Antitumor effects of alpha-interferon and gamma-interferon on a murine renal cancer (Renca) in vitro and in vivo.
Previous studies have shown that established murine renal cancer (Renca) can be successfully treated with the investigational drug flavone acetic acid (FAA) used in combination with recombinant interleukin 2 (IL-2). Additional experiments demonstrated that the in vivo administration of FAA rapidly induced the expression of the genes, as well as the biologically active proteins, for alpha- and beta-interferons (IFNs) as well as tumor necrosis factor alpha. Both IFN-alpha and IFN-gamma have been shown to have direct antiproliferative effects against some tumors, as well as being potent immunodulators for the induction of antitumor effector cells. Thus, the present study was designed to investigate the ability of IFN-alpha and/or IFN-gamma to mediate direct antiproliferative effects against Renca in vitro as well as to cause regression of Renca in vivo. The present study confirms that RAA and/or IL-2 are inactive against Renca in vitro, further suggesting an indirect mechanism for FAA-induced antitumor effects in vivo. However, the exposure of Renca in vitro to recombinant human IFN-alpha A/D, murine IFN-alpha or murine IFN-beta resulted in a dose dependent growth inhibition of Renca as assessed by the microculture tetrazolium dye incorporation assay. Very little growth inhibition was induced by recombinant murine IFN-gamma. Interestingly, IFN-alpha (100-1000 units/ml) when combined with very low doses of recombinant murine IFN-gamma (1-10 units/ml) yielded significantly more pronounced growth inhibition than either cytokine alone. This effect was most evident by 5 days of culture where combinations of 100-1000 units/ml recombinant human IFN-alpha A/D with 1-5 units/ml recombinant murine IFN-gamma yielded growth inhibition in the range of 45-99%. In order to determine whether the mechanisms for the antitumor activity of recombinant human IFN-alpha A/D and recombinant murine IFN-gamma was due to their direct antiproliferative effects, we also studied the efficacy of these combinations against i.p. Renca in athymic mice. In contrast to the potent antitumor effects observed in euthymic mice, the combination of IFN-alpha and IFN-gamma only slightly increased mean survival times in athymic mice and no long term survivors were obtained. Subsequent studies demonstrated that most mice (77%) cured of peritoneal Renca by recombinant human IFN-alpha A/D plus recombinant murine IFN-gamma were immune to rechallenge. Therefore the combination of IFN-alpha and IFN-gamma may directly inhibit the growth of Renca, but a major effect of IFNs in vivo must be to contribute to the induction of an anti-Renca immune response.
Sayers
T J
TJ
Biological Carcinogenesis Development Program, NCI-Frederick Cancer Research Facility, Maryland 21701-1013.
Wiltrout
T A
TA
McCormick
K
K
Husted
C
C
Wiltrout
R H
RH
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000627:therapeutic use; D005419:Flavonoids / Q000494:pharmacology; D007370:Interferon Type I / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D005419:Flavonoids; D007370:Interferon Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D007371:Interferon-gamma; C049328:flavone acetic acid