EVALUATION OF NOVEL PLATINUM COMPLEXES, INHIBITORS OF TOPOISOMERASE-IAND TOPOISOMERASE-II IN NONSMALL CELL LUNG-CANCER (NSCLC) SUBLINES RESISTANT TO CISPLATIN

We determined the in vitro cytotoxicities of promising new platinum co mplexes, an inhibitor of topoisomerase I, and novel anthracycline deri vatives, and examined using clonogenic assay whether these compounds a re cross-resistant in CDDP-resistant sublines derived from human non-s mall cell lung cancer (NSCLC) cell lines. Cytotoxicities were evaluate d by means of the relative antitumor activity (RAA = peak plasma conce ntration/IC50 values), which we reported previously as a model for pre dicting antitumor activity. Of the CDDP analogues tested, including ca rboplatin (CBDCA), [(glycolate-0,0') diammineplatinum (II) (254-S)], o nnaplatin achloro-(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. ME2302 [7-0-(2,6-dideoxy-2-fluoro-a-L-talopyranosyl) adriamycino ne-14-O-pimelate], a new anthracycline derivative, showed higher antit umor 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 co mpared to the respective parent cell lines. The CDDP analogues were al l 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 w as the most active against the CDDP-resistant sublines with relative r esistance values of 3.8 and 1.6 for PC-9/CDDP and PC-14/CDDP, respecti vely. ME2303 and CPT-11, (7-ethyl- 10-(4-(1-piperidino]-1 -piperidino) carbonyloxycamptothecin], an inhibitor to 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 clin ically resistant to CDDP.