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

• Published in: International journal of cancer 2010-12, Vol.127 (11), p.2699-2706
• Main Authors: Nagano, Tatsuya, Yasunaga, Masahiro, Goto, Koichi, Kenmotsu, Hirotsugu, Koga, Yoshikatsu, Kuroda, Jun‐ichiro, Nishimura, Yoshihiro, Sugino, Takashi, Nishiwaki, Yutaka, Matsumura, Yasuhiro
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - chemistry; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - toxicity; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacology; Camptothecin - toxicity; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; diarrhea; Dihydrouracil Dehydrogenase (NADP) - biosynthesis; Dihydrouracil Dehydrogenase (NADP) - genetics; Drug Combinations; drug delivery system; Drug Delivery Systems; Drug Synergism; Female; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Micelles; NK012; non‐small cell lung cancer; Oxonic Acid - administration & dosage; Oxonic Acid - chemistry; Oxonic Acid - pharmacology; Oxonic Acid - toxicity; Pneumology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; S‐1; Tegafur - administration & dosage; Tegafur - chemistry; Tegafur - pharmacology; Tegafur - toxicity; Thymidylate Synthase - biosynthesis; Thymidylate Synthase - genetics; Tumors; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25282

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.