ACCELERATION OF HEMATOPOIETIC RECONSTITUTION WITH A SYNTHETIC CYTOKINE (SC-55494) AFTER RADIATION-INDUCED BONE-MARROW APLASIA

The synthetic cytokine (Synthokine) SC-55494 is a high-affinity interl eukin-3 (IL-3) receptor ligand that stimulates greater in vitro multil ineage hematopoietic activity than native IL-3, while inducing no sign ificant increase in inflammatory activity relative to native IL-3. The aim of this study was to investigate the in vivo hematopoietic respon se of rhesus monkeys receiving Synthokine after radiation-induced marr ow aplasia. Administration schedule and dose of Synthokine were evalua ted. All animals were total-body irradiated (TBI) with 700 cGy Co-60 g amma radiation on day 0. Beginning on day 1, cohorts of animals (n = 5 ) received Synthokine subcutaneously (SC) twice daily with 25 mu g/kg/ d or 100 mu g/kg/d for 23 days or 100 mu g/kg/d for 14 days. Control a nimals (n = 9) received human serum albumin SC once daily at 15 mu g/k g/d for 23 days. Complete blood counts were monitored for 60 days post irradiation and the durations of neutropenia (NEUT; absolute neutrophi l count [ANC] <500/mu L) and thrombocytopenia (THROM; platelet count < 20,000/mu L) were assessed. Synthokine significantly (P < .05) reduced the duration of THROM versus the HSA-treated animals regardless of do se or protocol length. The most striking reduction was obtained in the animals receiving 100 mu g/kg/d for 23 days (THROM = 3.5 v 12.5 days in HSA control animals). Although the duration of NEUT was not signifi cantly altered, the depth of the nadir was significantly lessened in a ll animal cohorts treated with Synthokine regardless of dose versus sc hedule length. Bone marrow progenitor cell cultures indicated a benefi cial effect of Synthokine on the recovery of granulocyte-macrophage co lony-forming units that was significantly higher at day 24 post-TBI in both cohorts treated at 25 and 100 mu g/kg/d for 23 days relative to the control animals. Plasma pharmacokinetic parameters were evaluated in both normal and irradiated animals. Pharmacokinetic analysis perfor med in irradiated animals after 1 week of treatment suggests an effect of repetitive Synthokine schedule and/or TBI on distribution and/or e limination of Synthokine. These data show that the Synthokine, SC55494 , administered therapeutically post-TBI, significantly enhanced platel et recovery and modulated neutrophil nadir and may be clinically usefu l in the treatment of the myeloablated host. This is a US government w ork. There are no restrictions on its use.