7-Allyl-8-oxoguanosine (loxoribine) inhibits the metastasis of B16 melanoma cells and has adjuvant activity in mice immunized with a B16 tumor vaccine.
We have shown previously that loxoribine exhibits adjuvant activity for B cells, activates natural killer (NK) cells, and enhances the activation of lymphokine-activated killer cells by interleukin-2 (IL-2). In this study, we examined loxoribine for protective effects in a B16 melanoma lung tumor metastasis model. Significant inhibition of B16 metastasis was seen in mice given a single injection of 2 mg loxoribine as late as day 3 of tumor growth but the greatest inhibition (96%) was seen in mice given four injections of loxoribine on alternate days starting the day before tumor injection. In experiments in which both IL-2 and loxoribine were administered, both agents were active when tested alone, but the combination of IL-2 and loxoribine gave significantly greater inhibition of metastasis. Loxoribine partially inhibited the development of tumors in mice that had been depleted of NK cells by the administration of anti-asialo-GM1 or anti-NK1.1 antibodies and in NK-deficient beige mice. In all cases, protection was seen only when smaller tumor inocula were injected. Taken together, these data suggest that both NK and non-NK cell populations or effector mechanisms with antitumor activity were activated by loxoribine. Since substituted guanosine analogs have been shown to have adjuvant activity in B cell systems, we evaluated whether loxoribine was active as an adjuvant in a tumor protection model. Mice immunized with both irradiated tumor cells and loxoribine developed a significantly lower number of lung tumors when challenged by live B16 tumor cells, whereas mice injected with either vaccine or loxoribine alone were not protected. There was a clear dose response seen with both loxoribine and the vaccine preparations. These data suggest that loxoribine may be useful in tumor therapy as an immunomodulator or as an adjuvant for use with tumor vaccines.
Pope
B L
BL
R. W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.
Sigindere
J
J
Chourmouzis
E
E
MacIntyre
P
P
Goodman
M G
MG
D000276:Adjuvants, Immunologic; D000818:Animals; D005677:G(M1) Ganglioside / Q000276:immunology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control; D014612:Vaccines / Q000276:immunology
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D014612:Vaccines; D006151:Guanosine; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; C068562:loxoribine