This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toth, K. Articles by Rustum, Y. M. Search for Related Content PubMed PubMed Citation Articles by Toth, K. Articles by Rustum, Y. M.

American Journal of Pathology, Vol 149, 853-858, Copyright © 1996 by American Society for Investigative Pathology

REGULAR ARTICLES

MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors

K Toth, MM Vaughan, NS Peress, HK Slocum and YM Rustum
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

The expression of human MDR1 P-glycoprotein (Pgp) in the capillary endothelial cells of the central nervous system has been demonstrated. The brain capillary endothelial cells maintain the structure and function of the blood-brain barrier. Recently, the human MDR1 Pgp (and its mouse homologue MDR1a Pgp) has been shown to function as an important part of this barrier, pumping out xenobiotics from endothelial cells into the lumen of capillaries resulting in the protection of the brain parenchyma. To examine whether the endothelial cells of the newly formed capillaries during neoangiogenesis within malignant human brain tumors express MDR1 Pgp, 35 adult surgical brain tumor specimens (29 gliomas and 6 tumors metastatic to the brain) were obtained from previously untreated patients and studied by a new immunohistochemical sandwich method developed in our laboratory using the JSB-1 monoclonal antibody. JSB-1 is specific for the Pgp product of the human MDR1 (and not MDR3) gene. This sensitive method allows the detection of Pgp in capillary endothelial cells of normal brain in conventional paraffin sections after formalin fixation. The endothelial cells of the newly formed capillaries in 25 of 29 gliomas (86%) and 3 of 6 metastatic tumors, immunostained positive for MDR1 Pgp. The tumor cells in 7 of 35 cases were also positive for Pgp. In the 35 brain tumor cases investigated, the endothelial cells were Pgp positive in the tumor-brain border and in the brain further from the tumor. Capillary endothelial cells of neovasculature in 137 malignant tumors (non-brain) obtained from previously untreated patients showed no MDR1 Pgp expression. These results demonstrated that MDR1 Pgp is expressed not only in the capillaries of normal brain but also in the majority of the newly formed capillaries of brain tumors. Multidrug resistance of brain tumors may result not only from the expression of resistance markers in neoplastic cells but also from the MDR1 Pgp expression in endothelial cells of tumor capillaries. Pgp in this special localization can exclude chemotherapeutic agents from tumor cells that are located around the capillaries. The therapeutic benefit and selectivity of chemotherapeutic agents in combination with a Pgp- reversing agent should be evaluated.

This article has been cited by other articles:

				M. Schaich, L. Kestel, M. Pfirrmann, K. Robel, T. Illmer, M. Kramer, C. Dill, G. Ehninger, G. Schackert, and D. Krex A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients Ann. Onc., August 7, 2008; (2008) mdn548v1. [Abstract] [Full Text] [PDF]

				E. R. Gerstner and R. L. Fine Increased Permeability of the Blood-Brain Barrier to Chemotherapy in Metastatic Brain Tumors: Establishing a Treatment Paradigm J. Clin. Oncol., June 1, 2007; 25(16): 2306 - 2312. [Abstract] [Full Text] [PDF]

				J. F. Deeken and W. Loscher The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses Clin. Cancer Res., March 15, 2007; 13(6): 1663 - 1674. [Abstract] [Full Text] [PDF]

				R. L. Fine, J. Chen, C. Balmaceda, J. N. Bruce, M. Huang, M. Desai, M. B. Sisti, G. M. McKhann, R. R. Goodman, J. S. Bertino Jr., et al. Randomized study of Paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors. Clin. Cancer Res., October 1, 2006; 12(19): 5770 - 5776. [Abstract] [Full Text] [PDF]

				J. P. Fruehauf, H. Brem, S. Brem, A. Sloan, G. Barger, W. Huang, and R. Parker In vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas Clin. Cancer Res., August 1, 2006; 12(15): 4523 - 4532. [Abstract] [Full Text] [PDF]

				G. D. Leonard, T. Fojo, and S. E. Bates The Role of ABC Transporters in Clinical Practice Oncologist, October 1, 2003; 8(5): 411 - 424. [Abstract] [Full Text] [PDF]

				J. M. Gallo, S. Li, P. Guo, K. Reed, and J. Ma The Effect of P-glycoprotein on Paclitaxel Brain and Brain Tumor Distribution in Mice Cancer Res., August 15, 2003; 63(16): 5114 - 5117. [Abstract] [Full Text] [PDF]

				E. M. Kemper, A. E. van Zandbergen, C. Cleypool, H. A. Mos, W. Boogerd, J. H. Beijnen, and O. van Tellingen Increased Penetration of Paclitaxel into the Brain by Inhibition of P-Glycoprotein Clin. Cancer Res., July 1, 2003; 9(7): 2849 - 2855. [Abstract] [Full Text] [PDF]

				K. D. Miller, C. J. Sweeney, and G. W. Sledge The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era Ann. Onc., January 1, 2003; 14(1): 20 - 28. [Abstract] [Full Text] [PDF]

				K. D. Miller, C. J. Sweeney, and G. W. Sledge Jr Redefining the Target: Chemotherapeutics as Antiangiogenics J. Clin. Oncol., February 15, 2001; 19(4): 1195 - 1206. [Abstract] [Full Text] [PDF]

				K. Toth, M. M. Vaughan, G. Schwartz, J. S. Winston, B. S. Skenderis II, H. K. Slocum, and Y. M. Rustum Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections International Journal of Surgical Pathology, July 1, 1998; 6(3): 145 - 154. [Abstract] [PDF]