Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status

OBJECTIVES AND METHODS: The association oxaliplatin (OXA)-5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rgamma) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. RESULTS: Both cell lines exhibited similar dose response curves to Rgamma alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rgamma-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rgamma. The results from both calculation methods concurred: the combination of OXA-FUFA with Rgamma led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rgamma occurring when applied before or at mid-drug application. CONCLUSIONS: These results could be taken into consideration for an optimal design of clinical protocols associating Rgamma and OXA-FUFA.