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Spicamycin, induced differentiation of human myeloid leukemia cells (HL-60), is found to show a potent antitumor activity by inhibiting protein synthesis. Among the various semisynthetic derivatives of spicamycin, KRN5500 showed a marked efficacy in human tumor xenograft model. KRN5500 itself has, however, only minor inhibitory effects on protein synthesis in cell free system. A metabolite, SAN-Gly, which is thought to be generated through metabolism of KRN5500 by a cytosomal enzyme, exhibited a marked inhibitory effect. KRN5500 is expected to be useful even for treatment of refractory solid tumors because of its unique antitumor mechanism. A phase I clinical trials underwent at the National Cancer Center Hospital in Tokyo and at the National Cancer Institute in the USA. Unfortunately, the drug toxicities in addition to grade 4 pulmonary disorders were occurred, partly caused by the organic solvents and chemical essential for its dissolution. To overcome such a severe adverse effects, we conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce a pulmonary disorder using a bleomycin (BLM)-induced lung injury rat model or exhibit antitumor activity similar to KRN5500. In conclusion, this study demonstrated that KRN/m is superior to KRN5500 because the pulmonary toxicity was reduced and the potent antitumor activity of KRN5500 was retained after the incorporation of KRN5500 into micelles. We think that these results justify a clinical phase I trial of KRN/m.


Yasuo Mizumura. Spicamycin derivative]. Nihon rinsho. Japanese journal of clinical medicine. 2006 Feb;64(2):322-8

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PMID: 16454188

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