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The inhibition of neoplastic cell proliferation with human natural tumor necrosis factor
Abstract:
Purified human natural tumor necrosis factor (n-TNF) was prepared by stimulating human leukemic B cell line (BALL-1) with Sendai virus. The colony formations of all of 18 human cancer-derived abnormal cell lines were suppressed by 10(1)-10(6) U/ml of n-TNF, while n-TNF was nontoxic to all human normal fibroblast cells. This in vitro inhibition of cell growth was reversible. In breast adenocarcinoma MCF7 cells treated with n-TNF a specific decrease of DNA synthesis was observed, and DNA histograms showed a block at G1 in the cell cycle. In vivo studies revealed that n-TNF suppressed the tumor growth of murine Meth A sarcoma, human renal adenocarcinoma (ACHN), malignant melanoma (SK-MEL-28) and glioblastoma (U-373 MG). Isobologram analysis showed that n-TNF synergistically inhibited cell growth in combination with human natural interferon (IFN)-a. In vivo synergism of n-TNF and IFN-a was also found in the U-373 MG tumor model implanted into nude mice.
Insights
Human natural tumor necrosis factor (n-TNF) effectively inhibits cancer cell growth without harming normal cells. It also shows synergistic effects with natural interferon-alpha (IFN-a) in both in vitro and in vivo cancer models.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Tumor necrosis factor (TNF) is a cytokine with known roles in inflammation and immunity.
- Investigating the anti-cancer properties of purified human natural TNF (n-TNF) is crucial for developing novel cancer therapies.
Purpose of the Study:
- To evaluate the anti-cancer efficacy of n-TNF against various human cancer cell lines in vitro.
- To assess the in vivo anti-tumor activity of n-TNF in preclinical cancer models.
- To explore the synergistic effects of n-TNF in combination with human natural interferon-alpha (IFN-a).
Main Methods:
- n-TNF was prepared by stimulating a human leukemic B cell line (BALL-1) with Sendai virus.
- In vitro cytotoxicity and cell growth inhibition assays were performed on 18 human cancer cell lines and normal fibroblast cells.
- Cell cycle analysis (DNA histograms) and DNA synthesis assays were conducted on treated breast adenocarcinoma MCF7 cells.
- In vivo tumor growth suppression was evaluated using murine Meth A sarcoma and human tumor xenografts (ACHN, SK-MEL-28, U-373 MG) in mice.
- Isobologram analysis was used to assess synergistic effects of n-TNF with IFN-a in vitro and in vivo.
Main Results:
- n-TNF demonstrated potent inhibition of colony formation in all 18 tested human cancer cell lines at concentrations of 10(1)-10(6) U/ml.
- n-TNF exhibited no toxicity towards human normal fibroblast cells, indicating selective anti-cancer activity.
- Treatment with n-TNF induced a specific decrease in DNA synthesis and a G1 cell cycle block in MCF7 cells.
- In vivo studies confirmed that n-TNF suppressed tumor growth in multiple cancer models, including murine sarcoma and human renal adenocarcinoma, melanoma, and glioblastoma xenografts.
- Both in vitro and in vivo studies revealed synergistic anti-cancer effects when n-TNF was combined with IFN-a, particularly notable in the U-373 MG glioblastoma model.
Conclusions:
- Purified human natural TNF (n-TNF) possesses significant selective anti-cancer properties, inhibiting the growth of diverse human cancer cell lines without affecting normal cells.
- n-TNF effectively suppresses tumor growth in vivo across various preclinical models.
- The combination of n-TNF and IFN-a demonstrates synergistic anti-tumor activity, presenting a promising therapeutic strategy for cancer treatment.