Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors

Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGF beta receptors was shown recently to increase interstitial fluid press ure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this stud y, we show that treatment with the selective PDGF receptor kinase inhibitor , STI571, formerly known as CGP57148B, decreased the interstitial hypertens ion and increased capillary-to-interstitium transport of Cr-51-EDTA in s.c. growing rat PROb colonic carcinomas, Furthermore, treatment with an antago nistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension i n these tumors, PDGF beta receptors were expressed in blood vessels and str omal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biolog y, although similar effects of PDGF on IFP have been demonstrated previousl y in the dermis, The data suggest interference with PDGF receptors, or thei r ligands, as a novel strategy to increase drug uptake and therapeutic effe ctiveness of cancer chemotherapy.