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

Background

In previous studies in a tumor-bearing hamster model, we demonstrated protection and rescue from radio-antibody-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).

Purpose

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.

Methods

We administered IL-1 for 7 days at 1 × 10 ³ U twice a day and GM-CSF starting on the same day for 12 days at a dose of 0.5 μg twice a day, alone or in combination. The doses of iodine 131 ( ¹³¹ I)-NP-4 IgG (anti-carcinoembryonic antigen monoclonal antibody) radioantibody used were 270, 340, and 370 μCi; the MTD in mice is 270 μCi. 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.

Results

A 25% increase to 340 μCi 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 μCi 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.

Conclusions

These studies are the first demonstration that cytokines could be used to reduce radioantibody-induced leukopenia and thrombo-cytopenia and to escalate the tolerated dose of radioantibody by 25%.

Implications

We plan to evaluate the potential therapeutic benefit of a 25% increase in radioantibody dose in a tumor-bearing mouse model. [J Natl Cancer Inst 84:399–407, 1992]