Transforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin.
The gene for transforming growth factor-beta 1 (TGF-beta 1) was transfected into the murine EMT-6/Parent mammary carcinoma tumor line to form the EMT6/PRK5 beta 1E tumor line. In monolayer culture the EMT-6/PRK5 beta 1E tumor line secretes about 15-times as much TGF-beta 1 into the medium as the EMT-6/Parent line. There was no difference in the response of these two cell lines to 4-hydroperoxycyclophosphamide, cisplatin, melphalan or thiotepa in monolayer culture. When the EMT-6/PRK5 beta 1E cells were grown as a solid tumor in Balb/C mice, plasma levels of TGF-beta 1 were about 5-fold higher than in animals bearing the EMT-6/Parent tumor. The EMT-6/PRK5 beta 1E tumor was markedly resistant to a dosage range of cyclophosphamide, cisplatin, melphalan and thiotepa compared with the EMT-6/Parent tumor. The bone marrow CFU-GM from the animals bearing the EMT-6/PRK5 beta 1E tumor were spared from the cytotoxicity of the drugs compared with the bone marrow CFU-GM from animals bearing the EMT-6/Parent tumor. Administration of decorin, a naturally occurring inhibitor of TGF-beta 1, to animals bearing the EMT-6/PRK5 beta 1E tumor prior to treatment of the animals with the antitumor alkylating agents restored drug sensitivity to the tumor and to the bone marrow CFU-GM. Administration of decorin prior to the antitumor alkylating agents produced very little or no increase in the response of the EMT6/Parent tumor or the bone marrow CFU-GM from those animals. The EMT6/PRK5 beta 1E tumor model allows the effect of secretion of TGF-beta 1 on therapeutic resistance to be assessed directly compared with the EMT-6/Parent tumor. In vivo resistance occurred in the presence of high levels of TGF-beta 1 and was reversed by the TGF-beta 1 inhibitor decorin.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Ikebe
M
M
Ara
G
G
Keyes
S R
SR
Herbst
R S
RS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D058575:Decorin; D019008:Drug Resistance, Neoplasm; D016326:Extracellular Matrix Proteins; D005260:Female; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011509:Proteoglycans / Q000494:pharmacology*; D013852:Thiotepa / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D003520:Cyclophosphamide; D013852:Thiotepa; D002945:Cisplatin; D008558:Melphalan