krn-5500 and Breast-Neoplasms

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.

Topics: Animals; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Division; Colonic Neoplasms; Humans; Lung Neoplasms; Mice; Neoplasm Transplantation; Protein Synthesis Inhibitors; Purine Nucleosides; Rabbits; Stomach Neoplasms; Tumor Cells, Cultured

For intravenous (i.v.) injection of a water-insoluble antitumor drug, KRN5500, we have successfully incorporated KRN5500 into polymeric micelles. In the present study, in vitro and in vivo anti-tumor activity against several human tumor cell lines and toxicity in mice of polymeric micelles incorporating KRN5500 (KRN/m) were evaluated in comparison with those of the prototype KRN5500. KRN/m was found to express similar antitumor activity to KRN5500 in the in vitro and in vivo systems. However, the vascular damage and liver focal necrosis observed with KRN5500 i.v. injection were not seen when KRN/m was administered i.v. Therefore, we expect that KRN/m will be superior to KRN5500 for clinical use and that the methodology of polymeric micelle drug carrier systems can be applied to other water-insoluble drugs.

Topics: Animals; Antibiotics, Antineoplastic; Blood Vessels; Breast Neoplasms; Cell Survival; Chemical and Drug Induced Liver Injury; Colonic Neoplasms; Female; Heart; Humans; Injections, Intravenous; Liver; Lung; Mice; Mice, Nude; Micelles; Myocardium; Purine Nucleosides; Stomach Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured