Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide

Abstract

Transfection of cDNA for IL‐10 into line 66.1 murine mammary tumor cells results in marked suppression of tumor growth and metastasis. Others have reported that nitric oxide has potent antitumor activity and IL‐10 is known to regulate the inducible isoform of nitric oxide synthase (iNOS) expressed in macrophages. We identified nitric oxide production in mammary tumors as indicated by electron paramagnetic resonance detection of nitric oxide‐hemoglobin (NO‐Hb). IL‐10 expression resulted in elevated levels of NO‐Hb in mammary tumors. Immunohistochemical examination of mammary tumors for iNOS protein revealed few positively staining cells in parental or control neo‐transfected tumors but strong iNOS staining in all IL‐10 transfected tumors, consistent with the NO‐Hb data. To determine if mammary epithelial tumor cells themselves, express nitric oxide synthase activity, cultured tumor cells were treated with pro‐inflammatory cytokines and nitrite accumulation was assessed in the conditioned medium. All IL‐10 producing cell lines accumulated uM concentrations of nitrite in response to short term (24 hr) cytokine stimulation. Cells not expressing IL‐10 (parental and neo‐transfectants) accumulated no nitrite under similar culture conditions. After longer stimulation (48 hr), parental and 66‐neo cells accumulated lower amounts of nitrite. IL‐10 gene transfer is associated with increased iNOS protein expression and enzymatic activity detected both in vitro<0R> and in vivo<0R>. Our findings suggest that the antimetastatic and antitumor activity of IL‐10 is related to enhanced production of nitric oxide. Int. J. Cancer 76:713–719, 1998.© 1998 Wiley‐Liss, Inc.

Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo

“…Overexpression of MDA-7 in lung tumor cells resulted in downregulation of VEGF and transforming growth factor-beta (TGF-b) mRNA (data not shown), all known modulators of angiogenesis (Rowe et al, 2000;Jain et al, 1996;Roberts and Sporn, 1989). It is also possible that mda-7, which shares low level of homology with interleukin 10 (IL-10) inhibits angiogenesis similar to that observed with IL-10 ( Kundu et al, 1998). Since the exact function of mda-7 and its interactions with other genes are unknown, we evaluated the e ects of Ad-mda7 on the expression of other genes by microarray analysis.…”

Interleukin-10 Therapy—Review of a New Approach

“…The activity of this enzyme was elevated as well. This can result in elevated levels of nitric oxide in transfected tumor cells (Kundu et al, 1998). Nitric oxide is known to show potent antitumor activity.…”

Interleukin-10 gene transfer to peritoneal mesothelial cells suppresses peritoneal dissemination of gastric cancer cells due to a persistently high concentration in the peritoneal cavity

“…[5][6][7] This action is mediated by various mechanisms. [8][9][10][11][12][13][14] IL-10 also improves cancer-associated cachexia through suppression of the production of TNF-a and other cytokines. 3,32 Thus, IL-10 may be an important factor for improving conditions associated with malignant tumors.…”

“…8 These antitumor mechanisms have been found to be dependent upon immune cells such as natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) and macrophages. [9][10][11][12][13][14] Unfortunately, however, the half life of IL-10 is approximately 20 min and it is difficult to maintain a high concentration after administration of IL-10 alone. [15][16][17] Gastric cancer is one of the most common malignancies in the world, especially in Eastern Asia.…”