquired resistance to camptothecin analogs. Studies of drug resistance will be done in close collaboration with Program 3. 5. Drug distribution studies in tumor-bearing mice will test, following subcutaneous, intravenous or femoral drug administration, drug plasma levels, disposition via urinary and hepatobiliary tract, as well as tissue distribution.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA050529-01A2
Application #
3808091
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
New York University
Department
Type
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Sewak, Sanjeev; Sorich, Joan; O'Leary, James (2006) Phase I trial of continuous infusion 9-aminocamptothecin in patients with advanced solid tumors: 21-day infusion is an active well-tolerated regimen. Anticancer Drugs 17:571-9
O'Leary, J J; Shapiro, R L; Ren, C J et al. (1999) Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin Cancer Res 5:181-7
Wall, M E; Wani, M C (1996) Camptothecin. Discovery to clinic. Ann N Y Acad Sci 803:1-12
Potmesil, M; Arbuck, S G; Takimoto, C H et al. (1996) 9-Aminocamptothecin and beyond. Preclinical and clinical studies. Ann N Y Acad Sci 803:231-46
D'Arpa, P; Liu, L F (1995) Cell cycle-specific and transcription-related phosphorylation of mammalian topoisomerase I. Exp Cell Res 217:125-31
Newcomb, E W; Thomas, A; Selkirk, A et al. (1995) Frequent homozygous deletions of D13S218 on 13q14 in B-cell chronic lymphocytic leukemia independent of disease stage and retinoblastoma gene inactivation. Cancer Res 55:2044-7
Bodley, A L; Wani, M C; Wall, M E et al. (1995) Antitrypanosomal activity of camptothecin analogs. Structure-activity correlations. Biochem Pharmacol 50:937-42
Potmesil, M; Vardeman, D; Kozielski, A J et al. (1995) Growth inhibition of human cancer metastases by camptothecins in newly developed xenograft models. Cancer Res 55:5637-41
Silber, R; Degar, B; Costin, D et al. (1994) Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs. Blood 84:3440-6
Pantazis, P; Kozielski, A; Rodriguez, R et al. (1994) Therapeutic efficacy of camptothecin derivatives against human malignant melanoma xenografts. Melanoma Res 4:5-10

Showing the most recent 10 out of 17 publications