Abstract

Camptothecin is a plant alkaloid with strong antitumor activity in experimental animals. Its cellular target has recently been identified to be DNA topoisomerase I, an important nuclear enzyme involved in a number of DNA processes such as DNA replication and RNA transcription. A number of camptothecin derivatives (e.g. 9-amino-camptothecin and 10, 11- methylenedioxy-camptothecin) have shown strong antitumor activity against human colon xenografts in nude mice. Because of the potential importance of camptothecin in cancer chemotherapy, we propose to study the mechanism of action of camptothecin and its analogs using human colon tumors as a model system. This program has four specific aims; (1) we will provide a panel of in vitro assays for selecting the most potent camptothecin analogs for in vivo testing. (2) We will study the possible altered regulation of toposomerase I in colon tumors. (3) We will investigate the interaction between replication complex and camptothecin-induced DNA """"""""damage"""""""". (4) We will study the molecular mechanism underlying camptothecin resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA050529-03
Application #
3773502
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
New York University
Department
Type
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012

  Publications

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
Pantazis, P; Kozielski, A; Rodriguez, R et al. (1994) Therapeutic efficacy of camptothecin derivatives against human malignant melanoma xenografts. Melanoma Res 4:5-10
Potmesil, M (1994) Camptothecins: from bench research to hospital wards. Cancer Res 54:1431-9

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