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.
BACKGROUND
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).


OBJECTIVE
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 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.


RESULTS
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.


CONCLUSIONS
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%.


CONCLUSIONS
We plan to evaluate the potential therapeutic benefit of a 25% increase in radioantibody dose in a tumor-bearing mouse model.
Blumenthal
R D
RD
Garden State Cancer Center and Center for Molecular Medicine and Immunology, Newark, N.J. 07103.
Sharkey
R M
RM
Goldenberg
D M
DM
D000704:Analysis of Variance; D000818:Animals; D001855:Bone Marrow Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000627:therapeutic use*; D007958:Leukocyte Count / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011994:Recombinant Proteins / Q000627:therapeutic use
D007375:Interleukin-1; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor