Antitumor activity of NK012 combined with cisplatin against small-cell lung cancer and intestinal mucosal changes in tumor-bearing mouse after treatment

Abstract

e13522 Background: The novel SN-38-incorporating polymeric micelles NK012 has been shown to have significant antitumor activity against several cancer mouse models compared with CPT-11. The phase I study demonstrated that patients treated with NK012 did not develop grade 3/4 diarrhea, one of the major adverse effects of CPT-11. The aim of this study is to investigate the advantages of NK012 combined with cisplatin (cis-dichlorodiammineplatinum (II): CDDP) over CPT-11/CDDP, one of the most active regimens against small-cell and non-small-cell lung cancers in the clinic, in mice bearing a small-cell lung cancer (SCLC) xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. Methods: Cytotoxic effects were evaluated in human SCLC cell lines (H69, H82, vascular endothelial growth factor [VEGF]-secreting cells, SBC-3/VEGF and its mock transfectant SBC-3/Neo). In vivo antitumor effects were evaluated in SBC-3/Neo-and SBC-3/VEGF-bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. Results: The in vitro growth inhibitory effects of NK012 were 198- to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT- 11/CDDP treatments (P=0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice, but were commonly observed in CPT-11-treated mice. Moreover, a large amount of CPT-11 was excreted into the feces and high CPT-11 concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity, and therefore warrants further clinical evaluation. No significant financial relationships to disclose.