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.