Successful immunotherapy of murine melanoma metastases with 7-thia-8-oxoguanosine.
We have recently reported that a synthetic nucleoside, 7-thia-8-oxoguanosine (7T8OG) is a potent activator of a number of effectors which are involved in anti-tumor immune responses. 7T8OG was found to induce interferon (IFN) production, to activate asialo-GM1 positive (AGM+1) killer cells, and to enhance specific antibody responses. In the present study, we investigated the effect of 7T8OG on growth of the murine pulmonary B16 melanoma and on formation of metastases. C57BL/6 mice were injected i.p. with 50-150 mg/kg 7T8OG before or after i.v. inoculation of B16 melanoma tumor cells, and 17-19 days after tumor inoculation, the number of metastases in the lungs were counted. 7T8OG given systemically in a single or a divided dose 24 h prior to the challenge of tumor cells reduced the number of lung tumor metastases by 89-99% which is highly significant as compared to untreated control (P less than 0.001). Occasional extra pulmonary tumor growth in the thoracic cavity and neck lymph node was also completely inhibited. The reduction in the number of tumor nodules was dose dependent. A single dose of 150 mg/kg of 7T8OG was also effective in inhibiting the growth of 3-5 day old metastatic tumors. The cytotoxic activity of killer cells induced in vivo by 7T8OG was completely abolished by in vitro treatment of cells with anti-AGM1 antibody plus complement. Administration of anti-AGM1 antibody following the 7T8OG treatment completely abrogated the anti-tumor effect of 7T8OG, resulting in a massive increase in the number of tumor foci in the lungs. Administration of carageenan or silica followed by injection of 7T8OG caused a significant increase (P less than 0.01) in the number of pulmonary tumor nodules compared to treatment with 7T8OG only. These findings indicate that activated macrophages or perhaps their cytokine (tumor necrosis factor) also contribute to the host tumor defense by 7T8OG.
ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626.
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Sharma
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Balazs
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Jin
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Jolley
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Robins
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005677:G(M1) Ganglioside / Q000276:immunology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use; D007111:Immunity, Cellular; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL
D000276:Adjuvants, Immunologic; D000906:Antibodies; D006151:Guanosine; D005677:G(M1) Ganglioside; C061136:isatoribine