Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin

Anticancer Res. Mar-Apr 1995;15(2):393-8.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Carboplatin / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cisplatin / pharmacology*
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / pharmacology
  • Drug Design
  • Drug Resistance, Multiple
  • Etoposide / pharmacology
  • Irinotecan
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*
  • Tumor Stem Cell Assay


  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Oxaliplatin
  • ME 2303
  • Etoposide
  • Irinotecan
  • Doxorubicin
  • nedaplatin
  • Carboplatin
  • Cisplatin
  • ormaplatin
  • Camptothecin