Dose escalation of radioantibody in a mouse model with the use of recombinant human interleukin-1 and granulocyte-macrophage colony-stimulating factor intervention to reduce myelosuppression.

Abstract

In previous studies in a tumor-bearing hamster model, we demonstrated protection and rescue from radioantibody-induced hematopoietic toxicity by treatment with interleukin-1 (IL-1) before or after radioantibody treatment, as well as attenuation of duration of myelosuppression by administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). The purpose of this study was to evaluate the ability of recombinant human IL-1 and recombinant murine GM-CSF to reduce myelosuppression and increase survival of non-tumor-bearing, female BALB/c mice while escalating the maximal tolerated dose (MTD) of radioantibody--the highest dose that results in no deaths. We administered IL-1 for 7 days at 1 x 10(3) U twice a day and GM-CSF starting on the same day for 12 days at a dose of 0.5 micrograms twice a day, alone or in combination. The doses of iodine 131 (131I)-NP-4 IgG (anti-carcinoembryonic antigen monoclonal antibody) radioantibody used were 270, 340, and 370 microCi; the MTD in mice is 270 microCi. The 12-day schedule of cytokine administration was initiated at various times with respect to the radioantibody dose: on the same day; 6 or 3 days before radioantibody; or 3, 6, or 9 days after radioantibody. Treatment efficacy was measured by survival and white blood cell and platelet counts. A 25% increase to 340 microCi of radioantibody used alone resulted in 100% lethality within 25 days of treatment. The optimal cytokine schedule was a 12-day treatment with the combination of cytokines initiated 3 days before radioantibody. This treatment resulted in 100% survival and significantly reduced the magnitude and duration of hematopoietic toxicity. The increase in radioantibody dose resulted in an 85%-95% decrease in peripheral white blood cells and a 75%-85% reduction in platelets within 14 days of radioantibody administration. Further dose escalation to 370 microCi of radioantibody used alone (37% increase above the MTD) resulted in lethality to 12% of the mice. IL-1 or GM-CSF alone was minimally effective. These studies are the first demonstration that cytokines could be used to reduce radioantibody-induced leukopenia and thrombocytopenia and to escalate the tolerated dose of radioantibody by 25%. We plan to evaluate the potential therapeutic benefit of a 25% increase in radioantibody dose in a tumor-bearing mouse model.