Extremely weak tumor-promoting effect of troglitazone on splenic hemangiosarcomas in rasH2 mice induced by urethane

Arch Toxicol. 2008 Oct;82(10):771-7. doi: 10.1007/s00204-008-0293-y. Epub 2008 May 9.


To examine the tumor-promoting effect of troglitazone (TRG), a novel thiazolidinedione insulin-sensitizing agent, on splenic hemangiosarcomas in rasH2 mice, histopathological and molecular analyses were performed in the spleen of female rasH2 mice fed a diet containing 6,000 or 0 ppm TRG for 16 weeks after 1,000 or 0 mg/kg urethane (UR) initiation. Histopathologically, splenic hemangiosarcomas were observed in the UR-alone and UR + TRG groups, but there was no significant difference in the incidence of splenic hemangiosarcomas between the UR-alone and UR+TRG groups. There were increasing tendencies in the number of positive cells for anti-PCNA antibody and gene expression in the UR + TRG group, but such a change was not statistically significant as compared to that in the UR-alone group. The gene expressions of VEGF, VEGFR1, VEGFC, VEGFR2 and Tie2 related to angiogenesis; c-fos related to MAPK cascade activation; and cyclin D1 related to cell cycle in the UR-alone and UR + TRG groups were significantly higher than those in the untreated control group. However, only the Tie2 gene in the UR + TRG group was significantly increased as compared to that in the UR-alone group. These results suggest that the vascular tumor-promoting activity of TRG in rasH2 mice is extremely low in the present experimental condition and a part of the gene related to angiogenesis probably contributes to the promotion of splenic hemangiosarcomas in rasH2 mice given TRG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / genetics
  • Animals
  • Body Weight / drug effects
  • Carcinogens / toxicity*
  • Cell Proliferation / drug effects
  • Chromans / toxicity*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hemangiosarcoma / blood supply
  • Hemangiosarcoma / chemically induced*
  • Hemangiosarcoma / genetics
  • Hemangiosarcoma / pathology
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / chemically induced*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / chemically induced
  • Neovascularization, Pathologic / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Splenic Neoplasms / blood supply
  • Splenic Neoplasms / chemically induced*
  • Splenic Neoplasms / genetics
  • Splenic Neoplasms / pathology
  • Thiazolidinediones / toxicity*
  • Time Factors
  • Troglitazone
  • Urethane


  • Angiogenic Proteins
  • Carcinogens
  • Chromans
  • Thiazolidinediones
  • Urethane
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Troglitazone