Limited tumor growth (HT29) in vivo under RO205-2349 is due to increased apoptosis and reduced cell volume but not to decreased proliferation rate.
The peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that plays a regulatory role in cell differentiation and proliferation. PPARgamma was first detected in adipocytes, however, it has been shown that this receptor is also expressed in normal as well as tumor cells including malignant colonic epithelial cells. In this study, the effect of the PPARgamma agonist RO205-2349, a recently developed thiazolidinedione, on tumor growth was evaluated. For this purpose, human colon cancer cells (HT29) were grown in severe combined immunodeficient mice. Under daily RO205-2349 treatment (50 mg/kg/day) a significantly reduced tumor weight became evident after 3 weeks. In the control (n = 10) and treatment (n = 10) groups the mean tumor weights were 0.45 and 0.16 g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the control and treatment groups, respectively, and the cell diameter measured on average 11.4 and 9.4 microm. In contrast, cell proliferation and differentiation, which are considered to be influenced by the PPARgamma, remained unaffected as could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating that increased rate of apoptosis and cell shrinkage are responsible for the differences in tumor growth. Hence, in this human/mouse xenograft model, mechanisms other than the classical activation of PPARgamma are likely reasons causing limited tumor growth.
Katoh
Marcus
M
Institute for Anatomy II: Experimental Morphology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, Hamburg D-20246, Germany.
Feldhaus
Susanne
S
Schnitzer
Tobias
T
Bauer
Sabine
S
Schumacher
Udo
U
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019073:HT29 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D045162:Thiazolidinediones / Q000097:blood / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists*; D014183:Transplantation, Heterologous
D002272:Carcinoembryonic Antigen; D019394:Ki-67 Antigen; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione