title: Synergism of CPT-11 and Apo2L/TRAIL against two differentially sensitive human colon tumor xenografts.
abstract: OBJECTIVE
  The ability to sustain and grow portions of human tumors as xenografts in SCID mice provides a valuable preclinical opportunity to test the response of human tumors to treatments, both individually and in combination. Using this model, our laboratory has previously demonstrated that the growth of several human adenocarcinomas can be inhibited by Apo2L/TRAIL. Apo2L/TRAIL triggers apoptosis in many types of tumor cells, and when combined with various chemotherapeutic agents results in enhanced inhibition of tumor growth in many xenograft models.
  
  
  METHODS
  To gain further insight into the antitumor potential of Apo2L/TRAIL in combination with chemotherapy, we compared the responses of 2 human colon adenocarcinomas, both of which were sensitive to CPT-11 while one was sensitive and the other comparatively resistant to Apo2L/TRAIL.
  
  
  RESULTS
  In both cases, a greater degree of growth inhibition was achieved when these agents were used in combination. Western blot analysis demonstrated that in the Apo2L/TRAIL-sensitive tumor total cellular expression of Apo2L/TRAIL death receptors (DR4 and DR5) as well as protein expression of the pro-apoptotic molecule BAX were higher and the anti-apoptotic molecule Bcl-2 was lower in comparison to the Apo2L/TRAIL-resistant tumor.
  
  
  CONCLUSIONS
  These results indicate that both Apo2L/TRAIL-sensitive and -resistant colon tumors will respond to a combination of CPT-11 and Apo2L/TRAIL and predict that this will be useful in the treatment of human colon cancers in a clinical setting.
authors: First Department of Surgery, Tottori University School of Medicine, Yonago, Japan.
authors: Kenji
authors: K
authors: Sugamura
authors: John F
authors: JF
authors: Gibbs
authors: Alan
authors: A
authors: Belicha-Villanueva
authors: Christopher
authors: C
authors: Andrews
authors: Elizabeth A
authors: EA
authors: Repasky
authors: Bonnie L
authors: BL
authors: Hylander
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary / Q000628:therapy; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin