The cell growth inhibitory activity, antitumor activity and toxicity of
M-16 and M-18, the major metabolites of a new
mitomycin C (MMC) derivative
KW-2149, in mouse and human were compared with those of
KW-2149 or MMC in vitro and in vivo. The growth inhibitory activity of M-18, a symmetrical
disulfide dimer, against human uterine cervix
carcinoma HeLa S3 cells was almost equivalent to that of
KW-2149 and their IC50 values were about 10-fold smaller than that of MMC. The activity of
M-16, a methyl
sulfide form, was almost equivalent to that of MMC. The cell-killing activity of MMC and
M-16 was augmented in the hypoxic condition, whereas that of
KW-2149 and M-18 was reduced.
M-16 also exhibited almost equivalent activities to MMC in vivo in terms of many
biological profiles, i.e., antitumor activity against murine
P388 leukemia, ascitic or solid
B16 melanoma or human lung
carcinoma xenograft L-27, and bone marrow toxicity in mice. These in vitro and in vivo results indicate that the antitumor activity and toxicity of
KW-2149 might not be mediated by
M-16 in mice. On the other hand, M-18 exhibited almost equivalent activities to
KW-2149 in these regards, suggesting the involvement of M-18 in the
biological activities of
KW-2149. However, the small values of the area under the curve of M-18 in mice make this unlikely. Thus the
biological activities of
KW-2149 in mice are not explained by the
M-16 or M-18 concentration in plasma and are postulated to be manifested by
KW-2149 itself.