title: In vitro schedule-dependent interaction between melphalan and oxaliplatin in human colorectal cancer cell lines.
abstract: 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.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Liselot B J
authors.initials: LB
authors.lastname: van Iersel
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Koudijs
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hoekman
authors.forename: Connie M
authors.initials: CM
authors.lastname: Janssen-van Rhijn
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Vahrmeijer
authors.forename: Johan W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D008558:Melphalan