Drug-induced down-regulation of topoisomerase I in human epidermoid cancer cells resistant to saintopin and camptothecins.

Abstract

The anticancer agent saintopin induces DNA cleavage mediated by both topoisomerase (topo) I and topo II in vitro through stabilization of the reversible enzyme-DNA cleavable complex. We established saintopin-resistant cell lines (KB/STP-1 and KB/STP-2) from human epidermoid cancer KB cells by stepwise exposure to increasing doses of the drug. KB/STP-1 and KB/STP-2 cells showed 12- and 44-fold increases, respectively, in resistance to saintopin relative to that of KB cells. Both saintopin-resistant cell lines showed only small reductions in sensitivity to the topo II inhibitor etoposide but developed marked cross-resistance to the topo I-targeting camptothecin derivative CPT-11 [(4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbony loxy] dione hydrochloride trihydrate] and its active form, SN-38 (7-ethyl-10-hydroxycamptothecin). In contrast, both KB/STP-1 and KB/STP-2 cells showed increased collateral sensitivity to cisplatin, a nitrosourea derivative, mitomycin C, and UV light. The protein concentration, activity, and mRNA abundance of both topo I and topo II were similar in KB/STP-1, KB/STP-2, and the parental KB cells. There were no significant changes in the drug-stabilized topo-DNA cleavable complex formation in KB and KB/STP-2 cells. Two point mutations were detected in topo I cDNA from KB/STP-2 cells, but these were also present in KB cells. Topo I mRNA abundance decreased markedly immediately after exposure of KB/STP-2 cells to saintopin; no such effects were apparent in KB cells. In contrast, topo II mRNA was not markedly affected by saintopin in either KB or KB/STP-2 cells. Treatment with CPT-11 or SN-38 also induced a markedly greater and more persistent reduction in topo I mRNA abundance in KB/STP-2 cells than in KB cells. Etoposide had no marked effect on topo I mRNA abundance in either KB/STP-2 or KB cells. Topo I mRNA was highly unstable in KB/STP-2 cells in comparison to KB cells when incubated with saintopin. This novel regulation of topo I mRNA by topo I-targeting agents could be associated with acquirement of drug resistance to saintopin or SN-38/CPT-11 in KB/STP-2 cells.

• Authors: K Taniguchi, K Kohno, K Kawanami, M Wada, T Kanematsu, M Kuwano
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 10 Pg. 2348-54 (May 15 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8625310 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Benz(a)Anthracenes
• Neoplasm Proteins
• RNA, Messenger
• RNA, Neoplasm
• Topoisomerase I Inhibitors
• saintopin
• Dactinomycin
• Irinotecan
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II
• Camptothecin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Benz(a)Anthracenes (pharmacology)
• Camptothecin (analogs & derivatives, pharmacology)
• Carcinoma, Squamous Cell (enzymology, pathology)
• DNA Topoisomerases, Type I (biosynthesis, genetics)
• DNA Topoisomerases, Type II (metabolism)
• Dactinomycin (pharmacology)
• Drug Resistance, Neoplasm
• Enzyme Induction (drug effects)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Irinotecan
• KB Cells (drug effects, enzymology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• Topoisomerase I Inhibitors
• Tumor Cells, Cultured