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.

[1]  R. Reed,et al.  Lowering of tumoral interstitial fluid pressure by prostaglandin E1 is paralleled by an increased uptake of 51Cr‐EDTA , 2000, International journal of cancer.

[2]  C. Heldin,et al.  Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3' kinase signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Fischman,et al.  Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  A. Siegbahn,et al.  Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium. , 1998, Cell adhesion and communication.

[5]  H. Eichler,et al.  Interstitial methotrexate kinetics in primary breast cancer lesions. , 1998, Cancer research.

[6]  F. Yuan,et al.  Transvascular drug delivery in solid tumors. , 1998, Seminars in radiation oncology.

[7]  K. Rubin,et al.  Tumor cell and connective tissue cell interactions in human colorectal adenocarcinoma. Transfer of platelet-derived growth factor-AB/BB to stromal cells. , 1997, The American journal of pathology.

[8]  T. Helbich,et al.  5-fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients. , 1997, Cancer research.

[9]  R. Reed,et al.  Integrins and control of interstitial fluid pressure. , 1997 .

[10]  K. Giercksky,et al.  Continuous intratumoral microdialysis during high-dose methotrexate therapy in a patient with malignant fibrous histiocytoma of the femur: a case report , 1996, Cancer Chemotherapy and Pharmacology.

[11]  Nebojsa Janjic,et al.  Inhibitory DNA ligands to platelet-derived growth factor B-chain. , 1996, Biochemistry.

[12]  R. Reed,et al.  A novel physiological function for platelet‐derived growth factor‐BB in rat dermis. , 1996, The Journal of physiology.

[13]  R. K. Jain,et al.  Reduction of interstitial fluid pressure after TNF-alpha treatment of three human melanoma xenografts. , 1996, British Journal of Cancer.

[14]  D. Mendrick,et al.  Colon‐cancer cell variants producing regressive tumors in syngeneic rats, unlike variants yielding progressive tumors, attach to interstitial collagens through integrin α2β1 , 1996, International journal of cancer.

[15]  R K Jain,et al.  Delivery of Molecular Medicine to Solid Tumors , 1996, Science.

[16]  M. Shibuya,et al.  Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. , 1994, The Journal of biological chemistry.

[17]  L. Påhlman,et al.  Stromal expression of platelet-derived growth factor beta-receptor and platelet-derived growth factor B-chain in colorectal cancer. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[18]  K. Rubin,et al.  Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. , 1993, The American journal of pathology.

[19]  R. Jain,et al.  Dexamethasone reduces the interstitial fluid pressure in a human colon adenocarcinoma xenograft. , 1993, Cancer research.

[20]  R. Jain,et al.  Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications. , 1992, Cancer research.

[21]  J. Double,et al.  A critical appraisal of the predictive value of in vitro chemosensitivity assays. , 1990, Journal of the National Cancer Institute.

[22]  L. Gold,et al.  Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. , 1990, Science.

[23]  R K Jain,et al.  Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. , 1988, Cancer research.

[24]  C. Heldin,et al.  cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules , 1988, Molecular and cellular biology.

[25]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[26]  F. A. Meyer,et al.  Macromolecular basis of globular protein exclusion and of swelling pressure in loose connective tissue (umbilical cord). , 1983, Biochimica et biophysica acta.

[27]  P. Sejrsen,et al.  Transcapillary exchange of 14C-inulin by free diffusion in channels of fused vesicles. , 1977, Acta physiologica Scandinavica.

[28]  P. Gullino,et al.  THE INTERSTITIAL FLUID OF SOLID TUMORS. , 1964, Cancer research.

[29]  C. Heldin,et al.  Involvement of platelet-derived growth factor in disease: development of specific antagonists. , 2001, Advances in cancer research.

[30]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[31]  N. Janjić,et al.  Novel approach to specific growth factor inhibition in vivo: antagonism of platelet-derived growth factor in glomerulonephritis by aptamers. , 1999, The American journal of pathology.

[32]  T. Meyer,et al.  Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. , 1996, Cancer research.

[33]  T. Borg,et al.  Molecular recognition of the extracellular matrix by cell surface receptors. , 1996 .

[34]  B. Haraldsson,et al.  Transport of macromolecules across microvascular walls: the two-pore theory. , 1994, Physiological reviews.

[35]  R. Reed,et al.  Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. , 1993, Physiological reviews.

[36]  R. Reed,et al.  Interstitial fluid pressure in DMBA-induced rat mammary tumours. , 1982, Scandinavian journal of clinical and laboratory investigation.