336 Journal of Leukocyte Biology Volume 51, April 1992 In vitro modulation of the toxicity associated with the use of zidovudine on normal murine, human, and murine retrovirus-infected hematopoietic progenitor stem cells with basic fibroblast growth factor and synergistic activity with interleuki n-i Vincent S. Gallicchio, Nedda K. Hughes, and Ben C. Hulette Hematology/Oncology Division, Departments of Medicine, Microbiology and Immunology, and Clinical Sciences, Lucille P Markey Cancer Center, University of Kentucky Medical Center and Veterans Administration Medical Center, Lexington, Kentucky Abstract: The antiviral drug used in the treatment of acquired immunodeficiency syndrome, zidovudine, has proved effective in ameliorating the morbidity and mor- tality associated with human immunodeficiency virus in- fection. However, associated with zidovudine is the de- velopment of severe bone marrow toxicity manifested by anemia, neutropenia, and occasionally thrombocytope- nia. We report the results of studies that demonstrate the ability of basic fibroblast growth factor (B-FGF) to reduce zidovudine toxicity to several classes of hematopoietic progenitors (granulocyte-macrophage, CFU-GM; mega- karyocyte. CFU-Meg; and erythroid, BFU-E) from nor- mal murine, human, and murine retrovirus-infected bone marrow cells when cocultured with zidovudine in vitro. Optimal response to B-FGF was observed at a dose concentration of 10 ng/ml. The specificity of B-FGF was demonstrated in the presence of protamine sulfate, an effective inhibitor of B-FGF mitogenic activity. In addi- tion, synergistic activity of B-FGF on zidovudine- induced hematopoietic stem cell toxicity was observed in the presence of interleukin 1 (IL-i) (30 ng/ml). These studies demonstrate that B-FGF is capable of reducing the hematopoietic toxicity associated with zidovudine and that such an effect can be amplified in the presence of IL-i. J. Leukoc. Biol. 51: 336-342; 1992. Key Words: basic Jibroblast growth factor (B-FGF) interleukin 1 zidovudine toxicity hematopoieiic stem cells INTRODUCTION The drug zidovudine (3’-azido-3-deoxythymidine, AZT), a synthetic thymidine analogue, has been used clinically in the management of acquired immunodeficiency syndrome (AIDS) [48]. The drug is an effective inhibitor of viral reverse transcriptase activity because of its altered chemical structure, with an azido group in place of a hydroxyl group at the 3’-carbon position in the basic sugar molecule [31]. This alteration results in inability of newly synthesized nucleotides to be effective in attachment to continue the 5’-to-3’ phosphodiester linkage necessary to synthesize DNA. Although zidovudine has been demonstrated clinically to in- duce immunological improvement, decrease the incidence of opportunistic infections, and reduce mortality in AIDS [5], its use has been associated with suppression of hematopoiesis [6, 9, 21, 25, 26, 38, 46]. Studies have shown that this toxicity is due to inhibition of hematopoietic progenitors-e.g., hu- man CFU-GM [4, 42]; CFU-E, BFU-E, and CFU-Meg [14]; and murine CFU-S, CFU-GM, and BFU-E-following ad- ministration in vivo [2]. Drug toxicity is the result of produc- ing pyrimidine starvation by depleting both intracellular thymidine triphosphate and deoxythymidine pools, although this effect has remained controversial [5, 42]. The antiviral activity of zidovudine was first demonstrated in mice in- fected with Rauscher leukemia virus (RLV) [39]. This model determined the effectiveness of zidovudine inhibition of retroviral reverse transcriptase activity. In studies conducted using this RLV model, zidovudine prevented infection of splenocytes, the development of splenomegaly, and increased mortality. Hematopoietic progenitor stem cell proliferation and differentiation is modulated by specific growth factors termed hematopoietins, such as colony-stimulating factors [3, 41] and interleukins [37]. These factors are produced and released by such accessory cells as monocytes-macrophages, T cells, and fibroblast-reticulum cells. In addition, these poietins can act synergistically on several aspects of hematopoieses. For instance, interleukin 1 (IL-i) is a multi- functional cytokine that can potentiate hematopoiesis [16, 28] by increasing granulocyte-macrophage colony-stimulating factor (GM-CSF) synthesis [1, 13, 49], supporting the sur- vival of early hematopoietic progenitors [32], and acting syn- ergistically with GM-CSF to stimulate primitive hematopoietic progenitors (i.e., CFU-S) [15]. Pertinent to the results reported here, previous findings from this laboratory have demonstrated that IL-i reduces the hematopoietic toxicity associated with zidovudine when combined with normal bone marrow cells in vitro [14, 17]. Other interleukins have been investigated for synergism when combined with a number of the CSFs [5, 46]; however, Abbreviations: AIDS, acquired immunodeficiency syndrome; AZT, 3-azido-3-deoxythymidine; B-FGF, basic tibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; ID50, 50% inhibition dose; IL-I, interleukin 1; RLV, Rauscher leukemia virus. Reprint requests: Vincent S. Gallicchio, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, Rm # CC-406, 800 Rose Street, Lexington, KY 40536-0084. Received July 9, 1991; accepted September 16, 1991.