Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.
Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.
Guba
Markus
M
Department of Surgery, University of Regensburg, Regensburg, Germany. markus.guba@klinik.uni-regensburg.de
von Breitenbuch
Philipp
P
Steinbauer
Markus
M
Koehl
Gudrun
G
Flegel
Stefanie
S
Hornung
Matthias
M
Bruns
Christiane J
CJ
Zuelke
Carl
C
Farkas
Stefan
S
Anthuber
Matthias
M
Jauch
Karl-Walter
KW
Geissler
Edward K
EK
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000502:physiology*; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D020123:Sirolimus / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020123:Sirolimus