title: Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin.
abstract: We determined the in vitro cytotoxicities of promising new platinum complexes, an inhibitor of topoisomerase I, and novel anthracycline derivatives, and examined using clonogenic assay whether these compounds are cross-resistant in CDDP-resistant sublines derived from human non-small cell lung cancer (NSCLC) cell lines. Cytotoxicities were evaluated by means of the relative antitumor activity (RAA = peak plasma concentration/IC50 values), which we reported previously as a model for predicting antitumor activity. Of the CDDP analogues tested, including carboplatin (CBDCA), [(glycolate-0,0') diammineplatinum (II) (254-S)], ormaplatin [tetrachloro-(d,1-trans)- 1,2-diaminocyclohexaneplatinum (IV) (OP)] and oxaliplatin [oxalato (trans-1-1,2-diaminocyclohexane) platinum (II) (1-OHP)], no agent showed superior antitumor activity compared to CDDP. ME2303 [7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) adriamycinone-14-O -pimelate], a new anthracycline derivative, showed higher antitumor activity than adriamycin (ADM). The CDDPresistant sublines, PC-9/CDDP and PC-14/CDDP, were 18.3- and 7.7-fold more resistant to CDDP compared to the respective parent cell lines. The CDDP analogues were all cross-resistant to CDDP and the order of relative resistance values was CBDCA > 254-S > 1-OHP > OP for PC9/CDDP and 254-S > CBDCA > 1-OHP > OP for PC-14/CDDP. Although OP showed cross-resistance to CDDP, OP was the most active against the CDDP-resistant sublines with relative resistance values of 3.8 and 1.6 for PC-9/CDDP and PC-14/CDDP, respectively. ME2303 and CPT-11, [7-ethyl-10-(4-[1-piperidino]-1-piperidino) carbonyloxycamptothecin], an inhibitor of topoisomerase I, was active against CDDP-resistant human NSCLC cell lines. These results suggest that OP, ME2303 and CPT-11 could be active in patients with, NSCLC clinically resistant to CDDP.
authors.affiliation: Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: Y
authors.initials: Y
authors.lastname: Ohe
authors.forename: F
authors.initials: F
authors.lastname: Kanzawa
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: K
authors.initials: K
authors.lastname: Hara
authors.forename: N
authors.initials: N
authors.lastname: Saijo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000494:pharmacology; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D000077150:Oxaliplatin; C059081:ME 2303; D005047:Etoposide; D000077146:Irinotecan; D004317:Doxorubicin; C053989:nedaplatin; D016190:Carboplatin; D002945:Cisplatin; C049777:ormaplatin; D002166:Camptothecin