Da. Fowler et al., PROTECTION AND RESCUE FROM 2',3'-DIDEOXYPYRIMIDINE NUCLEOSIDE ANALOG TOXICITY BY HEMIN IN HUMAN BONE-MARROW PROGENITOR CELLS, Antimicrobial agents and chemotherapy, 40(1), 1996, pp. 191-195
Long-term therapy of AIDS patients with 3'-azido-3'-deoxythymidine (AZ
T) remains of concern because of resulting hematopoietic toxicity, Whi
le the mechanism(s) of this toxicity remains elusive, alternative stra
tegies are being developed to reduce these toxic effects, including co
mbination therapy with nonmyelotoxic antihuman immunodeficiency virus
drugs and/or administration of protective oi rescue agents, including
cytokines and growth factors. By using a particularly relevant human C
D34(+) liquid culture system, the unique profiles of dideoxynucleoside
(ddN) toxicities to both proliferation and differentiation were demon
strated, with decreased potencies in the order of 3'-fluoro-3'-deoxyth
ymidine (FLT) = 3'-amino-3'-deoxythymidine (AMT) 2',3'-dideoxycytidine
> AZT for inhibition of proliferation and in the order of FLT = AMT >
AZT much greater than 2',3'-dideoxycytidine for inhibition of hemoglo
bin synthesis, Hemin selectively protected erythroid-lineage human bur
st-forming unit-erythroid cells from AZT- and AMT-induced inhibition b
ut had no effect on FLT toxicity under similar conditions, Myeloid-lin
eage human CFU-granulocyte-macrophages were also not protected by hemi
n against all three ddN analogs, The simultaneous exposure of cells to
hemin and AZT resulted in a complete protection of both cell prolifer
ation and hemoglobin synthesis, In contrast, in reversal studies only
the inhibition of the percentage of hemoglobin-synthesizing cells retu
rned to control levels, but the inhibition of proliferation of cells p
reviously exposed to AZT was not reversed by hemin, These studies furt
her define the unique and multifactorial mechanism(s) of ddN-induced t
oxic effects during hematopoietic development of pluripotent stem cell
s and suggest that the use of hemin could be beneficial in alleviating
the toxicity of certain ddN analogs.