Anti-tumor activity of cytokines against opportunistic vascular tumors in mice.
Polyoma middle T (PmT)-transformed endothelial cells may represent a unique murine model for human opportunistic vascular tumors. The present study was designed to evaluate the anti-tumor potential of a panel of 13 cytokines against murine PmT-transformed endothelial cells. Interferon gamma (IFNgamma) and transforming growth factor beta 1 (TGFbeta1) substantially decreased in a dose-dependent manner the proliferation of a panel of 6 PmT-transformed cell lines. IFNalpha and tumor necrosis factor alpha(TNFalpha) had marginal anti-proliferative activity, whereas other molecules (interleukins-1, -2, -4, -6 and -13, IFNbeta, leukemia inhibitory factor, oncostatin M, granulocyte-macrophage colony-stimulating factor) caused no growth inhibition. IFNgamma and TGFbeta1 were therefore selected for further analysis of their mechanism of action and in vivo relevance. IFNgamma and TGFbeta1 reduced the activity of phosphatidylinositol-3-kinase and the production of phosphatidylinositol 3,4-biphosphate, without modifying the tyrosine kinase(s) activity associated with PmT. IFNgamma and TGFbeta1 were also tested for their ability to modify the in vivo growth of the PmT-transformed endothelial cells H5V in syngeneic C57B1/6 mice. Treatment with IFNnu and TGFbeta1 significantly delayed tumor growth and increased survival time. In contrast, treatment with IFNalpha and TNFalpha failed to prolong survival. In nude mice, IFNgamma and TGFbeta1 had a transient effect on tumor growth but no effect on survival, suggesting a contribution of T cells to the in vivo anti-tumor activity of these cytokines.
Dong
Q G
QG
Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy.
Graziani
A
A
Garlanda
C
C
De Calmanovici
R W
RW
Arese
M
M
Soldi
R
R
Vecchi
A
A
Mantovani
A
A
Bussolino
F
F
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002472:Cell Transformation, Viral; D016207:Cytokines / Q000627:therapeutic use*; D005260:Female; D006390:Hemangioendothelioma; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019043:Vascular Neoplasms / Q000188:drug therapy*
D000952:Antigens, Polyomavirus Transforming; D016207:Cytokines; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)