REVERSAL OF IN-VIVO DRUG-RESISTANCE BY THE TRANSFORMING GROWTH-FACTOR-BETA INHIBITOR DECORIN

Transforming growth factor-beta (TGF-beta) has been implicated in the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP murine mammary tumo rs. Both of these tumors have a higher number of intratumoral vessels than the EMT-6/parent tumor. Animals bearing the resistant tumors have higher plasma levels of TGF-beta than animals bearing the parent tumo rs; however, upon treatment with cytotoxic therapies there is a greate r rise in plasma TGF-beta levels in animals bearing the parent tumor t han in animals bearing the resistant tumors. In site hybridization for TGF-beta mRNA and immunohistochemical staining for TGF-beta protein s howed that the resistant tumor levels of this growth factor are higher than those of the parent tumor prior to treatment; however, after cyt otoxic therapy the increase in TGF-beta is greater in the parent tumor than in the resistant tumors. Treatment of tumor-bearing animals with the naturally occurring TGF-beta inhibitor decorin did not alter the sensitivity of the parent tumor to cyclophosphamide or to CDDP as dete rmined by tumor cell survival assay. However, administration of decori n increased the sensitivity of the EMT-6/CTX tumor to cyclophosphamide and of the EMT-6/CDDP tumor to CDDP so that the drug resistance of th ese tumors was nearly ablated. A similar pattern was observed in the d rug response of the bone marrow granulocyte-macrophage colony-stimulat ing factor of animals bearing each of the 3 tumors. (C) 1997 Wiley-Lis s, Inc.