Effect of Human Recombinant Interferon-α on the Activity of cis-Diamminedichloroplatinum(II) in Human Non-Small Cell Lung Cancer Xenografts

Abstract

Interferons (IFNs) augment the effect of some antitumor agents, including cisdiamminedichloroplatinum(II) (cDDP), in experimental systems. The effect of human recombinant interferon-alpha_2b (rIFNα) on the cDDP-dependent growth delay of a human non-small cell lung cancer established as a xenograft in nude mice (NX002) has been investigated. IFN (10⁵ IU/mouse, s.c.) as a single agent had no effect on the growth of the xenograft. cDDP (4.2 mg/kg, i.p.) caused a specific growth delay of 0.42, and this delay was significantly enhanced (to 1.08) by concomitant dosing with the otherwise inactive IFN. Possible mechanisms for this supra-additive relationship between IFN and cDDP have been investigated: increased intratumoral accumulation of platinum was seen at late time points (maximally at 36 hr) during the pharmacokinetic β-phase of cDDP elimination from the plasma of the nude mice. Tumor: plasma platinum concentration ratios at 36–48 hr indicated significantly increased accumulation of platinum in tumors from IFN-treated mice compared to controls (p < 0.05). Scheduling experiments suggest that this IFN-mediated effect can persist for 4 hr. These differences may account for the enhanced antitumor activity of cDDP when coadministered with IFN.