title: Effect of thalidomide on colorectal cancer liver metastases in CBA mice.
abstract: OBJECTIVE
  Thalidomide has undergone resurgence in the treatment of specific malignancies. One of the possible actions of thalidomide may be an antiangiogenic effect. This study investigates the effects of thalidomide on tumor growth and long-term survival in a murine model of colorectal liver metastases.
  
  
  METHODS
  Liver metastases were produced in male CBA mice by intrasplenic injection of a dimethyl hydrazine induced MoCR colon cancer murine cell line. Thalidomide was administered daily at doses ranging from 50 to 300 mg/kg by intraperitoneal injection. Tumor growth was assessed using quantitative stereological analysis. The effect on long-term survival was determined at the maximum tolerated dose using Kaplan-Meier analysis. The microvascular effects of thalidomide were assessed by laser Doppler flowmetry (LDF) and microvascular resin casting. Immunohistochemistry was used to determine vascular endothelial growth factor (VGEF) and basic fibroblast growth factor (bFGF) expression.
  
  
  RESULTS
  Thalidomide, (50-300 mg/kg) caused no significant reduction in tumor growth by day 21 following induction of liver metastases and caused systemic toxicity at a dose of 300 mg/kg. At a dose of 200 mg/kg given beyond 35 days, thalidomide significantly reduced tumor growth compared to control, (P = 0.029). No significant impact on survival was however observed (P = 0.93). LDF and microvascular resin casting showed no differences in blood flow or tumor microvascular architecture. VGEF and FGF were expressed in tumors, but remained unaltered by thalidomide administration compared to matched controls.
  
  
  CONCLUSIONS
  Thalidomide caused a significant reduction in the volume of colorectal liver metastases during the late phase of tumor growth. There was however no improvement in survival. Tumor growth reduction in this model did not appear to be due to microvascular changes or altered expression of VGEF or basic FGF. Further investigation into potential mechanisms of action of thalidomide and its synergistic use with other therapies is required.
authors: The University of Melbourne, Department of Surgery, Austin Health Hospital, Studley Road, Heidelberg, Australia. jurstine@pgrad.unimelb.edu.au
authors: Jurstine
authors: J
authors: Daruwalla
authors: Mehrdad
authors: M
authors: Nikfarjam
authors: Cathy
authors: C
authors: Malcontenti-Wilson
authors: Vijayaragavan
authors: V
authors: Muralidharan
authors: Chris
authors: C
authors: Christophi
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide