Combination Of Interferon-gamma Research Articles

Differentiation‐inducing and cytotoxic effects of tumor necrosis factor and interferon‐gamma in myeloblastic ML‐1 cells

The effects of the tumor necrosis factor (TNF), and a second pleiotropic cytokine interferon-gamma (IFN), were examined in a line of human myeloblastic leukemia cells (ML-1). By itself, TNF causes ML-1 to differentiate along the monocytic pathway. The cells exhibit an increase in Fc receptors and acquire the morphological characteristics of maturing phenotype. They remain viable and continue to proliferate (at greater than or equal to 50% of the control growth rate) even with 10(2)-10(4) units/ml TNF. IFN alone has similar effects, causing an increase in Fc receptors but little cytotoxicity. In contrast to either cytokine alone, the combination of TNF plus IFN causes a cessation of proliferation and extensive cell death. Cytotoxicity occurs in a synergistic fashion; it requires the simultaneous presence of both cytokines, occurring with concurrent but not sequential exposure. These different responses, differentiation (TNF alone) and cytotoxicity (TNF + IFN), occur with a similar range of doses (approximately 10(2)-10(4) units/ml) and in a similar time frame (beginning on day 2). In other cell types, IFN can augment either the differentiation-inducing or the cytotoxic effect of TNF. In ML-1, the combined application of TNF plus IFN results in a shift from differentiation to cytotoxicity.

Interferon treatment of renal cell carcinoma. Current status and future prospects

Studies with various interferon alpha preparations, including interferons induced in human leukocytes, interferon alfa-N1, interferon alfa-2a, and interferon alfa-2b, have all provided evidence for modest but reproducible antitumor activity in advanced renal cell carcinoma. Review of the data suggests that maximal response rates are achieved when interferon alpha is administered within a fairly restricted range of moderate to high doses, whereas extremely low or extremely high dosage regimens appear less likely to induce therapeutic response. Preliminary evidence suggests that interferons beta and gamma may also induce regression of metastatic renal cell carcinoma. Recent in vitro and animal studies have shown that combinations of interferon gamma with interferon alpha or interferon beta, produce synergistic biologic activities, suggesting that the various interferons may have different pathways of action related to agent-specific cellular receptors. Possible interactions of different interferon species given concurrently to patients with renal cell carcinoma are under investigation, as are combinations of interferon alpha with chemotherapeutic agents. Despite in vitro data suggesting enhanced antiproliferative activity for the combination of interferon alpha and vinblastine, most clinical studies of this combination have proved to be no more effective than interferon alpha alone, but they have provided evidence of increased toxicity. The recent identification and purification of other biologically active cytokines, such as tumor necrosis factor and interleukin-2, and of monoclonal antibodies that recognize unique cell surface antigens on renal carcinoma cells, provide exciting possibilities for combination regimens with various interferon species.

Interferon treatment of renal cell carcinoma. Current status and future prospects.

Studies with various interferon alpha preparations, including interferons induced in human leukocytes, interferon alfa-N1, interferon alfa-2a, and interferon alfa-2b, have all provided evidence for modest but reproducible antitumor activity in advanced renal cell carcinoma. Review of the data suggests that maximal response rates are achieved when interferon alpha is administered within a fairly restricted range of moderate to high doses, whereas extremely low or extremely high dosage regimens appear less likely to induce therapeutic response. Preliminary evidence suggests that interferons beta and gamma may also induce regression of metastatic renal cell carcinoma. Recent in vitro and animal studies have shown that combinations of interferon gamma with interferon alpha or interferon beta, produce synergistic biologic activities, suggesting that the various interferons may have different pathways of action related to agent-specific cellular receptors. Possible interactions of different interferon species given concurrently to patients with renal cell carcinoma are under investigation, as are combinations of interferon alpha with chemotherapeutic agents. Despite in vitro data suggesting enhanced antiproliferative activity for the combination of interferon alpha and vinblastine, most clinical studies of this combination have proved to be no more effective than interferon alpha alone, but they have provided evidence of increased toxicity. The recent identification and purification of other biologically active cytokines, such as tumor necrosis factor and interleukin-2, and of monoclonal antibodies that recognize unique cell surface antigens on renal carcinoma cells, provide exciting possibilities for combination regimens with various interferon species.

Antitumor effect of recombinant human interferon-beta and interferon-gamma in combination against human colon cancer cell line in vitro and in nude mice.

The antiproliferative activity of recombinant human interferon (rIFN)-beta and rIFN-gamma, alone or in combination, against a human colon cancer cell line (RPMI 4788) was examined in vitro and in nude mice. rIFN-beta and rIFN-gamma interacted synergistically in vitro. In experimental pulmonary metastasis and intraabdominal carcinomatosis in nude mice, rIFN-beta and rIFN-gamma were administered iv and ip, respectively, alone or in combination, for 10 consecutive days beginning 2 days after RPMI 4788 cells were inoculated. In both models, rIFN-beta and rIFN-gamma alone had significant antitumor effects compared with the saline-control group. Combined administration of rIFN-beta and rIFN-gamma resulted in marked antitumor effects. In the pulmonary metastasis model, there were no pulmonary metastatic nodules in the group treated with the combination of rIFN-beta and rIFN-gamma (P less than 0.001), while there were 324.6 +/- 83.1 (mean +/- SD) nodules in the control group. In the intraabdominal carcinomatosis model, the mean survival time was 114.0 +/- 8.2 days (P less than 0.01) for the combination therapy group, but only 41.8 +/- 5.6 days for the control group. These results suggest that combined treatment with rIFN-beta and rIFN-gamma might be a promising therapy for pulmonary metastasis and intraabdominal carcinomatosis of human cancers.

Interferon potentiation occurs at a pretranscriptive stage

Combination of interferon-gamma (IFN-gamma) with a mixture of IFN-alpha and IFN-beta (IFN-alpha/beta) produce a potentiated antiviral state. The onset of induction of the potentiated antiviral state was observed to be more rapid than the onset of induction of either IFN-gamma or IFN-alpha/beta separately. The onset of viral resistance to combined IFN-gamma and IFN-alpha/beta (25 U/ml each) began after 2 h, compared with 4 h for IFN-alpha/beta (25 U/ml) alone and 8 h for IFN-gamma (25 U/ml) alone. By adding actinomycin D at various times after interferon treatment, this more rapid onset of induction of the potentiated antiviral state was shown to be the result of a more rapid onset of cellular transcription. To determine whether increased concentrations of IFN-alpha/beta acted through a similar mechanism, we performed kinetic experiments with several concentrations of IFN-alpha/beta and with combined preparations of IFN-gamma and IFN-alpha/beta. The findings showed that treatment of cells with the combined interferons and with a high concentration of IFN-alpha/beta resulted in more rapid onset of cellular transcription and more rapid development of the antiviral state. Thus, the cellular response to potentiation appeared to involve perception by the cell of the combined interferons as a higher-than-expected effective concentration of interferon, resulting in more rapid onset of cellular transcription of mRNA for antiviral proteins.