SPK-241

The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)‐Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time‐ and dose‐dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra‐bone injection of INA‐6 cells to subcutaneously implanted rabbit bones (SCID‐rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID‐rab model. These results suggest that KRN5500 exerts anti‐MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.

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.