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 PDGFbeta 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. PDGFbeta 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.
Pietras
K
K
Ludwig Institute for Cancer Research, Uppsala, Sweden.
Ostman
A
A
Sjöquist
M
M
Buchdunger
E
E
Reed
R K
RK
Heldin
C H
CH
Rubin
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism*; D004492:Edetic Acid / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000068877:Imatinib Mesylate; D017551:Microdialysis; D009841:Oligonucleotides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D040281:Vascular Endothelial Growth Factor Receptor-1
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D009841:Oligonucleotides; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004492:Edetic Acid; C501164:Flt1 protein, rat; C099852:PDGF receptor tyrosine kinase; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1