A comparison of three nucleoside analogs with anti-retroviral activity on immune and hematopoietic functions in mice: in vitro toxicity to precursor cells and microstromal environment.
A number of 2'3'-dideoxynucleosides have been reported to markedly inhibit the in vitro growth of HIV, the causative agent of acquired immunodeficiency syndrome (AIDS). Clinical trials have shown that the continued therapeutic use of these nucleoside derivatives can be associated with adverse side effects. Since these side effects include myelotoxicity, as occurs in many patients treated with zidovudine (AZT; 3'-azido'3-deoxythymidine), and AIDS patients already represent an immunologically compromised population, we examined the immunological effects of three nucleoside inhibitors, including zidovudine, 2'3'-dideoxycytidine, and 2'3'-dideoxyadenosine (DDA) in a mouse model. Additional studies were conducted to further determine and characterize the potential toxic effects associated with these drugs on the hematopoietic system. Of the three dideoxynucleosides examined, only DDA altered immune functions following a 30-day subchronic exposure in mice. This was evidenced by a marked suppression of the antibody plaque-forming cell response and a slight alteration in macrophage function. None of the nucleoside derivatives affected bone marrow function following in vivo exposure, although AZT produced a mild macrocytic anemia in vivo and was myelotoxic when added in vitro to bone marrow cell cultures. In vitro studies indicated that AZT was capable of affecting both proliferating stem cells as well as the stromal cell microenvironment, both of which play a role in hematopoiesis. These data indicate that, although the mice may not develop the identical toxicities associated with nucleoside therapy in humans, certain adverse immunological and hematological effects were readily discerned which could have relevance to humans.
Luster
M I
MI
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Germolec
D R
DR
White
K L
KL
Fuchs
B A
BA
Fort
M M
MM
Tomaszewski
J E
JE
Thompson
M
M
Blair
P C
PC
McCay
J A
JA
Munson
A E
AE
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D000937:Antigen-Antibody Reactions / Q000187:drug effects; D000998:Antiviral Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D016048:Dideoxyadenosine / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D006678:HIV / Q000187:drug effects / Q000254:growth & development; D006410:Hematopoiesis / Q000187:drug effects*; D007111:Immunity, Cellular / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013234:Stem Cells / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000627:therapeutic use / Q000633:toxicity*; D015215:Zidovudine / Q000627:therapeutic use / Q000633:toxicity*
D000998:Antiviral Agents; D015215:Zidovudine; D016048:Dideoxyadenosine; D016047:Zalcitabine