Abstract | BACKGROUND:
Small-cell lung cancer (SCLC) is a highly chemosensitive tumor, but the recurrent disease that is common after initial response is often unresponsive to further chemotherapy. Although the mechanisms of drug resistance in SCLC have not been established, studies suggest that alterations of the nuclear enzyme DNA topoisomerase II may reduce the sensitivity of the cell to drug action. This enzyme is recognized as a primary target for cytotoxic activity of important antitumor agents. PURPOSE: In this study, we attempted to determine if altered forms of DNA topoisomerase II are responsible for reduced drug sensitivity. METHODS: RESULTS: In addition to the normal 6.2-kilobase (kb) topoisomerase II messenger RNA ( mRNA), the NCI-H69 line expressed a 7.4-kb topoisomerase II transcript, presumably encoded by the rearranged allele. Moreover, this transcript, although longer than the normal mRNA, lacked a substantial portion of the 3'-terminal p170 gene coding sequence. Topoisomerase II activity in nuclear extracts, as determined by the P4 phage DNA-unknotting assay, was more easily detected and measured at lower NaCl concentrations in NCI-H69 than in NCI-H187 cells. CONCLUSION: These results are consistent with the hypothesis that the chemoresistant NCI-H69 cell line may express, in addition to the normal enzyme, an altered topoisomerase II enzyme possibly encoded by the 7.4-kb mRNA, which in turn may be transcribed from the rearranged gene allele. IMPLICATION:
|
Authors | M Binaschi, G Giaccone, A F Gazdar, P De Isabella, G C Ricotti, G Capranico, F Zunino |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 84
Issue 22
Pg. 1710-6
(Nov 18 1992)
ISSN: 0027-8874 [Print] United States |
PMID | 1331483
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- DNA, Neoplasm
- RNA, Messenger
- DNA Topoisomerases, Type II
|
Topics |
- Alleles
- Carcinoma, Small Cell
(genetics)
- DNA Topoisomerases, Type II
(genetics, metabolism)
- DNA, Neoplasm
(genetics)
- Gene Expression
- Gene Rearrangement
- Humans
- Lung Neoplasms
(genetics)
- RNA, Messenger
(genetics)
- Restriction Mapping
- Tumor Cells, Cultured
|