Prevention of adriamycin-induced mdr1 gene amplification and expression in mouse leukemia cells by simultaneous treatment with the anti-recombinogen bromovinyldeoxyuridine.
The anti-recombinogenic substance (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was tested for its ability to prevent adriamycin-induced mdr1 gene amplification and expression in mouse leukemia cells in vitro. F4-6 cells that were treated with stepwise enhanced doses of adriamycin acquired resistance against adriamycin. While 20 ng/ml adriamycin showed strong toxic effects in sensitive cells, the same dose was tolerated at the end of the long-term experiment following treatment with stepwise enhanced doses of adriamycin. In parallel experiments, 0.5 or 1 microg/ml BVDU was given together with adriamycin. BVDU prevented the formation of resistance against adriamycin treatment. Using differential PCR, the signal intensity of the mdr1a-specific band appeared markedly increased in adriamycin-resistant cells, while the signal intensities of the adriamycin + BVDU-treated cells resembled the intensity ratio of the untreated control cells. Beyond that, in resistant F4-6 cells increased expression of mdr genes was demonstrated by Northern blot analysis.
Fahrig
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RESprotect GmbH-Prevention of Chemoresistance, Dresden, Germany. fahrig@resprotect.de
Steinkamp-Zucht
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Schaefer
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D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005784:Gene Amplification / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; C020235:brivudine; D004317:Doxorubicin; D001973:Bromodeoxyuridine