Vol. 284, Issue 2, 449-454, February 1998

Efficacy of an Insulin-Like Growth Factor-Interleukin-3 Fusion Protein in Reversing the Hematopoietic Toxicity Associated with Azidothymidine in Mice¹

Marcos R. Difalco, Line Dufresne and Luis Fernando Congote

Endocrine Laboratory, Royal Victoria Hospital and Departments of Medicine and Biochemistry, McGill University, Montreal, Canada, H3A 1A1

The effect of 406, a novel fusion protein between the N-terminal sequence of the insect insulin-like peptide, bombyxin, human insulin-like growth factor II and mouse interleukin 3 was investigated in its capacity to abrogate the toxic effects of azidothymidine (AZT) in C57BL/6 mice. Mice receiving 2.5 mg/ml AZT in their drinking water were concurrently treated with daily s.c. injections of 14, 140 or 1400 ng 406 for 4 wk. AZT-treated mice had a lower total weight, hemoglobin content and white blood cells than non treated controls. 406 significantly increased the number of circulating white blood cells at all doses, and the optimal effects were observed at a dose of 140 ng/mouse. Using this optimal dose, 406 completely abrogated the AZT-mediated weight loss. The effects on erythroid cells depended on the severity of the AZT-induced anemia. The amounts of hemoglobin were equal or slightly lower than those of controls under conditions of mild anemia, but were significantly higher than controls under conditions of severe anemia. 406 significantly increased the number of all hematopoietic colony-forming cells in bone marrow and spleen, but the effects were particularly striking in granulocyte-macrophage precursors. Blood glucose levels did not change at optimal or suboptimal 406 doses but increased at a dose of 1.4 µg/mouse. These experiments demonstrate the usefulness of these IGF-cytokine fusion proteins, whose low cost production represents a significant advantage for future in vivo studies.