INCREASED HEMATOPOIETIC TOXICITY FOLLOWING ADMINISTRATION OF INTERFERON-(A)OVER-CIRCLE WITH COMBINATION DIDEOXYNUCLEOSIDE THERAPY (ZIDOVUDINE PLUS DDI) ADMINISTERED IN NORMAL MICE

Because of the urgency to develop drugs which will effectively combat HIV infection, many combination therapies which have proved effective against HIV in vitro have undergone, or are undergoing clinical trial. Unfortunately many of drugs are being used without rigorous and exhau stive preclinical evaluation to assess their potential to develop hema topoietic toxicity. We report here the results of two in vivo studies performed to analyze the effect of combined zidovudine (AZT) plus dida nosine (ddI) therapy, either with or-without interferon-(a) over circl e (IFN-(a) over circle, on murine hematopoiesis. Normal C57BL/6 female mice were administered AZT (1.0 mg/ml) plus dose-escalation ddI (0.1, 1.0 and 2.5 mg/ml) placed in their drinking water. Control mice recei ved IFN-(a) over circle (100 units/ml) alone. Mice were serially bled and sacrificed over a six-week period for assessment of hematopoietic toxicity measured by peripheral blood indices and assays of hematopoie tic progenitors, i.e., erythroid (BFU-E), myeloid (CFU-GM), and megaka ryocyte (CFU-Meg) cultured from bone marrow and spleen. AZT plus dose- escalation ddI decreased the hematocrit and white blood cell count whe n administered to normal mice compared to untreated controls during th e six-week examination period. Marrow derived BFU-E, CFU-GM, and CFU-M eg were all reduced, however an increase was observed from the spleen for all three progenitor cell types. Use of IFN-(a) over circle, in ad dition to combination AZT plus ddI further decreased the hematocrit, w hite blood cells and platelets. Marrow derived CFU-GM and CFU-Meg were increased slightly and only marginally for BFU-E with a similar respo nse observed from the spleen. These results demonstrate that combinati on AZT plus ddI when used in vivo may produce synergistic hematopoieti c toxicity, and that the addition of IFN-(a) over circle to this treat ment regimen increases this toxicity. These data indicate caution when this therapeutic approach is suggested for patients infected with HIV . If used, these patients will require careful monitoring for blood ce ll toxicity.