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[Cancer Research 61, 2929-2934, April 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Inhibition of Platelet-derived Growth Factor Receptors Reduces Interstitial Hypertension and Increases Transcapillary Transport in Tumors1

Kristian Pietras2, Arne Östman2, Mats Sjöquist, Elisabeth Buchdunger, Rolf K. Reed, Carl-Henrik Heldin and Kristofer Rubin3

Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden [K. P., A. Ö., C-H. H.]; Department of Physiology and Comparative Medicine, Uppsala University, SE-751 23 Uppsala, Sweden [M. S.]; Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland [E. B.]; Department of Physiology, University of Bergen, N-5009 Bergen, Norway [R. K. R.]; and Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden [K. R.]

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 PDGFß receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to- interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFß receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.




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