Synergistic antitumor activity of the SN-38-incorporating polymeric micelles NK012 with S-1 in a mouse model of non-small cell lung cancer.

Abstract

The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants 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: International journal of cancer (Int J Cancer) Vol. 127 Issue 11 Pg. 2699-706 (Dec 01 2010) ISSN: 1097-0215 [Electronic] United States
• PMID: 20198621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• Micelles
• RNA, Messenger
• S 1 (combination)
• Tegafur
• Oxonic Acid
• Irinotecan
• Dihydrouracil Dehydrogenase (NADP)
• Thymidylate Synthase
• Camptothecin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, chemistry, pharmacology, toxicity)
• Camptothecin (administration & dosage, analogs & derivatives, chemistry, pharmacology, toxicity)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Dihydrouracil Dehydrogenase (NADP) (biosynthesis, genetics)
• Drug Combinations
• Drug Delivery Systems
• Drug Synergism
• Female
• Humans
• Intestinal Mucosa (drug effects, pathology)
• Irinotecan
• Lung Neoplasms (drug therapy, enzymology, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Micelles
• Oxonic Acid (administration & dosage, chemistry, pharmacology, toxicity)
• RNA, Messenger (biosynthesis, genetics)
• Tegafur (administration & dosage, chemistry, pharmacology, toxicity)
• Thymidylate Synthase (biosynthesis, genetics)
• Xenograft Model Antitumor Assays