Activation of 2′,5′-oligoadenylate synthetase and B-2 microglobulin in cancer patients treated with partially pure gamma interferon: Dependence of biological effect on administration route

Partially pure immune (gamma) interferon (IFN-gamma) was administered to patients intramuscularly (IM), by rapid IV bolus, and by 6-h continuous infusion as part of a phase I clinical trial. The activity of 2′,5′-oligoadenylate synthetase (2,5 A) in peripheral blood cells and the concentration of beta-2 microglobulin (B-2M) in serum were monitored as indicators of interferon biological activity in vivo. Five patients received IFN-gamma by the IM route in doses ranging from 6.5×10⁵ to 9.6×10⁶ antiviral units daily. There was little induction either of serum B-2M or of 2,5A in peripheral blood cells. Eight patients received IFN-gamma by rapid (5 min) IV bolus infusion in doses ranging from 6.5×10⁵ to 54×10⁶ antiviral units daily. As with IM administration, there was little significant induction of 2,5A synthetase, but the concentration of B-2M was increased above pretherapy values in most patients. Eleven patients received IFN-gamma by 6-h infusion daily for 10 days at a dosage of 27×10⁶ units/day. In contrast to IM and IV bolus administration, 6-h infusion of IFN-gamma resulted in significant induction of both B-2M serum concentration and of 2,5A activity in all patients. The induction of 2,5A was highest on days 2 and 4 of therapy and decreased to pretherapy values by day 7. During the second 10-day course of the infusion study 2,5A activity was not induced until day 7 of therapy, and it decreased rapidly thereafter. These studies show clearly that consistent biological activity such as B-2M activation and specific intracellular biochemical events such as 2,5A induction may be optimally obtained by the administration of IFN-gamma by continuous IV infusion.