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Resistance of Human Cervical Carcinoma Cells to Tumor Necrosis Factor Correlates with Their Increased Sensitivity to Cisplatin: Evidence of a Role for DNA Repair and Epidermal Growth Factor Receptor¹

Departments of Medical Oncology [K. N., R. A. N., T. K. P., W. N. H.] and Clinical Immunology and Biological Therapy [M. G. R., N. J. D.], University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030

Alternations in cellular biochemistry which are associated with the development of resistance to cytotoxic peptides, such as tumor necrosis factor (TNF), may also be responsible for changes in the response of cells to cytotoxic agents. Culturing ME-180 cervical carcinoma cells in the presence of escalating concentrations of TNF resulted in the development of an ME-180 cell variant (ME-180R) resistant to TNF but expressing a 3–5-fold increased sensitivity to cis-platin (CDDP) when measured following continuous exposure (low doses) or short-term incubation with CDDP (high doses) and clonogenic analysis. Cellular platinum uptake, efflux, and nuclear platinum content as well as the extent of DNA platination were examined and found to be identical in both ME-180 parental and ME-180R cell lines. Although ME-180R cells showed a relatively higher glutathione content than ME-180 parental cells, the effect of buthionine sulfoximine on the cellular sensitivity to CDDP and glutathione S-transferase activities of both cell lines were almost identical, suggesting that glutathione content or its metabolism did not appear to play a major role in differential CDDP cytotoxicity. Unscheduled DNA synthesis following exposure to CDDP was more inducible in ME-180 parental cells than in CDDP-sensitive ME-180R cells. Alkaline elution studies of cross-linked DNA in CDDP-treated ME-180 cells suggested that accumulation of DNA adducts reached maximal levels 10–15 h after CDDP treatment and was similar in both TNF-resistant and parental cells. Within 24 h after CDDP exposure, the extent of DNA cross-linking was markedly reduced in parental cells but remained elevated in the CDDP-sensitive ME-180R cell line. To examine the proposed regulatory role of phosphorylation in CDDP and TNF-mediated cytotoxicity, epidermal growth factor (EGF) receptor tyrosine kinase activity was measured in both TNF-resistant and parental ME-180 cells. Analysis of cell lysates demonstrated a 3–4-fold higher EGF receptor tyrosine kinase activity in ME-180R cells when compared to the parental population which correlated with increased expression of EGF receptor protein by immunoblot analysis. Based upon colony-forming assays, EGF treatment of ME-180 parental cells resulted in an increased sensitivity to CDDP (similar to ME-180R cells) and 3-fold stimulation of EGF receptor tyrosine kinase activity. Taken together, these results suggest that TNF resistance in ME-180 cervical carcinoma cells correlates with both increased EGF receptor expression and enhanced CDDP cytotoxicity. In TNF-resistant ME-180R cells, CDDP-induced cytotoxicity appears to be mediated at the level of DNA repair and may be modulated by EGF receptor expression or the state of its activation.

¹ Research conducted, in part, by the Clayton Foundation for Research and supported by grants (CA48906 to N. J. D. and CA27931 to W. N. H.) from the NIH.

² Present address: Nippon Kayaku, Research Labs, 3–31, Shimo, Kita-ku, Tokyo, 115 Japan.

³ To whom requests for reprints should be addressed at Department of Clinical Immunology and Biological Therapy, Box 041, 1515 Holcombe Blvd., Houston, TX 77030.

Received 3/12/92. Accepted 6/24/92.

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