In vitro schedule-dependent interaction between melphalan and oxaliplatin in human colorectal cancer cell lines.
OBJECTIVE
In order to determine the applicability of oxaliplatin in isolated liver perfusion, we identified the interaction between combinations of oxaliplatin and melphalan in 13 human colorectal cancer cell lines.


METHODS
Cytotoxic activity was determined by the MTT-assay. Three different administration schedules of the two drugs were compared and median effect isobologram analysis was applied to the results, to determine the presence of synergism, additive effects, or antagonism as described by Chou and Talalay.


RESULTS
Resistance to melphalan did not correspond to resistance to oxaliplatin. All combinations of melphalan and oxaliplatin showed synergistic or additive interaction in the majority of the cell lines. One hour of oxaliplatin followed by 1h of melphalan showed the lowest percentage of cell viability, with synergy in 10 out of 13 cell lines at 50% cell viability. Simultaneous treatment showed the highest cell viability, with antagonism in six cell lines, additivity in two cell lines, synergism in five cell lines at 50% cell viability. One hour of melphalan followed by 1h of oxaliplatin showed synergy in six cell lines, antagonism in another six, and additivity in one cell line.


CONCLUSIONS
Our findings suggest a schedule-dependent synergistic interaction between melphalan and oxaliplatin. Therefore, oxaliplatin should be considered as a new, potentially valuable additional agent to the currently commonly used melphalan in isolated hepatic perfusion in colorectal cancer patients.
van Iersel
Liselot B J
LB
Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Koudijs
Tamara M
TM
Hoekman
Ellen J
EJ
Janssen-van Rhijn
Connie M
CM
Vahrmeijer
Alexander L
AL
Nortier
Johan W R
JW
van de Velde
Cornelis J H
CJ
Gelderblom
Hans
H
Kuppen
Peter J K
PJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D066298:In Vitro Techniques; D008558:Melphalan / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000077150:Oxaliplatin; D013997:Time Factors
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D008558:Melphalan