ANTISENSE OLIGONUCLEOTIDES SPECIFIC FOR TRANSFORMING-GROWTH-FACTOR BETA-2 INHIBIT THE GROWTH OF MALIGNANT MESOTHELIOMA BOTH IN-VITRO AND IN-VIVO

Transforming growth factor beta (TGF-beta) is a potent growth-regulato ry and immunomodulatory cytokine that exerts a diverse range of effect s on many types of cells. High levels of TGF-beta are produced by seve ral human and mouse malignant mesothelioma (MM) cell lines, and it is known to act as a growth factor for these cells, Antisense oligonucleo tides (ODNs), targeted against specific TGF-beta mRNA, were used to bl ock TGF-beta production from MIM cells in vitro and in vivo. TGF-beta antisense ODNs were encapsulated in liposomes and transfected into MM cells or delivered intratumorally. TGF-beta 2 mRNA levels, assessed by semiquantitative PCR, and TGF-beta 2 protein secretion were reduced a fter TGF-beta 2 antisense ODN transfection. MM cell proliferation, ass essed by tritiated thymidine uptake, was specifically inhibited by bot h TGF-beta 1- and TGF-beta 2-specific antisense ODNs, In vivo administ ration of TGF-beta 2 antisense ODNs, delivered locally, reduced tumor growth, These data show that the blockade of TGF-beta 2 within this tu mor reduces tumor growth and raises the possibility that TGF-beta 2 an tisense ODNs may be useful as a therapy for this disease.