Cytokinetic evaluation of the four-drug combination of bleomycin, vincristine, mitomycin c, and methotrexate (BOMM) in cultured burkitt'S lymphoma cells and human bone marrow

The four-drug combination of bleomycin, vincristine, mitomycin C and methotrexate produces a high response rate in patients with squamous cell carcinoma. In this study we have examined the cytokinetic effects of this drug combination in vitro and in human bone marrow in vivo. The in vitro analysis revealed that mitomycin C produces a concentration dependent slowing of S-phase transit with partial G2/M and G1/S blocks in cell cycle progression. A partially synchronized S-wave occurs 4-8 and 16-20 hours following a two-hour drug exposure. Bleomycin produces a dose dependent G2/M block during a 14-hour drug exposure. Drug removal did not result in appreciable cell cycle synchrony. In vitro exposure to the two drug combination resulted in loss of both the marked G2/M accumulation seen with bleomycin, and the partially synchronized S-phase waves seen following mitomycin C exposure. The sequential changes in bone marrow cytokinetics were determined in eight patients during and following administration of vincristine, mitomycin C and a continuous four-day infusion of bleomycin. The major cytokinetic changes observed were an increase in G2/M phase cells 18 hours following vincristine, and an increase in thymidine incorporation and S-phase cells 24 and 48 hours following the end of the bleomycin infusion. The clinical course of 24 patients was reviewed. Eleven patients who received methotrexate 36 to 42 hours following bleomycin had a subsequent median leukocyte nadir of 1.8 x 10(3)/mm3. Thirteen patients receiving methotrexate 60 to 72 hours after bleomycin had median leukocyte nadir of 3.9 x 10(3)/mm3. The objective response rates in the two groups was 75% and 80%, respectively. This study demonstrates that bone marrow cytokinetic analysis may allow schedule modification to avoid myelosuppression without loss of therapeutic activity.