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Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy
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 Medical Biochemistry and Microbiology.ORCID iD: 0000-0003-2789-6276
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Novartis Pharma AG, Oncology Research, CH-4002 Basel, Switzerland.
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2002 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 62, no 19, 5476-5484 p.Article in journal (Refereed) Published
Abstract [en]

Lowering of tumor interstitial hypertension, which acts as a barrier for tumor transvascular transport, has been proposed as a general strategy to enhance tumor uptake and therapeutic effects of anticancer drugs. The tyrosine kinase platelet-derived growth factor (PDGF) beta-receptor is one mediator of tumor hypertension. The effects of PDGF antagonists on chemotherapy response were investigated in two tumor models that display PDGF receptor expression restricted to the tumor stroma, and in which PDGF antagonists relieve tumor hypertension. Inhibitory PDGF aptamers and the PDGF receptor tyrosine kinase inhibitor STI571 enhanced the antitumor effect of Taxol on s.c. KAT-4 tumors in SCID mice. Treatment with only PDGF antagonists had no effect on tumor growth. Taxol uptake in tumors was increased by treatment with PDGF antagonists. Cotreatment with PDGF antagonists and Taxol was not associated with antiangiogenic effects, and PDGF antagonists did not enhance the Taxol effect on in vitro growth of KAT-4 cells. STI571 also increased the antitumor effects of 5-fluorouracil on s.c. PROb tumors in syngeneic BDIX rats, without increasing the effect of 5-fluorouracil on cultured PROb cells. Expression of PDGF receptors in tumor stroma, as well as tumor hypertension, occurs in most common solid tumors. Therefore, our results have implications for treatment regimens for large patient groups and merit clinical testing. In conclusion, our study identifies inhibition of PDGF signaling in tumor stroma as a novel, possibly general strategy for enhancement of the therapeutic effects chemotherapy.

Place, publisher, year, edition, pages
2002. Vol. 62, no 19, 5476-5484 p.
Keyword [en]
Enzyme, Transferases, Vertebrata, Mammalia, Rodentia, Stroma, Signal transduction, Pyrimidine derivatives, Fluoropyrimidine derivatives, Taxane derivatives, Cell proliferation, Potentiation, Protein-tyrosine kinase, Enzyme inhibitor, Platelet derived growth factor, Growth factor receptor, Antagonist, Drug combination, Chemotherapy, Antineoplastic agent, Treatment, Malignant tumor, Mouse, Animal, Fluorouracil, Paclitaxel
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89963PubMedID: 12359756OAI: oai:DiVA.org:uu-89963DiVA: diva2:161950
Available from: 2002-09-20 Created: 2002-09-20 Last updated: 2017-12-14Bibliographically 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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Rubin, KristoferHeldin, Carl-Henrik

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