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Specificity of heme for hemopoietic recovery from AZT toxicity
The toxicity of azidothymidine (AZT) was studied on normal human bone marrow hemopoietic colony growth as determined by assays of CFU-E, BFU-E, and CFU-GM. The potential sparing effect of hemin and heme analogues on AZT-suppressed bone marrow was also investigated. AZT at a lower concentration (0.1 mumol/L) inhibited CFU-E by 68%, BFU-E by 84%, and CFU-GM by 59%. AZT at a higher concentration (1.0 mumol/L) inhibited CFU-E by 88%, BFU-E by 90%, and CFU-GM by 69%. Addition of hemin (10 mumol/L) to cultures containing AZT (0.1 mumol/L) increased CFU-E growth by 279%, BFU-E by 282%, and CFU-GM by 72%. A similar concentration of heme analogues did not have an enhancing effect; in contrast, zinc protoporphyrin (ZnPP) was inhibitory to bone marrow progenitors CFU-E, BFU-E, and CFU-GM. In addition, no enhancement of colony growth was obtained when progenitor cells were cultured in the presence of 10(-2)-10(-5) M iron. These results demonstrate that exogenous hemin has a specific beneficial effect on human bone marrow hematopoietic progenitor cells which is not seen with iron or other metalloporphyrins. Furthermore, this beneficial effect includes a reversal of the cytotoxic effect of AZT on bone marrow progenitors.
The toxicity of azidothymidine (AZT) was studied on normal human bone marrow hemopoietic colony growth as determined by assays of CFU-E, BFU-E, and CFU-GM. The potential sparing effect of hemin and heme analogues on AZT-suppressed bone marrow was also investigated. AZT at a lower concentration (0.1 mumol/L) inhibited CFU-E by 68%, BFU-E by 84%, and CFU-GM by 59%. AZT at a higher concentration (1.0 mumol/L) inhibited CFU-E by 88%, BFU-E by 90%, and CFU-GM by 69%. Addition of hemin (10 mumol/L) to cultures containing AZT (0.1 mumol/L) increased CFU-E growth by 279%, BFU-E by 282%, and CFU-GM by 72%. A similar concentration of heme analogues did not have an enhancing effect; in contrast, zinc protoporphyrin (ZnPP) was inhibitory to bone marrow progenitors CFU-E, BFU-E, and CFU-GM. In addition, no enhancement of colony growth was obtained when progenitor cells were cultured in the presence of 10(-2)-10(-5) M iron. These results demonstrate that exogenous hemin has a specific beneficial effect on human bone marrow hematopoietic progenitor cells which is not seen with iron or other metalloporphyrins. Furthermore, this beneficial effect includes a reversal of the cytotoxic effect of AZT on bone marrow progenitors.