REDUCED BONE-MARROW TOXICITY OF KW-2149, A MITOMYCIN-C DERIVATIVE, IN MICE

The bone marrow toxicity of KW-2149, a newly synthesized mitomycin C (MMC) derivative, was compared with MMC in different aged ddY mice. Both MMC and KW-2149 exhibited a similar type of leukopenia in young adult mice. However, in mature adult mice, the recovery from leukopenia was rapid in KW-2149-treated mice, whereas in the MMC-treated mice, it was delayed. The difference between KW-2149 and MMC was more significant in thrombocytopenia in mature mice, and that induced by KW-2149 was mild, whereas that by MMC was severe and delayed. This reduced bone marrow toxicity of KW-2149 in mature mice was confirmed by the assay of colony-forming units in culture, progenitors of granulocytes or macrophages, and megakaryocytic colony-forming units, progenitors of platelets, in the bone marrow cells. The bone marrow toxicity and lethal toxicity of MMC was augmented by weekly intermittent treatment; in contrast, that of KW-2149 was not, suggesting that bone marrow toxicity may have a critical role in the lethal toxicity of MMC. The non-cumulative bone marrow toxicity of KW-2149 enabled the weekly intermittent treatment of human lung adenocarcinoma L-27 inoculated into nude mice. Thus its antitumor activity was greater than with single treatment.