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 tumors. 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 tumors; however, upon treatment with cytotoxic therapies there is a greater rise in plasma TGF-beta levels in animals bearing the parent tumor than in animals bearing the resistant tumors. In situ hybridization for TGF-beta mRNA and immunohistochemical staining for TGF-beta protein showed that the resistant tumor levels of this growth factor are higher than those of the parent tumor prior to treatment; however, after cytotoxic 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 determined by tumor cell survival assay. However, administration of decorin 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 these tumors was nearly ablated. A similar pattern was observed in the drug response of the bone marrow granulocyte-macrophage colony-stimulating factor of animals bearing each of the 3 tumors.