[Antitumor effects of 5-fluorouracil-bound organic silicon compound].

Abstract

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.

• Authors: K Fukushima
• Journal: Gan to kagaku ryoho. Cancer & chemotherapy (Gan To Kagaku Ryoho) Vol. 16 Issue 9 Pg. 3243-50 (Sep 1989) ISSN: 0385-0684 [Print] Japan
• PMID: 2782916 (Publication Type: Journal Article)

Chemical References

• Ethylamines
• Organosilicon Compounds
• Pyrimidinones
• SDK 12B-5
• ((2-dimethylphenylsilyl)ethylthio)ethylamine
• carmofur
• Fluorouracil

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use)
• Breast Neoplasms (drug therapy)
• Colonic Neoplasms (drug therapy)
• Ethylamines (therapeutic use)
• Female
• Fluorouracil (analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy)
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Mice, Inbred Strains
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy)
• Organosilicon Compounds
• Pyrimidinones (therapeutic use)
• Sarcoma, Experimental (drug therapy)
• Transplantation, Heterologous