In vitro characterization of the myelotoxicity of cyclopentenyl cytosine.
We studied the toxicity of a new experimental anticancer drug, cyclopentenyl cytosine (CPE-C), to human and murine hematopoietic progenitor cells in vitro. Due to CPE-C's in vivo myelotoxicity, it was important to characterize its potential adverse effects on human marrow cells during preclinical development of the drug. Marrow cells were exposed to CPE-C for either 1 h prior to addition in clonal assays or continuously during their culture period. The inhibitory effects of CPE-C on myeloid (CFU-gm) and erythroid (CFU-e, BFU-e) colony formation were concentration- and time-dependent, with continuous CPE-C exposure being significantly more inhibitory than 1-h exposure. The results of both exposure experiments were combined to investigate colony inhibition as a function of overall drug exposure (concentration x time, AUC) and data analyzed by the nonlinear Emax equation. Human and murine CFU-gm had similar AUC-response curves and IAUC70 values (i.e., AUC at 70% colony inhibition) of 40.8 and 41.9 microM h, respectively. In contrast, murine CFU-e and BFU-e were more sensitive to CPE-C, having lower IAUC70 values (both, 21.1 microM h) than human CFU-e and BFU-e (107.8 and 33.0 microM h, respectively). This difference was most prominent with the late erythroid progenitor, CFU-e, in that the human cells were 5 times more resistant to inhibition by CPE-C. CPE-C was myelotoxic in vitro to human and murine marrow cells and toxicity correlated with overall drug exposure.
Volpe
D A
DA
Hipple Cancer Research Center, Dayton, OH 45439-2092.
Du
D L
DL
Grieshaber
C K
CK
Murphy
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002330:Carmustine / Q000633:toxicity; D002452:Cell Count / Q000187:drug effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003562:Cytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D013997:Time Factors
D000970:Antineoplastic Agents; D003562:Cytidine; C045911:cyclopentenyl cytosine; D002330:Carmustine