Microenvironmental toxicity of azidothymidine: partial sparing with hemin

Abstract

Azidothymidine (AZT) is a useful drug in management of AIDS. Nevertheless, its hematologic toxicity such as anemia and neutropenia present further complications to an already compromised hematopoietic state in patients. We studied the effects of AZT on human and murine bone marrow (BM) colony growth as determined by assays of CFU-E, BFU-E, CFU-GM, and fibroblastoid stromal (CFU-Fb) colonies. Cultures were grown in methylcellulose with growth factors and scored after three- to 14-day incubation. In general, murine marrow cultures were more sensitive to AZT as compared with human marrow. Furthermore, interindividual variation in toxicity to AZT was observed between marrow samples; 1 mumol/L AZT inhibited murine CFU-E, BFU-E, and CFU-GM by 98% to 100%, whereas human marrow was inhibited by 52%, 87%, and 65%, respectively. Lower concentrations of AZT (0.1 mumol/L) inhibited murine erythroid colony growth by 85% to 90%, whereas human growth was inhibited by only 39% to 52%. Myeloid colony inhibition was similar for human and murine systems. CFU-Fb growth was markedly suppressed (75%) by 1 mumol/L AZT. Hemin, at a concentration of 10 mumol/L, overcame some of the inhibitory effects of 1 to 0.1 mumol/L AZT without hindering antiviral activity. Inhibition of human CFU-E growth was completely overcome with hemin, whereas CFU-GM growth was recovered to 66% to 74% of control. A similar but less pronounced effect was observed for BFU-E. Furthermore, hemin does not decrease AZT's effects of HIV antigen content in vitro. We conclude that anemia and neutropenia, occurring as a result of AZT, may not be as pronounced in the presence of hemin. Furthermore, CFU-Fb was significantly reduced in the presence of low concentrations of AZT. This may indicate a major target site for BM toxicity since the stromal microenvironment may be responsible for maintaining short- and long-term hematopoiesis.

Inhibitory Effects of Kampo Medicine on Human UGT2B7 Activity

“…22) This causes serious hematologic toxicity such as anemia and leucopenia. 30) In combination with fluconazole, the plasma concentration of AZT glucuronide is decreased, which results in a higher plasma concentration and prolonged half-life of AZT. 31,32) Fluconazole inhibited AZT glucuronidation with 1.4 mM of Ki in HLM.…”

Nonclinical Toxicology Studies with Zidovudine: Acute, Subacute, and Chronic Toxicity in Rodents, Dogs, and Monkeys

“…Dainiak and his colleagues (1988) also demonstrated that ZDV impairs the proliferation of human hemapoietic progenitors and that erythroid precursors are particularly sensitive. Abraham et al (1989) demonstrated that ZDV suppresses human and mouse bone marrow colony growth (CFU-E, BFU-E, CFU-GM, and CFU-Fb) and that bone marrow colonies from mice were more sensitive than those from humans. They further showed that some of the inhibitory effects of ZDV could be overcome by the addition of hemin to the cultures.…”

Mutagenesis of key residues identifies the connection subdomain of HIV‐1 reverse transcriptase as the site of inhibition by heme

“…The antiviral properties of heme in the inhibition of replication of HIV‐1 as well as the enhancement of the antiviral action of AZT‐TP in bone marrow cultures from AZT‐resistant patients have recently been demonstrated [3]. Earlier studies have demonstrated that heme can exert a protective effect against the bone marrow toxicity of AZT‐TP [4–6]. Recent studies have also manifested that metalloporphyrins inhibit HIV‐1 RT activity in a noncompetitive manner with respect to deoxythimidine triphosphate and markedly enhance the inhibitory effect of AZT‐TP on HIV‐1 RT [7].…”