title: Efficacy of cisplatin and Lipoplatin™ in combined treatment with radiation of a colorectal tumor in nude mouse.
abstract: BACKGROUND
  Optimal conditions for efficient concomitant chemoradiation treatment of colorectal cancer with cisplatin still need to be better defined. In addition, intolerance of healthy tissue to cisplatin prevents the full exploitation of its radiosensitizing potential. A liposomal formulation of cisplatin, Lipoplatin™, was proposed to overcome its toxicity. Using an animal model of colorectal cancer, we determined the platinum window, defined by studying the pharmacokinetics and time-dependent intracellular distribution of cisplatin and Lipoplatin™.
  
  
  METHODS
  In nude mice bearing HCT116 human colorectal carcinoma treated with cisplatin or Lipoplatin™, the platinum accumulation in blood, serum, different normal tissues, tumor and different tumor cell compartments was measured by inductively coupled plasma mass spectrometry. Radiation treatment (15 Gy) was given 4, 24, and 48 h after drug administration and was correlated to the amount of platinum-DNA adducts in the cancer cells. The resulting tumor growth delay is reported and correlated to apoptosis analysis.
  
  
  RESULTS
  The greatest effects and highest apoptosis were observed when radiation was given at 4 h or 48 h after drug injection. These times correspond to the times of maximal platinum binding to tumor DNA. An enhancement factor (ratio of group treated by combined treatment compared to chemotherapy alone) of 13.00 was obtained with Lipoplatin™, and 4.09 for cisplatin when tumor irradiation was performed 48 h after drug administration.
  
  
  CONCLUSIONS
  The most efficient combination treatment of radiation with cisplatin or Lipoplatin™ was observed when binding of platinum to DNA was highest. These results improve our understanding over the mechanisms of platinum-induced radiosensitization and should have significant impact on the design of more efficient treatment protocols.
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, QC, Canada, J1H 5N4. Leon.Sanche@USherbrooke.ca
authors.forename: Thititip
authors.initials: T
authors.lastname: Tippayamontri
authors.forename: Rami
authors.initials: R
authors.lastname: Kotb
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
authors.forename: Léon
authors.initials: L
authors.lastname: Sanche
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010984:Platinum / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C503131:lipoplatin; D010984:Platinum; D002945:Cisplatin
keywords: Lipoplatin™; Radiotherapy; chemotherapy; cisplatin; colorectal cancer; concomitant therapy