Protective action of polyinosinic-polycytidylic acid in viral and transplanted leukemia in mice

Abstract

The inhibitory effects of polynucleotides on leukemia development and transplantability have been studied. RFM/Un mice, injected neonatally with leukemogenic Graffi virus, received 0.02 mg polyinosinic-polycytidylic acid (Poly I:C) intraperitoneally, twice a week, for two months starting 24 hrs after virus injection. Leukemia incidence in treated mice was significantly reduced, i.e., 56% with a mean latent period of 19 weeks as compared to 87% and 15 weeks latency in the control animals. RFM/Un adult mice, injected intravenously with different cell doses of two transplantable syngeneic leukemias, received four doses of 0.1 mg Poly I:C on alternate days starting 24 hrs after cell transplant. The evaluation of neoplastic nodules on the spleen surface according to the method of Bruce and Van Der Gaag (2) was the parameter of leukemic growth. Mice receiving Poly I:C showed a marked reduction in spleen nodule counts for all cell doses of both leukemia lines and histological examination of the spleen confirmed actual decrease in leukemic foci and disclosed enlargement of germinal centers and periarteriolar areas of lymphoid follicles. To investigate whether Poly I:C is capable of abolishing the state of immunological tolerance (operationally speaking) to cellular virus-induced antigens (CBA x C57BL)F1 adult mice, injected neonatally with Graffi virus, received 0.20 mg Poly I:C i.p. together with 104 or 105 cells from a syngeneic transplantable leukemia originally induced by Graffi virus. No differences in leukemic deaths were observed between Poly I:C treated virus-injected animals and controls, even though normal mice receiving Poly I:C and 10* cells showed 50% survival compared to 0% in control groups. Leukemic cells incubated in vitro in HE-MEM containing 0.1, 1, 10 or 100 μg Poly I:C/ml for 2, 4, 8 and 24 hrs (37 °C, 5% CO2) did not exhibit significant changes in viability as evaluated by phase contrast microscopy. On the basis of present and previous results (6), the possible mechanisms of antineoplastic action exerted by polynucleotides are discussed. It is concluded that while interferon production by synthetic RNAs may represent a major inhibiting factor in virus-induced tumors, non specific stimulation of immune reactivity and direct effect on cell metabolism and replication may play a significant role in other neoplastic conditions.