[Protein synthesis inhibitor--antitumor activity and mode of action of KRN 5500].
KRN 5500 is a new semi-synthetic antitumor compound derived from spicamycin and has a unique structure. The compound showed a broad spectrum of antitumor activity against human colon, stomach, esophageal, breast and lung cancer xenografts in nude mice. Therapeutic efficacy of KRN 5500 against liver metastasis of COL-1 human colon cancer scid mice was examined. The treatment with KRN 5500 inhibited tumor growth in the liver and reduced the serum TPA concentration to a normal level. KRN 5500 inhibits protein synthesis in rabbit reticulocyte lysates. Among several metabolites of KRN 5500, only SAN-Gly showed a potent inhibitory activity against protein synthesis in reticulocyte lysates. TLC analysis of KRN 5500 metabolites using 7 human colon cancer cell lines and 3 normal cell lines demonstrated a correlation between the cytotoxicity of KRN 5500 and converting activity from KRN 5500 to SAN-Gly. These results indicate that SAN-Gly is the intracellular active metabolite and that converting activity from KRN 5500 to SAN-Gly is the major determinant of KRN 5500 cytotoxicity.
Kawai
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Pharmaceutical Division, Kirin Brewery Co., Ltd.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011684:Purine Nucleosides / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013274:Stomach Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D011500:Protein Synthesis Inhibitors; D011684:Purine Nucleosides; C092296:KRN 5500