MYELOTOXIC EFFECTS OF THE BIFUNCTIONAL ALKYLATING AGENT BIZELESIN ON HUMAN, CANINE AND MURINE MYELOID PROGENITOR CELLS

Bizelesin is a potent synthetic derivative of the anticancer agent CC- 1065 that preferentially alkylates and binds the minor grove of DNA. P reclinical animal studies have found bizelesin to be more toxic to bea gle dogs than to rodents and that myelosuppression was the dose-limiti ng toxicity. This toxicity was dose- and time-dependent in all species . Due to the significant difference in the in vivo myelotoxicity betwe en species, it was important to determine which one most closely resem bles humans on a pharmacodynamic basis. Therefore, hematopoietic clona l assays were utilized to evaluate the effects of bizelesin on granulo cyte-macrophage (CFU-gm) colony formation. Marrow cells were exposed i n vitro to bizelesin (0.001-1000 nM) for 1 or sh and then assayed for colony formation. There was a 3-log difference in drug concentration a t which 100% colony inhibition occurred (1 or 8 h) for murine CFU-gm v ersus human or canine CFU-gm. The IC70 value after an 8-h bizelesin ex posure for human CFU-gm (0.006 +/- 0.002 nM) was 2220-times lower than for murine CFU-gm (13.32 +/- 8.31 nM). At any given concentration, an 8 h drug exposure resulted in greater colony inhibition than a 1 h ex posure for all species (P < 0.05). Increasing exposure time from 1 to 8 h increased toxicity to human and canine CFU-gm much more than to mu rine CFU-gm. The clinically formulated drug solution was a more potent inhibitor of human colony formation than drug dissolved in DMSO. The IC70 value after a 1-h exposure was 1.7 times lower for human CFU-gm w ith formulated bizelesin (0.106 +/- 0.105 nM) than bulk drug in DMSO ( 0.184 +/- 0.044 nM). The results of these in vitro clonal assays were qualitatively consistent with those seen in whole animal studies, sugg esting that bizelesin will be a potent myelosuppressive agent in the c linic. Since the dose-limiting toxicity in preclinical models is myelo suppression and the in vitro sensitivity of human and canine CFU-gm is similar, the canine maximum tolerated dose (MTD) is better than the m urine MTD to determine a safe starting dose for phase I clinical trial s.