In vitro effects of combinations of cis-amminedichloro (2-methylpyridine) platinum (II) (ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line

Abstract

Among numerous clinical regimens of combination chemotherapy, synergy has been observed to be particularly marked with combinations containing cisplatin (CDDP). However, the clinical use of CDDP has sometimes been limited by acquired resistance. The new-generation platinum drug, ZD0473, was synthesized with the aim of hindering the reaction of the drug with thiols, by the introduction of a 2-methylpyridine ligand. This enables the drug to exert antitumor activity against cisplatin-resistant cancer cells with elevated glutathione and/or metallothionein levels. The drug was also shown experimentally to overcome cisplatin resistance due to impaired drug accumulation, and enhanced DNA repair/tolerance to platinum-DNA adducts. We investigated the effects of combinations of ZD0473 with other anticancer drugs on the growth of a human small-cell lung cancer cell line (SBC-3). Six novel anticancer drugs were tested: docetaxel (TXT), paclitaxel (TXL), vinorelbine (VNB), irinotecan (CPT-11), gemcitabine (GEM) and pemetrexed (MTA). The growth inhibitory effect of the drugs was measured by MTT assay and the effects of the combination regimens were evaluated by the combination index analysis method developed by Chou and Talalay. Synergy was demonstrated for the combination regimens of ZD0473-GEM and ZD0473-TXL, while an additive effect was observed with combinations containing TXT, VNB, CPT-11 or MTA. In the case of the ZD0473-GEM combination, synergy was observed over a wide range of inhibition levels at dose ratios of 50:1, 100:1 and 250:1. The level of synergy was equivalent to that observed for combinations of CDDP-etoposide, CDDP-GEM and nedaplatin-CPT-11. The results suggest that the combination of ZD0473 with GEM merits further investigation in small cell lung cancer.