DNA Topoisomerase I-Targeted Chemotherapy of Human Colon Cancer in Xenografts

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 func...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1989-11, Vol.246 (4933), p.1046-1048
Main Authors: Giovanella, Beppino C., Stehlin, John S., Wall, Monroe E., Wani, Mansukh C., Nicholas, Allan W., Liu, Leroy F., Silber, Robert, Potmesil, Milan
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma - analysis
Adenocarcinoma - drug therapy
Adenocarcinoma - enzymology
Animals
Antimitotic agents
Antineoplastic agents
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Biomarkers, Tumor - analysis
Body weight
Camptothecin - analogs & derivatives
Camptothecin - therapeutic use
Camptothecin - toxicity
Cancer
carcinoma
Chemotherapy
colon
Colonic Neoplasms - analysis
Colonic Neoplasms - drug therapy
Colonic Neoplasms - enzymology
Colorectal cancer
DNA
DNA Topoisomerases, Type I - analysis
DNA, Neoplasm - analysis
Dosage
Drug Design
Drugs
Enzymes
Gastroenterology. Liver. Pancreas. Abdomen
Heterologous transplantation
Humans
Intestinal Mucosa - enzymology
Medical research
Medical sciences
Mice
Mice, Inbred Strains
Mucosa
Neoplasm Transplantation
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
T lymphocytes
Topoisomerase I Inhibitors
Transplantation, Heterologous
Tumors
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.2555920