Zidovudine plus sulfamethoxazole-trimethoprim adversely affects B lymphocyte maturation in bone marrow of normal mice.
Sulfamethoxazole-trimethoprim and zidovudine (AZT), drugs used often in combination in patients infected with HIV, were investigated for their effects on B cell development in a mouse model. BALB/c mice were randomized to receive oral doses of AZT, sulfamethoxazole-trimethoprim, or the combination via oral gavage for up to 28 days. Immune cell populations in the spleen, lung, and peripheral blood were examined, and toxicity to B lineage subtypes in the bone marrow was investigated by phenotypic analysis via flow cytometry. Pre-pro-B, pro-B, early pre-B, and late pre-B cells were assayed for apoptosis and analyzed for cell cycle profile. Total as well as B cell splenic and bone marrow cellularities were significantly decreased by using the drugs concomitantly, while B cell populations in the lungs and percentage in the peripheral blood were not affected. Combination therapy caused significant increases in apoptosis in B cells and granulocytes in the bone marrow, with the late pre-B cell population being the most depleted. The proliferative expansion and differentiation of early pre-B cells (B220+/CD43+/BP-1+/HSA+) to the late pre-B cell (B220+/CD43-/IgM-) stage was blocked, with early pre-B cells accumulating in the proliferative phases of the cell cycle. This apoptosis increase is likely due to elevated blood sulfamethoxazole concentrations that were observed in mice also receiving AZT. Concurrent sub-chronic administration of AZT and sulfamethoxazole-trimethoprim adversely affected B lymphocyte development in mouse bone marrow.
Feola
David J
DJ
Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY 40536, USA. djfeol2@email.uky.edu
Garvy
Beth A
BA
D000818:Animals; D019380:Anti-HIV Agents; D017209:Apoptosis / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000187:drug effects; D016130:Immunophenotyping; D007519:Isoantigens / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D051917:Leukosialin / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D019380:Anti-HIV Agents; C069449:BP-1 alloantigen; D007519:Isoantigens; D051917:Leukosialin; D015215:Zidovudine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D017493:Leukocyte Common Antigens