Correlation of hematologic toxicity of antineoplastic agents with their effects on bone marrow stem cells:...

The effects of 22 anticancer agents on bone marrow granulocyte-macrophage-committed colony-forming cells (CFC) have been studied using the agar diffusion chamber (ADC) assay, which allows in vivo metabolism of the injected drug by the chamber-bearing mouse. Dose-response curves at 18 h were obtained using mouse, dog, and human bone marrow in the chamber, and mouse marrow in situ. Comparisons between intrinsic sensitivities of CFC from different species were thus possible, as were also comparisons of the effect of different drugs on the same species. When possible, correlations were made with available in vivo clinical or toxicologic data, using the effect of a single intravenous dose on the blood granulocyte concentration. Dose-response curves were either exponential or formed a plateau, the latter reflecting phase specificity of the agent being studied. Species CFC sensitivities were highly variable between different drugs and the order was not predictable. Good correlation between rank order of drug efficacy in vivo and in the assay was observed for drugs in the same species. Drugs with little or no myelosuppressive effects in vivo were likewise inactive in the assay (e.g., spirogermanium). Prospective trials of new agents in the drug development process (toxicology and phase-I clinical trials) using the ADC assay are warranted.