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Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Comparative Medicine.
Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
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2001 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 61, no 7, 2929-2934 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for Cancer Research , 2001. Vol. 61, no 7, 2929-2934 p.
Identifiers
URN: urn:nbn:se:uu:diva-89962PubMedID: 11306470OAI: oai:DiVA.org:uu-89962DiVA: diva2:161949
Available from: 2002-09-20 Created: 2002-09-20 Last updated: 2017-11-10Bibliographically approved
In thesis
1. Inhibition of PDGF receptor signaling in tumor stroma: Effects on interstitial hypertension, drug uptake and therapeutic response
Open this publication in new window or tab >>Inhibition of PDGF receptor signaling in tumor stroma: Effects on interstitial hypertension, drug uptake and therapeutic response
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The role of platelet-derived growth factor (PDGF) in malignancies involves both autocrine and paracrine stimulation of cells within the tumor. The interstitial fluid pressure (IFP) is one of the forces that govern the transvascular flow of fluids. In both experimental and clinical cancers, the IFP is elevated and is thought to act as a barrier for delivery of drugs. Increasing evidence points to PDGF as a positive regulator of the interstitial fluid pressure in loose connective tissue. In this thesis, the effect of PDGF receptor inhibition on the tumor IFP, transvascular transport and efficacy of anti-cancer drugs is investigated.

All studies were performed using tumor models that display extensive tumor stroma and PDGF receptor expression restricted to stroma cells. Blocking of PDGF receptor signaling significantly reduced the tumor IFP in various tumor models. In parallel, pre-treatment with PDGF antagonists increased the tumor content of cytotoxic agents without affecting the uptake in other organs. Moreover, combination treatment with PDGF receptor inhibitors and chemotherapeutic agents dramatically enhanced the anti-tumor effects of the cytotoxic drugs, whereas treatment with only PDGF receptor inhibitors did not affect the growth of the tumors. Beneficial effects on the tumor reponse to radioimmunotherapy were also produced after concomitant administration of PDGF antagonists. Importantly, anti-angiogenic effects, changes in cell composition and increased tumor cell sensitivity to cytotoxic agents were ruled out as the cause for the synergistic effects.

Studies with different temporal scheduling of PDGF receptor inhibitors demonstrated a perfect correlation between a reduced IFP, an increased transvascular transport and an enhanced therapeutic effect of cytotoxic drugs, strongly suggesting that the phenomena are causally linked.

The studies presented herein illustrate for the first time the potential of cells in the stroma compartment as a target for efforts to treat cancer. In conclusion, a novel, possibly general, strategy to enhance the effects of conventional anti-cancer drugs has been identified.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 66 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1181
Keyword
Oncology, PDGF, tumor, stroma, tyrosine kinase inhibitor, combination therapy, Onkologi
National Category
Cancer and Oncology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-2633 (URN)91-554-5403-8 (ISBN)
Public defence
2002-10-11, B41, Uppsala, 09:15
Opponent
Available from: 2002-09-20 Created: 2002-09-20Bibliographically approved

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Heldin, Carl-HenrikRubin, Kristofer

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