Interferon Induction and Therapy of Brain Tumors in Rats by Poly(ICLC)

Several investigators have tried to induce interferon with poly(I) -polyjC) in man (2-4, 11). None of them have been able to prove it to be a satisfactory interferon inducer for clinical use. Although a severe toxic effect was seen in some animals (10), Freeman et al (3) stated that toxicity of polyf Ij-polyfC) is acceptable for man at a dose of 9 mgjkg, at which it is lethal for dogs (10) and rabbits (unpublished data). Thus, toxicity of polyf Ij-polyt C) seems to vary with the species. In addition, Guggenheim and Baron (4) pointed out that polyf lj-polyfC] is rather safe but that the low titers of interferon induced might limit its clinical usefulness. Since Levy and his co-workers (7,8, 12) reported that poly(ICLC), polyf Ij-polyjC) stabilized with poly-r-Iysine and carboxymethylcellulose, induces a high level of interferon in primates, it has been expected to be a potent interferon inducer appropriate for clinical use. Toxicological studies have shown that the inducer is as tolerable as polyfIj-polyjC) in monkeys (8) and more tolerable than polyfl i-poly (C) in cats (14). In the present paper, the interferon-inducing and antitumor activities of poly(ICLC) in rats are described in comparison with those of the parental compound, poly(I)·poly(C). Poly(I) (molecular size, 6S) and poly(C) (molecular size, 9S) (Yamasa Shoyu Co., Ltd.) dissolved in pyrogen-free saline were mixed after filtration through a membrane filter. The molecular size of the resulting poly(I)'poly(C) is 15S. By using this polyjIj-polyfC) preparation, poly(ICLC) was prepared according to the method of Levy et al (8) with a slight modification: 2 or 3 mg of poly-r.-lysine (Miles Laboratories, Inc., Elkhart, Ind., molecular weight 26,000) per ml of saline was poured slowly, with stirring, into an equal volume of saline containing 1% carboxymethylcellulose sodium salt (CMC; Nakarai Chemicals, Ltd., Kyoto, molecular weight 135,000) to make a poly-t-Iysine-ClvfC solution. Then 2 mg of the polyt Ij-polyf C) solution per ml was poured slowly, with stirring, into an equal volume of the poly-r-Iysine-Clvlt.l solution. The solution thus obtained contained I mg of poly(I) -polyt C) and 0.5 (poly(ICLC)-B) or 0.75 (poly(ICLC)-A) mg of poly-r-lysine per ml in 0.25% CMC. The amount of inducer was expressed in terms of poly(I) -polyfC) in the preparations.