An Animal Model System for Investigating the AntiTumor Effects of Human Interferon

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Abstract
Human lymphoblastoid cell-derived alpha interferon, HuIFN-alpha N, strongly inhibited human breast carcinoma cells grown as xenografts in nude mice. This inhibition was dose dependent, required daily therapy and was manifested as a decline in tumor growth rate. Effects were generally reversible although tumors grew at a slower rate after therapy. Two studies indicated a direct effect of IFN on the tumor: 1) HuIFN therapy stimulated 2-5A synthetase levels in the tumor but did not effect mouse spleen cells; 2) HuIFN did not influence nude mouse NK cell activity. Mouse IFN also inhibited the growth of the tumor (which has a human karyotype) and preliminary studies indicate an indirect effect. Thus, combinations of mouse and human IFNs may improve the model. This system has been used to screen new IFNs and IFN/drug combinations and results of such experiments are described. In particular, combinations of low doses of cyclophosphamide and HuIFN-alpha were strongly synergistic and resulted in "cure" of tumors which had never been seen with either agent alone at these doses. Metabolism of cyclophosphamide may be affected by homologous IFN and experiments on the addition of mouse IFN to the combination, and on mechanisms of the synergism are reported.