Cytokine intervention permits dose escalation of radioantibody. An analysis of myelostimulation by bolus versus continuous infusion of IL-1/GM-CSF.
BACKGROUND
The authors recently reported that a 12-day schedule (beginning 3 days before radioantibody treatment) of twice-daily dosing of rH-IL-1 (1 x 10(3) U/dose) and rM-GM-CSF (0.5 micrograms/dose) can reduce the magnitude and duration of radioantibody-induced myelosuppression, thereby permitting a 25-30% increase in the dose of radioantibody that can be administered without the dose proving lethal. In an effort to further reduce toxicity and escalate the tolerated dose, the authors altered the method of administration of cytokines from daily bolus dosing to continuous infusion by implantable osmotic pumps.


METHODS
A control group of mice was compared to five groups of mice that either did or did not receive a 340 microCi dose of radioantibody, and received no cytokines, cytokines by bolus dosing, or cytokines by continuous infusion. For 4 weeks, peripheral white blood cell and thrombocyte counts and thymus and spleen weights were taken, marrow cell number was monitored, and marrow colony-forming unit activity was evaluated weekly in the untreated control mice and the treated mice.


RESULTS
These studies demonstrated that after a dose of radioantibody, continuous dosing of cytokines resulted in higher white blood cell (WBC) and platelet values than if bolus delivery was used (day 7, WBC: 110% vs. 59%; day 14, WBC: 85% vs. 62%; day 21, WBC: 98% vs. 42%; day 7, platelets: 122% vs. 51%; day 14, platelets: 159% vs. 72%; day 21, platelets: 239% vs. 171%). A comparison of bolus versus continuous dosing in the absence of radioantibody indicated that spleen weight increased by 40-60% after continuous infusion of cytokines and by 20-25% after bolus dosing. The 20-30% decrease in thymus weight was similar with both dosing regimens. Colony-forming units (CFUs) in marrow increased from 30-35 in untreated mice to 50-55 in mice given cytokines by bolus injection, and to 150-180 in mice given continuous infusion of cytokines. Spleen CFUs exhibited an insignificant increase after bolus dosing of cytokines but increased almost fourfold after continuous dosing. Peak stimulation of marrow and spleen CFUs occurred 28 days after initiation of cytokine administration (2 weeks after cytokines administration was stopped). The probability of survival for 6 weeks after further dose escalation to 360 microCi I-131-MN-14 immunoglobulin G was 16.4% +/- 8.6% after bolus dosing and 58.1% +/- 11.3% after continuous infusion of cytokines.


CONCLUSIONS
Although continuous infusion of cytokines proved to be a better method of reducing hematopoietic toxicity, further dose escalation of radioimmunotherapy using the "pump" method of cytokine delivery was not possible. Cytokine intervention by either mode of delivery permits a 25% dose intensification without the dose becoming lethal. Further escalation is not feasible, possibly because of other end organ toxicity.
Blumenthal
R D
RD
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, New Jersey 07103.
Sharkey
R M
RM
Forman
D
D
Wong
G
G
Goldenberg
D M
DM
D000818:Animals; D001792:Blood Platelets; D001853:Bone Marrow; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003114:Colony-Forming Units Assay; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007261:Infusions, Intra-Arterial; D007267:Injections; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D007457:Iodine Radioisotopes / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000494:pharmacology
D002272:Carcinoembryonic Antigen; D007375:Interleukin-1; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor