[Antitumor effects of 5-fluorouracil-bound organic silicon compound].
5-fluoro-3,4-dihydro-2,4-dioxo-N-[2-2- (dimethylphenylsilyl)ethylthioethyl]-1(2H)-pyrimidinocarb oxamide (SDK-12B-5), a novel antitumor agent, is covalently linked with 5-fluorouracil (5-FU) and 2-[(2-dimethylphenylsilyl)ethylthio] ethylamine(SDK-103) which possesses itself antitumor activity against murine solid tumors. It has a broad antitumor spectrum in experimental tumor systems including murine leukemias. Furthermore, SDK-12B-5 administered p.o. with various treatment schedules inhibited significantly the tumor growth of human breast cancer (MX-1), colon cancer (Co-4) and lung cancer (LX-1 and OAT) cells in BALB/c nu/nu mice and the chemotherapeutic index was about 10 for 4 different human cancer xenografts. In the Lewis lung carcinoma (LLC) metastasis model, SDK-12B-5 in combination with amputation of tumors inhibited significantly both the lymph node metastases and lung metastases of LLC and prolonged the life span (%ILS:91%) of BDF1 mice. We also found that the cell killing effect of SDK-12B-5 was affected by both concentration and exposure time in cultured human lung cancer (OAT) cells using soft-agar colony assay. A significant augmentation of delayed type hypersensitivity (DTH) response induced by SDK-12B-5 in comparison with the mixture of SDK-103 and 5-FU was seen when it was administered p.o. simultaneously with the immunization of sheep red blood cell (SRBC) in retired CD1 mice. From the studies on tissue distribution and pharmaco-kinetics of SDK-12B-5 by HPLC and ICP analysis. the persistence of SDK-12B-5 levels in serum and tumors was correlated with the findings that a maximum chemotherapeutic effect was obtained when SDK-12B-5 was administered p.o. repeatedly with every other day to avoid the cumulative toxicity.
Division of Chemotherapy, School of Medicine, Keio University.
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Fukushima
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005021:Ethylamines / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017646:Organosilicon Compounds; D011744:Pyrimidinones / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014183:Transplantation, Heterologous
D005021:Ethylamines; D017646:Organosilicon Compounds; D011744:Pyrimidinones; C061139:SDK 12B-5; C061138:((2-dimethylphenylsilyl)ethylthio)ethylamine; C017367:carmofur; D005472:Fluorouracil