Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status.
OBJECTIVE
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.
Magné
Nicolas
N
Oncopharmacology Laboratory, Centre Antoine Lacassagne, 33 Avenue de Valombrose, F-06189 Nice Cedex 2, France.
Fischel
Jean Louis
JL
Formento
Patricia
P
Etienne
Marie-Christine
MC
Dubreuil
Alain
A
Marcié
Serge
S
Lagrange
Jean-Léon
JL
Milano
Gérard
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage; D005720:Gamma Rays; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil