ANTITUMOR-ACTIVITY OF A SPICAMYCIN DERIVATIVE, KRN5500, AND ITS ACTIVE METABOLITE IN TUMOR-CELLS

KRN5500, ycero-beta-L-mannoheptopyranosyl]amino-9H-purine), was semi-s ynthesized in an attempt to increase the therapeutic effects of spicam ycin analogues. The present study evaluated the antitumor activity of KRN5500 against murine tumors and human tumor xenografts. KRN5500 prol onged the survival of P388 leukemia- and B16 melanoma-bearing mice but was marginally effective on colon adenocarcinoma 26. The antitumor ac tivity of KRN5500 (4 mg/kg/day x 5, IV) against xenografts of 10 human stomach, 14 colon and 2 esophageal cancers was evaluated with two par ameters: the tumor growth inhibition rate (TGIR) and the tumor mass re duction by comparison with mitomycin C (MMC, 6.7 mg/kg/day x 1, IV). K RN5500 showed a marked efficacy in the human tumor xenograft model. Th e overall response rate of 26 cancers to KRN5500, evaluated by TGIR, w as approximately equal to their response rate to MMC (72% vs. 73%). Ho wever, more tumors were reduced by KRN5500 than by MMC (52% vs. 39%). It is notable that the response rates of 14 colon cancers to KRN5500 w ere significantly higher than those to MMC, both in TGIR (69% vs. 58%) and in tumor mass reduction (46% vs. 23%). Among the tumors sensitive to KRN5500, COL-1 showed a marked response (TGIR 93%) and a significa nt reduction in tumor mass (0.22-fold the starting volume). In the mod e of action, KRN5500 was found to show an inhibitory effect on protein synthesis in P388 cells IC50 1.5 mu M). However, KRN5500 was ineffect ive even at 170 mu M in inhibition of protein synthesis in rabbit reti culocyte lysates. 4'-N-glycyl spicamycin amino nucleoside (SAN-Gly), w hich is an intracellular metabolite of KRN5500, exhibited a marked inh ibitory effect on protein synthesis in this cell-free system (IC50 2.3 mu M). Intracellular metabolism of [C-14]-KRN5500 to the active metab olite, [C-14]-SAN-Gly, in P388 cells was demonstrated by thin-layer ch romatography analysis. SAN-Gly showed a weaker cytotoxicity and a much lower intracellular incorporation than those of KRN5500. These result s suggest the intracellular conversion of KRN5500 to SAN-Gly to exert an antitumor effect. Because of this unique property and its excellent antitumor activity against human tumor xenografts, KRN5500 is an inte resting candidate to be a new antitumor drug.