Antitumor and cytocidal activities of a newly isolated benzenoid ansamycin, macbecin I.

Macbecin I showed marked antitumor activity against intraperitoneally (ip) inoculated leukemia P388, melanoma B16, and Ehrlich carcinoma in mice on ip administration. The maximum effect measured in terms of ILS% (increase of life span) was 97 at a daily dose level of 10 mg/kg for leukemia P388, 103 at 5 mg/kg for melanoma B16, and 206 at 10 mg/kg for Ehrlich carcinoma. The effect of macbecin I on leukemia L1210 was slight (39 ILS%) and no activity was observed against leukemia L5178Y or P388/P-3 (a line of P388 resistant to ansamitocin P-3), or MOPC-104E myloma. Three to six hours after administration of 0.5 mg/kg or more of macbecin I to mice bearing ascites leukemia P388 cells, typical karyorrhexis followed by cytolysis in P388 cells was observed. Cytocidal changes induced by macbecin I were also observed in cells which were temporarily prevented from entering mitosis by treatment with known antitumor agents such as 5-fluorouracil, cyclophosphamide, and neocarzinostatin, whereas such cytolysis was not observed in cells which were arrested in metaphase by treatment with ansamitocin P-3. Cytotoxicity of macbecin I to cultured KB cells was observed at doses of 10(-1) micrograms/ml and more. Reverse transcriptase and terminal deoxynucleotidyl transferase activities were not inhibited by macbecin I.