Reversal of "atypical"-multidrug resistance by recombinant human tumor necrosis factor in the human ovarian cancer cell line A2780-DX3.
A2780 human ovarian cancer cell line and its multidrug resistant counterpart A2780-DX3 were utilized for this in vitro study. A2780-DX3 is resistant in various degrees to several topoisomerase II inhibitors but sensitive to vinca alkaloids. Simultaneous treatment of the A2780-DX3 line with 1000 U/mL rHuTNF largely reverses resistance to most topoisomerase II inhibitors. By itself, 1000 U/mL rHuTNF is not toxic to the resistant line. Uptake and retention of [3H]-Mitoxantrone are not modified by rHuTNF, whereas rHuTNF is very active in potentiating the effects of Mitoxantrone. After treatment with topoisomerase II inhibitors, Doxorubicin, Mitoxantrone, or VP16, rHuTNF restores DNA-SSB and DNA-protein cross-links in the resistant line to the level of the wild type. The cleavage activity of topoisomerase II in the resistant line is about 40% of the level present in the parental line. Five minutes after the addition of 1000 U/mL of rHuTNF, the cleavage activity in the resistant line is about 85% of the level present in the parental line. The catalytic activity of topoisomerase II is only 15% lower in the resistant line, but it is increased by about 50% 5 min after the addition of rHuTNF to the resistant line. These effects are transient and cannot be observed after 30 min. These transient direct effects of rHuTNF on topoisomerase II could be associated with its ability to restore sensitivity to inhibitors of topoisomerase II in the A2780-DX3 line.
Department of Chemical Carcinogenesis, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
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Valenti
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De Sessa
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D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D011994:Recombinant Proteins; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005047:Etoposide; D004317:Doxorubicin; D008942:Mitoxantrone