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A novel member of the multidnig resistance gene famiiy is expressed in human brain tumors
ily isexpressed
Becker, K-F., Becker *, I., Keimer, S. and I-Iiillt, V. Imitut,
Pettenkvferst
12, D-8000 Miinchen 2 and * Institut jiir Hirnfwschung
Calverstr. 3. D-7400 Tiiingen,
F. R.G.
Cross-resistance to multiple chemotherapeutic drugs is a major problem in the chemotherapy of human cancer. 1s have been shown to overexpress a plasma membrane glycoprotein of relative coprotein), which seems to function as an energy dependent drug efflux pump. member of the MDR transporter family from a mouse neuroblastoma X rat glioma hybrid cell This new clone was termed NG-TRA. A comparison between a partial sequence of about 2.2 kb of human mdrl cDNA, which codes for P-glycoprotein, demonstrated that 70% of the deduced amino acids were conserved. On Notbem blots with RNA from NG108-15 cells, our clone detected a single mRNA species of kb. NG-TRA is also expressed in organs with secretory and/or excretory function, such as kidney, liver and nal glaud, These sites are known to synthesize P-gfycoprotein. In situ hybridization experiments using slices of rat that NG-TRA is expressed in certain regions of the white matter. This finding indicates that glial cells major sites of biosynthesis of NG-TRA within the nervous system. P-glycoprotein - on the other hand - shows a nt distribution in human brain: it is synthesized in endothelial cells only. In order to find out whether NG-TRA is expressed in human brain tumors, we examined freshly frozen biopsies of ghal tumors. The patients had not been treated with chemotherapeutic drugs. Nothem blot analysis with RNA isolated from these biopsies showed a single mRNA band of 4.5 kb. In addition, we found a single mRNA species of the same length in A from primary cell cultures of human glial tumors. In conclusion: we isolated a partial cDNA (NG-TRA) from a NG108-I5 hybrid cell line which shows strong homology to the human mdrl cDNA. NG-TRA is expressed in organs that are known to synthesize P-glycoprotein. In contrast to the product of the human mdrl gene, NG-TRA is found in glial cells. We detected a human homologue of RA in biopsies and primarycell cultures of glial tumors. A number of tumors derived from glial cells are known mtrinsically resistant to chemotherapeutic drugs. Although the relationship between NG-TRA and the multidrug resistance remains to be examined, our results are in line with the assumption that, in addition to P-glycoprotein, other (putative) transporter may play a role in the MDR phenotype.
Davis, T.P., McInturff, B., Moody *, T.W. and Crowell, S.L. Department of Pharmacology. The University of Arizonq College of Medicine, Tucson, Arizona 85724 and * Department of Biochemistty, The George Washington University Medical Center. Washington. DC 20037. U.S.A.
tease bitors have been shown to suppress transformation in cell culture and tumorigenesis in animals. Tumorigenesis in mouse skin induced by 7,12dimethylbenz(a)anthracene and promoted by phorbol ester is inhibited by tosyl-phenylalanine-chloromethylketone (TPCK) and tosyl-L-lysl-chloromethylketone (TLCK), chemically synthesized inhibitors of chymotrypsin and trypsin, respectively. Also, small microbiologically derived peptide inhibitors leupeptin and anti pain inhibit in vitro transformation of mouse C3H/lOT1/2 cells by x-rays and promoted by phorbol ester (Kennedy and Little, 1981). Therefore, several proteases may be important in the development and maintenance of the transformed phenotype. Rmently wr: have shown that &endorphin. neurotensin and bombesin act as autocrine growth factors by
Becker, K-F., Becker *, I., Keimer, S. and I-Iiillt, V. Imitut,
Pettenkvferst
12, D-8000 Miinchen 2 and * Institut jiir Hirnfwschung
Calverstr. 3. D-7400 Tiiingen,
F. R.G.
Cross-resistance to multiple chemotherapeutic drugs is a major problem in the chemotherapy of human cancer. 1s have been shown to overexpress a plasma membrane glycoprotein of relative coprotein), which seems to function as an energy dependent drug efflux pump. member of the MDR transporter family from a mouse neuroblastoma X rat glioma hybrid cell This new clone was termed NG-TRA. A comparison between a partial sequence of about 2.2 kb of human mdrl cDNA, which codes for P-glycoprotein, demonstrated that 70% of the deduced amino acids were conserved. On Notbem blots with RNA from NG108-15 cells, our clone detected a single mRNA species of kb. NG-TRA is also expressed in organs with secretory and/or excretory function, such as kidney, liver and nal glaud, These sites are known to synthesize P-gfycoprotein. In situ hybridization experiments using slices of rat that NG-TRA is expressed in certain regions of the white matter. This finding indicates that glial cells major sites of biosynthesis of NG-TRA within the nervous system. P-glycoprotein - on the other hand - shows a nt distribution in human brain: it is synthesized in endothelial cells only. In order to find out whether NG-TRA is expressed in human brain tumors, we examined freshly frozen biopsies of ghal tumors. The patients had not been treated with chemotherapeutic drugs. Nothem blot analysis with RNA isolated from these biopsies showed a single mRNA band of 4.5 kb. In addition, we found a single mRNA species of the same length in A from primary cell cultures of human glial tumors. In conclusion: we isolated a partial cDNA (NG-TRA) from a NG108-I5 hybrid cell line which shows strong homology to the human mdrl cDNA. NG-TRA is expressed in organs that are known to synthesize P-glycoprotein. In contrast to the product of the human mdrl gene, NG-TRA is found in glial cells. We detected a human homologue of RA in biopsies and primarycell cultures of glial tumors. A number of tumors derived from glial cells are known mtrinsically resistant to chemotherapeutic drugs. Although the relationship between NG-TRA and the multidrug resistance remains to be examined, our results are in line with the assumption that, in addition to P-glycoprotein, other (putative) transporter may play a role in the MDR phenotype.
Davis, T.P., McInturff, B., Moody *, T.W. and Crowell, S.L. Department of Pharmacology. The University of Arizonq College of Medicine, Tucson, Arizona 85724 and * Department of Biochemistty, The George Washington University Medical Center. Washington. DC 20037. U.S.A.
tease bitors have been shown to suppress transformation in cell culture and tumorigenesis in animals. Tumorigenesis in mouse skin induced by 7,12dimethylbenz(a)anthracene and promoted by phorbol ester is inhibited by tosyl-phenylalanine-chloromethylketone (TPCK) and tosyl-L-lysl-chloromethylketone (TLCK), chemically synthesized inhibitors of chymotrypsin and trypsin, respectively. Also, small microbiologically derived peptide inhibitors leupeptin and anti pain inhibit in vitro transformation of mouse C3H/lOT1/2 cells by x-rays and promoted by phorbol ester (Kennedy and Little, 1981). Therefore, several proteases may be important in the development and maintenance of the transformed phenotype. Rmently wr: have shown that &endorphin. neurotensin and bombesin act as autocrine growth factors by