Comparative in vitro myelotoxicity of FCE 24517, a distamycin derivative, to human, canine and murine hematopoietic progenitor cells.
FCE 24517, a derivative of distamycin A, exhibits an unusual antitumor profile in experimental models. As part of its preclinical development, we evaluated the in vitro myelotoxicity of FCE 24517 to human, canine and murine hematopoietic cells. Marrow cells were exposed to the agent (2.7 x 10(-5) - 2.7 nM) for 4 h and then assayed in capillary (human) or Petri dish (canine, murine) clonal cultures. FCE 24517 inhibited myeloid (CFU-gm), erythroid (BFU-e, CFU-e) and megakaryocytic (CFU-meg) colony formation in a concentration-dependent manner. The progenitor cells were generally similar in their response to FCE 24517 within a species. Comparing the different progenitor cell response to FCE 24517, canine CFU-gm and CFU-e were 26- to 221-fold more sensitive to this drug's toxic effects than their human and murine counterparts. This was demonstrated by extremely low IC70 values for the canine CFU-gm (0.001 nM) and CFU-e (0.007 nM). Murine progenitors displayed 1.3- to 10.9-times higher IC70 values than human CFU-gm, BFU-e and CFU-e following 4 hr exposure to FCE 24517. The data demonstrated that a mouse model may better predict human in vitro myelotoxicity to FCE 24517 than beagle dogs.
Volpe
D A
DA
Hipple Cancer Research Center, Dayton, OH.
Du
D L
DL
Zurlo
M G
MG
Mongelli
N
N
Murphy
M J
MJ
D000818:Animals; D001855:Bone Marrow Diseases / Q000139:chemically induced; D003114:Colony-Forming Units Assay; D004214:Distamycins / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000633:toxicity*
D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine