Transforming growth factor β (TGF-β) is a potent growth-regulatory and immunomodulatory cytokine that exerts a diverse range of effects on many types of cells. High levels of TGF-β are produced by several human and mouse malignant mesothelioma (MM) cell lines, and it is known to act as a growth factor for these cells. Antisense oligonucleotides (ODNs), targeted against specific TGF-β mRNA, were used to block TGF-β production from MM cells in vitro and in vivo.
TGF-β antisense ODNs were encapsulated in liposomes and transfected into MM cells or delivered intratumorally. TGF-β2 mRNA levels, assessed by semiquantitative PCR, and TGF-β2 protein secretion were reduced after TGF-β2 antisense ODN transfection. MM cell proliferation, assessed by tritiated thymidine uptake, was specifically inhibited by both TGF-β1- and TGF-β2-specific antisense ODNs. In vivo administration of TGF-β2 antisense ODNs, delivered locally, reduced tumor growth. These data show that the blockade of TGF-β2 within this tumor reduces tumor growth and raises the possibility that TGF-β2 antisense ODNs may be useful as a therapy for this disease.
Supported by the National Health and Medical Research Council of Australia and the Medical Research Fund of Western Australia.