Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo.
The in vitro and in vivo combination of oxaliplatin and irinotecan was investigated in a panel of four human colon cancer cell lines and their counterpart xenografts. In vitro and in vivo experiments demonstrated a synergistic or additive interaction in three cell lines (HCT-116, HCT-8 and HT-29) and an antagonism in SW-620 cells. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in HCT-8 and SW-620 cells. Irinotecan slowed down the early platinum-DNA adducts repair (1 h after oxaliplatin exposure) in the presence of irinotecan only in HCT-8 cells (p=0.03, n=3). Moreover, a decrease of the expression of two proteins of the nucleotide excision repair (NER) system, ERCC1 and XPA, was observed. None of these effects was seen in SW-620 cells. Irinotecan induced apoptosis with an increase of poly(ADP-ribose) polymerase (PARP) cleavage in SW-620 cells (60 versus 7% basal level). Pretreatment of these cells with oxaliplatin abolished the increase in PARP cleavage induced by irinotecan (29%). In HCT-8 cells, a very little PARP cleavage was observed whatever the drug treatment. The persistence of platinum-DNA adducts in the presence of irinotecan could be due to a direct impact of irinotecan on NER gene expression or to an indirect effect on topoisomerase I activity. Complementary studies are required to determine if the cellular parameters identified in this study could be translated at the clinical level to predict clinical response after combined treatment with oxaliplatin and irinotecan in humans.
Guichard
S
S
Groupe de Pharmacologie clinique et expérimentale (EA 3035), Institut Claudius Regaud, 20-24 rue du pont St Pierre, 31052 Toulouse Cedex, France. guichard@icr.fnclcc.fr
Arnould
S
S
Hennebelle
I
I
Bugat
R
R
Canal
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy*; D018736:DNA Adducts; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004720:Endonucleases; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins; D016601:RNA-Binding Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051760:Xeroderma Pigmentosum Group A Protein
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D011506:Proteins; D016601:RNA-Binding Proteins; D059004:Topoisomerase I Inhibitors; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D000077150:Oxaliplatin; D000077146:Irinotecan; D011065:Poly(ADP-ribose) Polymerases; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D002166:Camptothecin