Cisplatin down-regulates topoisomerase I activity in lung cancer cell lines.
Many clinical studies have reported that irinotecan has reproducible antitumor activity against lung cancer. Both cisplatin and SN-38 are key drugs in the treatment of lung cancer, and their combination is one of the most promising regimens available. Using lung cancer cell lines, ABC-1 and SBC-3, we examined the cytotoxic effect of the schedule, as well as the effect of cisplatin on topoisomerase I activity. Cytotoxicity was determined by MTT assay. ABC-1 or SBC-3 cells were incubated with or without various concentrations of both drugs in 96-well microplates for 72 or 96 hours in a humidified 5% CO2 atmosphere at 37 degrees C. Synergism was evaluated by median-effect plot analysis and a combination index isobologram method by Chou and Talalay. After ABC-1 or SBC-3 cells had been exposed to 10/microM cisplatin for one hour, topoisomerase I activities were determined by supercoiled-DNA relaxation assay. Synergism was observed in ABC-1 and SBC-3 cells when cisplatin was given first, followed by SN-38 (7-ethyl-10-hydroxycamptothecin) and cisplatin. Topoisomerase I activity decreased at 1-2 hours after exposure to cisplatin and recovered gradually after 4-5 hours of cisplatin exposure in both ABC-1 and SBC-3 cells. Accordingly, pretreatment with cisplatin will have an impact on the sensitivity to SN-38.
Aoe
Keisuke
K
Department of Internal Medicine, Okayama University Medical School, Okayama, Japan. keisukeaoe@mtf.biglobe.ne.jp
Kiura
Katsuyuki
K
Ueoka
Hiroshi
H
Tabata
Masahiro
M
Chikamori
Masakazu
M
Kohara
Hiroyuki
H
Harada
Mine
M
Tanimoto
Mitsune
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D059004:Topoisomerase I Inhibitors
D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002945:Cisplatin; D002166:Camptothecin