M. Kamishohara et al., ANTITUMOR-ACTIVITY OF A SPICAMYCIN DERIVATIVE, KRN5500, AND ITS ACTIVE METABOLITE IN TUMOR-CELLS, Oncology research, 6(8), 1994, pp. 383-390
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.