Abstract | BACKGROUND: METHODS: We studied 20 topoisomerase II inhibitors and individual cell lines with or without activated ras oncogenes and with varying degrees of multidrug resistance. RESULTS: In the absence of multidrug resistance, human tumor cell lines with activated ras oncogenes were uniformly more sensitive to most topoisomerase II inhibitors than were cell lines containing wild-type ras alleles. The compounds NSC 284682 and NSC 659687 were especially effective irrespective of the multidrug resistant phenotype. The ras oncogene-mediated sensitization to topoisomerase II inhibitors was far more prominent with the non- DNA-intercalating epipodophyllotoxins than with the DNA-intercalating inhibitors. This difference in sensitization appears to be related to a difference in apoptotic sensitivity, since the level of DNA damage generated by etoposide (an epipodophyllotoxin derivative) in immortalized human kidney epithelial cells expressing an activated ras oncogene was similar to that in the parental cells, but apoptosis was enhanced only in the former cells. CONCLUSIONS:
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Authors | H M Koo, M Gray-Goodrich, G Kohlhagen, M J McWilliams, M Jeffers, A Vaigro-Wolff, W G Alvord, A Monks, K D Paull, Y Pommier, G F Vande Woude |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 91
Issue 3
Pg. 236-44
(Feb 03 1999)
ISSN: 0027-8874 [Print] United States |
PMID | 10037101
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Carbazoles
- NSC 284682
- NSC 659687
- Pyridines
- Topoisomerase II Inhibitors
- Daunorubicin
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Carbazoles
(pharmacology)
- Colonic Neoplasms
(drug therapy, genetics)
- Daunorubicin
(analogs & derivatives, pharmacology)
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- Genes, ras
(drug effects)
- Humans
- Mutation
- Phenotype
- Pyridines
(pharmacology)
- Topoisomerase II Inhibitors
- Transfection
- Tumor Cells, Cultured
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