DNA Topoisomerase I—Targeted Chemotherapy of Human Colon Cancer in Xenografts
- 24 November 1989
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 246 (4933), 1046-1048
- https://doi.org/10.1126/science.2555920
Abstract
Drug development is needed to improve chemotherapy of patients with locally advanced or metastatic colon carcinoma, who otherwise have an unfavorable prognosis. DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20(S)-camptothecin. Significantly increased concentrations of this enzyme, compared to that in normal colonic mucosa, were found in advanced stages of human colon adenocarcinoma and in xenografts of colon cancer carried by immunodeficient mice. Several synthetic analogs of camptothecin, selected by tests with the purified enzyme and tissue-culture screens, were evaluated in the xenograft model. Unlike other anticancer drugs tested, 20(RS)-9-amino-camptothecin (9-AC) induced disease-free remissions. The overall drug toxicity was low and allowed for repeated courses of treatment.This publication has 17 references indexed in Scilit:
- DNA TOPOISOMERASE POISONS AS ANTITUMOR DRUGSAnnual Review of Biochemistry, 1989
- Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12-13.2.Proceedings of the National Academy of Sciences, 1988
- Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-hydroxy-2'H,5'H,6'H-6'-oxopyrano[3',4'-f].DELTA.6,8-tetrahydroindolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecinJournal of Medicinal Chemistry, 1987
- Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogs. Structure-activity correlationsJournal of Medicinal Chemistry, 1987
- Plant antitumor agents. 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata decne: total synthesis and biological activityJournal of Medicinal Chemistry, 1986
- Prolongation of the Disease-Free Interval in Surgically Treated Rectal CarcinomaNew England Journal of Medicine, 1985
- DNA TOPOISOMERASESAnnual Review of Biochemistry, 1985
- Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogsJournal of Medicinal Chemistry, 1980
- Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2Journal of the American Chemical Society, 1966
- THE PROGNOSTIC SIGNIFICANCE OF DIRECT EXTENSION OF CARCINOMA OF THE COLON AND RECTUMAnnals of Surgery, 1954