Myeloid clonogenic assays for comparison of the in vitro toxicity of alkylating agents.
A battery of clonal assays for myeloid progenitor cells (HPP-CFC, CFU-gemm, CFU-gm, CFU-g) was utilized to evaluate the myelotoxicity of a series of alkylating agents representing the spectrum of clinical times to nadir. Bone marrow aspirates from normal volunteers were incubated with mechlorethamine, busulfan, melphalan, carmustine or lomustine for 1 h and then cultured in methylcellulose with 30% serum and cytokines. There was a concentration-dependent inhibition of colony formation and often a differential toxicity to the myeloid progenitors with the alkylators tested. On a molar basis, mechlorethamine and melphalan were the most toxic of the alkylator drugs to the myeloid precursors. The most sensitive progenitor was CFU-gemm with the lowest inhibitory concentration IC(70) concentrations for mechlorethamine, melphalan, carmustine and lomustine. Generally, there was great similarity for drug effects between CFU-g and CFU-gm with overlapping inhibition curves. HPP-CFC proved to be the least sensitive of the progenitors to the toxic actions of the drugs. While there was no correlation between the time to clinical neutropenic nadir and the most sensitive progenitor in the clonal assays, the CFU-gm assay remains a suitable method for determining the myelotoxic potential of cytotoxic agents.
Volpe
D A
DA
Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, 5600 Fishers Lane, 20857, Rockville, MD, USA. volpe@cder.fda.gov
Warren
M K
MK
D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D018929:Cell Culture Techniques; D006801:Humans; D023461:Myeloid Progenitor Cells / Q000187:drug effects*; D009503:Neutropenia / Q000139:chemically induced; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods
D018906:Antineoplastic Agents, Alkylating