Exposure-response relationships for oxaliplatin-treated colon cancer cells.
Data are lacking for an optimal infusion length for oxaliplatin administered intraperitoneally. Our objectives were to establish the roles of hyperthermia and an effective length of oxaliplatin treatment in maximizing antitumor activity. SW620 cells were treated for 0.5 vs. 2 h and at 37 vs. 42 degrees C. Cytotoxicity, cell cycle analysis, subG1 and survival were assessed with the MTT assay, flow cytometry and the clonogenic assay. The IC50 for cells treated at 37 degrees C was 2.90+/-0.83 microg/ml and at 42 degrees C, 1.99+/-0.66 microg/ml (P=0.14). The Emax for 37 degrees C was 93.9+/-2.57% and for 42 degrees C, 97.8+/-1.59% (P=0.05). The subG1 fraction did not differ between cells treated at 37 and 42 degrees C (P=0.12). The IC50 for the cells treated for 0.5 h was 10.6+/-0.60 microg/ml and for 2 h, 2.80+/-1.70 microg/ml (P=0.02). The Emax for 0.5 h was 87.9+/-5.13% and for 2 h, 96.6+/-3.35% (P=0.09). SubG1 for 0.5 h was 8.24+/-1.33% and for 2 h, 15.8+/-2.45% (P=0.02). Clonogenic assays demonstrated diminished survival when treated with low concentrations (10 microg/ml) of oxaliplatin combined with heat treatment (P=0.017) for 2 h, but not 0.5 h. Similar clonogenic assay experiments were performed with the oxaliplatin-resistant WiDr cell line, and differences in survival following oxaliplatin and heat treatment were again observed for 2 h, but not for 0.5 h (P=0.002). Drug treatment for 2 h of both SW620 and WiDr cell lines is superior to treatment for 0.5 h. Cell kill effects are reliant on treatment length; hence, the choice of time exposure must be made with a view to maintaining a balance between the cell kill effects and the clinical feasibility of treating the patient.
Kirstein
Mark N
MN
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA. kirst002@umn.edu
Root
Stephanie A
SA
Moore
Megan M
MM
Wieman
Katie M
KM
Williams
Brent W
BW
Jacobson
Pamala A
PA
Marker
Paul H
PH
Tuttle
Todd M
TM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006358:Hot Temperature; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D013997:Time Factors; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin