KRN5500, (6-[4-Deoxy-4-(2E,4E)-tetradecadienoylglycyl]amino-L-glycero - beta-L-mannoheptopyranosyl]amino-9H-
purine), was semi-synthesized in an attempt to increase the
therapeutic effects of
spicamycin analogues. The present study evaluated the antitumor activity of
KRN5500 against murine
tumors and human
tumor xenografts.
KRN5500 prolonged the survival of
P388 leukemia- and
B16 melanoma-bearing mice but was marginally effective on
colon adenocarcinoma 26. The antitumor activity 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 parameters: the
tumor growth inhibition rate (TGIR) and the
tumor mass reduction by comparison with
mitomycin C (MMC, 6.7 mg/kg/day x 1,IV).
KRN5500 showed a marked efficacy in the human
tumor xenograft model. The overall response rate of 26
cancers to
KRN5500, evaluated by TGIR, was approximately equal to their response rate to MMC (72% vs. 73%). However, 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 were 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 significant reduction in
tumor mass (0.22-fold the starting volume). In the mode of action,
KRN5500 was found to show an inhibitory effect on
protein synthesis in P388 cells (IC50 1.5 microM). However,
KRN5500 was ineffective even at 170 microM in inhibition of
protein synthesis in rabbit reticulocyte lysates.(ABSTRACT TRUNCATED AT 250 WORDS)