CHARACTERISTICS OF THE ANTITUMOR-ACTIVITY OF M-16 AND M-18, MAJOR METABOLITES OF A NEW MITOMYCIN-C DERIVATIVE KW-2149, IN MICE

The cell growth inhibitory activity, antitumor activity and toxicity o f M-16 and M-18, the major metabolites of a new mitomycin C (MMC) deri vative 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 S-3 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 con dition, whereas that of KW-2149 and M-18 was reduced. M-16 also exhibi ted almost equivalent activities to MMC in vivo in terms of many biolo gical 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 i ndicate 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 invo lvement 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 unl ikely. Thus the biological activities of KW-2149 in mice are not expla ined by the M-16 or M-18 concentration in plasma and are postulated to be manifested by KW-2149 itself.