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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / chemistry
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / toxicity
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Camptothecin / chemistry
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Camptothecin / pharmacology
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Camptothecin / toxicity
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / genetics
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Cell Line, Tumor
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Dihydrouracil Dehydrogenase (NADP) / biosynthesis
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Dihydrouracil Dehydrogenase (NADP) / genetics
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Drug Combinations
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Drug Delivery Systems
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Drug Synergism
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Female
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Humans
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / pathology
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Irinotecan
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Lung Neoplasms / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Micelles
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Oxonic Acid / administration & dosage
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Oxonic Acid / chemistry
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Oxonic Acid / pharmacology*
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Oxonic Acid / toxicity
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Tegafur / administration & dosage
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Tegafur / chemistry
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Tegafur / pharmacology*
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Tegafur / toxicity
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Thymidylate Synthase / biosynthesis
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Thymidylate Synthase / genetics
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Xenograft Model Antitumor Assays
Substances
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Drug Combinations
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Micelles
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RNA, Messenger
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S 1 (combination)
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Tegafur
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Oxonic Acid
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Irinotecan
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Dihydrouracil Dehydrogenase (NADP)
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Thymidylate Synthase
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Camptothecin