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[Mechanism of resistance to tumor necrosis factor]
M Pfreundschuh1, B Genth, H Kirchner
1Medizinische Klinik, Universität zu Köln.
Abstract:
To find clues as to the possible mechanisms of resistance against the cytotoxic activity of tumor necrosis factor (TNF), we developed TNF-resistant and TNF-sensitive subclones of the human cervic carcinoma cell line ME 180 and the mammary carcinoma cell line BT-20. Resistant subclones were selected by gradually increasing the TNF concentration in the culture medium over 4 months or 20 passages. Resistance to TNF was conserved in the absence of TNF after nearly 3 years and less than 100 passages. There were no differences in the number and affinity of TNF receptors between the sensitive and resistant clones. Similarly, SDS-PAGE of cell lysates showed identical bands. Sensitivity to actinomycin D, mitomycin C, and interferon-gamma was the same. No TNF message could be demonstrated in either subclone. As tumors grown in nude mice derived from the sensitive and resistant clones responded equally well to an intratumoral injection of TNF, we conclude that different mechanisms are responsible for sensitivity and resistance to the cytotoxic effect of TNF in vitro and in vivo.
Insights
Tumor necrosis factor (TNF) resistance in cancer cells involves mechanisms distinct from those governing sensitivity. In vitro and in vivo studies reveal differing pathways for TNF cytotoxic effects.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Context:
- Investigating mechanisms of resistance to tumor necrosis factor (TNF) in cancer therapy.
- Utilized human cervical (ME 180) and breast (BT-20) carcinoma cell lines.
- Developed and characterized TNF-resistant and TNF-sensitive subclones.
Purpose:
- To elucidate the molecular and cellular basis of resistance to TNF-induced cytotoxicity.
- To compare TNF receptor expression and signaling in sensitive versus resistant cell lines.
- To assess the in vitro and in vivo efficacy of TNF in resistant and sensitive tumor models.
Summary:
- TNF-resistant and sensitive subclones of ME 180 and BT-20 cells were generated.
- No significant differences were observed in TNF receptor number/affinity, protein expression, or sensitivity to other cytotoxic agents.
- TNF resistance was stable and did not correlate with TNF gene expression.
- Tumor xenografts showed similar responses to intratumoral TNF, irrespective of cellular sensitivity.
- Concluded that distinct mechanisms mediate TNF sensitivity and resistance in vitro versus in vivo.
Impact:
- Highlights the complexity of TNF resistance in cancer.
- Suggests that in vitro resistance assays may not accurately predict in vivo therapeutic response to TNF.
- Provides a foundation for developing strategies to overcome TNF resistance in cancer treatment.
- Differentiates between cellular mechanisms of TNF resistance and tumor response.