부산대학교 도서관

The role of TGF- in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF- play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-s inhibitory actions often leads to TGF- overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF- in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF- using antibodies, soluble receptors and small molecule inhibitors of TGF- signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF- and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF- antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF- antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF- antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF- antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.