Abstract
Abstract
The current standard of care for locally advanced cervical cancer is radiation therapy (RT) with adjunctive cisplatin chemotherapy for radiation sensitization. Some patients are unable to tolerate cisplatin secondary to renal compromise and may be better candidates for oxaliplatin therapy, which has never been evaluated in this role in clinical trials. This study aimed to evaluate the utility of cisplatin versus oxaliplatin in combination with RT in cervical cancer cell lines. Excision and mismatch repair enzymes were analyzed in these cell lines and evaluated for association with treatment response. Four cervical cancer cell lines (C33a, Caski, Me180, and Siha) were evaluated. On Day 0, cell lines were counted using trypan blue exclusion and were plated in 96 well plates. On Day 1, cells were irradiated and treated with cisplatin and oxaliplatin (chemotherapy doses were determined by dose finding experiments to establish an IC50 for each cell line). On Day 6, the XTT assay was used to determine cell viability. Cell line experiments were run in triplicate. Resulting data was processed using Calcusyn software for Chou analysis. Cell lines were lysed and nuclear excision (ERCC1) and mismatch repair proteins (MSH2 and MLH1) were semi-quantitatively evaluated using Western blot. Proteins were analyzed in ratio to beta actin controls. The cell lines showed variable response to therapy. IC50 values ranged from 0.8 (C33a) to 12.7 uM (Siha) for cisplatin, from 1.18 (Me180) to 41.4 uM (Siha) for oxaliplatin, and from 306.8 (C33a) to 1503 cGy (Siha) for radiation. Analysis of the combined therapy for additive/synergistic versus antagonistic response revealed oxaliplatin + RT to be statistically significantly better than cisplatin + RT in the C33a (p= 0.0189) and Me180 cell lines (p< 0.0001). The Siha cell line showed a trend favoring oxaliplatin + RT (p= 0.118), while the Caski cell line showed no difference. While three out of four cell lines showed additive to synergistic responses with oxaliplatin/RT and cisplatin/RT, the Me180 cell line demonstrated antagonistic response with the cisplatin/RT but synergistic response with the oxaliplatin/RT. A strong correlation was seen with ERCC1 and cisplatin (R= 0.97) and radiation (R= 0.96) and a trend toward correlation with oxaliplatin (R=0.79) in the C33a, Caski, and Me180 cell lines. MLH1 had a strong correlation with cisplatin (R= 0.88) and radiation (R= 0.86) and a trend toward correlation with oxaliplatin (R= 0.61) in the C33a, Caski, and Me180 cell lines. There was no correlation between MSH2 and IC50 values. Oxaliplatin acts synergistically and additively with RT in cell lines, and was superior to cisplatin + RT in two of the cell lines evaluated. Because oxaliplatin can be used in patients with renal impairment or who otherwise may not be candidates for cisplatin therapy, clinical trials evaluating this agent in conjunction with RT would be of interest.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1399.