[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.