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

Abstract

PURPOSE:

To investigate the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with cisplatin [cis-dichlorodiammineplatinum (II) (CDDP)] in mice bearing a small cell lung cancer xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity.

EXPERIMENTAL DESIGN:

Cytotoxic effects were evaluated in human small cell lung cancer cell lines [H69, H82, and 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-bearing 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.

• Authors: Tatsuya Nagano, Masahiro Yasunaga, Koichi Goto, Hirotsugu Kenmotsu, Yoshikatsu Koga, Jun-Ichiro Kuroda, Yoshihiro Nishimura, Takashi Sugino, Yutaka Nishiwaki, Yasuhiro Matsumura
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 13 Pg. 4348-55 (Jul 01 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19509138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Irinotecan
• Cisplatin
• Camptothecin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacology)
• Cisplatin (administration & dosage, adverse effects, pharmacology)
• Female
• Humans
• Intestinal Mucosa (drug effects, pathology)
• Irinotecan
• Lung Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Small Cell Lung Carcinoma (drug therapy, genetics, metabolism, pathology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xenograft Model Antitumor Assays