Antisense oligonucleotides specific for transforming growth factor beta2 inhibit the growth of malignant mesothelioma both in vitro and in vivo.
Transforming growth factor beta (TGF-beta) is a potent growth-regulatory and immunomodulatory cytokine that exerts a diverse range of effects on many types of cells. High levels of TGF-beta 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-beta mRNA, were used to block TGF-beta production from MM cells in vitro and in vivo. TGF-beta antisense ODNs were encapsulated in liposomes and transfected into MM cells or delivered intratumorally. TGF-beta2 mRNA levels, assessed by semiquantitative PCR, and TGF-beta2 protein secretion were reduced after TGF-beta2 antisense ODN transfection. MM cell proliferation, assessed by tritiated thymidine uptake, was specifically inhibited by both TGF-beta1- and TGF-beta2-specific antisense ODNs. In vivo administration of TGF-beta2 antisense ODNs, delivered locally, reduced tumor growth. These data show that the blockade of TGF-beta2 within this tumor reduces tumor growth and raises the possibility that TGF-beta2 antisense ODNs may be useful as a therapy for this disease.
Marzo
A L
AL
The University of Western Australia Department of Medicine, Queen Elizabeth II Medical Centre, Nedlands, Perth. amarzo@uniwa.uwa.edu.au
Fitzpatrick
D R
DR
Robinson
B W
BW
Scott
B
B
D000818:Animals; D001973:Bromodeoxyuridine / Q000032:analysis; D002455:Cell Division; D005260:Female; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D008654:Mesothelioma / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008808:Mice, Inbred CBA; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001973:Bromodeoxyuridine