Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance to chloroquine in Plasmodium falciparum bears a striking similarity to the multi-drug resistance (MDR) phenotype of mammalian tumor cells which is mediated by overexpression of P-glycoprotein. We show here that the P. falciparum homologue of the P-glycoprotein (Pgh1) is a 160,000-D protein that is expressed throughout the asexual erythrocytic life cycle of the parasite. Quantitative immunoblotting analysis has shown that the protein is expressed at approximately equal levels in chloroquine resistant and sensitive isolates suggesting that overexpression of Pgh1 is not essential for chloroquine resistance. The chloroquine-resistant cloned line FAC8 however, does express approximately threefold more Pgh1 protein than other isolates which is most likely because of the increased pfmdr1 gene copy number present in this isolate. Immunofluorescence and immunoelectron microscopy has demonstrated that Pgh1 is localized on the membrane of the digestive vacuole of mature parasites. This subcellular localization suggests that Pgh1 may modulate intracellular chloroquine concentrations and has important implications for the normal physiological function of this protein.
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PMID:A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. 167 43

Overexpression of the Multiple Drug Resistance gene (MDR1) has been proposed as a major mechanism related to both intrinsic and acquired resistance to chemotherapeutic agents. The gene product is a membrane protein (P-glycoprotein), that acts as an energy-dependent drug efflux pump decreasing drug accumulation in resistant tumor cells. We have characterized MDR1 and P-Glycoprotein expression in human gastric adenocarcinoma and in precursor lesions. MDR1 mRNAs, analyzed by dot-blot technique, were detected in 9 of 10 non-tumoral gastric mucosae and in 8 of 10 gastric adenocarcinomas. Immunohistochemical analysis, using the MRK16 monoclonal antibody, revealed heterogeneous expression of P-Glycoprotein in individual cells. The P-Glycoprotein was found on the surface of cells of gastric areas with intestinal metaplasia subtype III. This type of intestinal metaplasia, also called "colonic metaplasia", has been strongly associated with a high risk for the development of gastric cancer. The fact that the P-Glycoprotein was detected in this precursor lesion is consistent with the intestinal metaplasia-dysplasia and carcinoma sequence proposed in the histogenesis of this tumour. The finding that P-Glycoprotein was heterogeneously expressed in malignant cells of some gastric adenocarcinomas also suggests that this transporter system probably contributes to primary and secondary multidrug resistance in this neoplasm.
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PMID:Multidrug resistance gene and P-glycoprotein expression in gastric adenocarcinoma and precursor lesions. 167 10

We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA did not express MDR-1. Accumulation of ADM by K562/TPA was no lower than that of K562 although that of K562/ADM was 5-fold lower than K562. We examined the subcellular distribution of ADM by fluorescence microscopy. The fluorescence of ADM was located in the nucleus of K562 and mainly in the cytoplasm of K562/TPA and K562/ADM. The distribution of ADM in K562/TPA, however, was different from that in K562/ADM. These results suggested that K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.
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PMID:Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance. 167 41

Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents, the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients, total RNA analysis demonstrated no correlation with differentiation, but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor, poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors, both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma, a ganglioneuroma, had no detectable expression in the neurofibrillary material, but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.
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PMID:Expression of mdr-1/P-glycoprotein in human neuroblastoma. 167 52

The new nonimmunosuppressive cyclosporin analogue, SDZ PSC 833, is a very potent multidrug-resistance modifier. In vitro, it was shown to be at least 10-fold more active than cyclosporin A (Sandimmune), itself more active than verapamil, on most P-glycoprotein-expressing multidrug-resistant (MDR) tumor cell lines. In vivo, SDZ PSC 833 was tested in a few protocols of combined therapy with either Vinca alkaloids or doxorubicin as anticancer drugs, using the homologous tumor-host system (P388 cells of DBA/2 origin grafted into DBA/2 or B6D2F1 mice). Although these MDR-P388 tumor cells belong to a highly resistant variant that in vitro required about 150-fold more anticancer drug for 50% cell growth inhibition than the parental P388 cells, significant prolongation of survival times of the MDR-P388 tumor-bearing mice was obtained when treated with a combination of SDZ PSC 833 p.o. were otherwise ineffective doses of anticancer drugs given i.p. This chemosensitizing effect of SDZ PSC 833 was dose-dependent and was most effective in a protocol combining administration of SDZ PSC 833 p.o. 4 h before a doxorubicin i.p. injection: in comparison with the survival of MDR-P388 tumor-bearing mice treated with the anticancer drug alone, the pretreatment with SDZ PSC 833 at 25 and 50 mg/kg gave 2- to 3-fold increases of survival times. Since the MDR-P388 tumor cells used in our studies belong to a highly resistant variant, with a much higher degree of drug resistance than the one known to occur in cancer patients, SDZ PSC 833 appears to be a very promising chemosensitizer.
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PMID:In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. 167 13

Dipyridamole (DPM) at 10 microM enhanced the cytotoxicity of anti-tumor drugs, which were associated with multidrug resistance, more in multidrug-resistant human hepatoma PLC/PRF/5 cells (PLC/COL) than in its parental cells (PLC/S). DPM increased, dose-dependently, the intracellular accumulation of [3H]vinblastine in PLC/COL. However, the effect was immediately diminished by its removal from the medium, indicating that DPM needed to be present together with the anti-tumor drugs to enhance the intracellular accumulation of the drugs. DPM inhibited the efflux of [3H]vinblastine from the PLC/COL cells, the binding of [3H]vinblastine to membrane vesicles of PLC/COL, and the binding of [3H]azidopine to P-glycoprotein in the plasma membrane of PLC/COL. Apparently DPM binds to P-glycoprotein and inhibits active efflux. [14C]labeled DPM was quickly incorporated into the cells and the cellular level of [14C]DPM reached a plateau after 5 min. It was slightly higher in PLC/S than in PLC/COL. The cellular [14C]DPM quickly disappeared after its removal from the medium. These results indicate that DPM binds quickly but reversibly to various kinds of cellular proteins including P-glycoprotein and inhibits active efflux of some anti-tumor drugs in multi-drug-resistant tumor cells, resulting in the enhancement of the activities of these drugs.
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PMID:Enhancement of activities of anti-tumor drugs by dipyridamole against multidrug-resistant human hepatoma PLC/PRF/5 cells. 167 5

The multidrug transporting cell membrane molecule P-glycoprotein can be spontaneously expressed in human glioma cells. Transcripts of mdr genes were detected in glial tumor cells by polymerase chain reaction and Northern blotting, expression of P-glycoprotein was analyzed by immunocytochemistry and functional activity by cytofluorometry of fluorescent probe transport. In vitro treatment of glioma cells with vincristine induced coordinate over-expression of both mdr1 and mdr3 genes associated with very high P-glycoprotein-mediated multidrug transport, resistant to the inhibitory activity of chemosensitizers like verapamil. The physiological modulators of multidrug transport are as yet unknown. We therefore initiated a screening program to analyze the effects of cytokines on multidrug transport. We observed, that transforming growth factors (TGF)-beta 1, -beta 2, and -beta 1.2-but not the related bone morphogenetic protein (BMP) 2--inhibited multidrug transport. Interestingly, BMP 2 antagonized the TGF-beta induced inhibition of multidrug transport.
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PMID:Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type beta. 167 77

In vivo exposure of a human epidermoid lung carcinoma xenograft to seven irradiation treatments of 10 Gy in consecutive passages resulted in expression of resistance to vincristine. This about threefold drug resistance was detectable with a single dose of 1 mg/kg vincristine. Characterization of the radiation-pretreated subline showed that overexpression of P-glycoprotein, as determined by immunofluorescence and Mabs C219 and 265/F4, occurred in this tumor. After six X-ray fractions, only single positive cells were observed, whereas seven fractions produced an intense immunofluorescent reaction with both antibodies. Southern blot analyses indicated that no gene amplification had occurred. This result shows that irradiation can influence expression of P-glycoprotein and in this way influences drug resistance.
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PMID:Overexpression of P-glycoprotein in human lung carcinoma xenografts after fractionated irradiation in vivo. 167 64

P-glycoproteins are responsible for multidrug resistance in tumor cell lines and are thought to have a physiologic role in exporting cellular metabolites. We now report that a P-glycoprotein gene in the H region of the trypanosomatid protozoan Leishmania confers resistance to heavy metals when present in multiple copies. The Leishmania H region is frequently amplified in drug-resistant lines and is associated with metal resistance. Leishmania expression vectors were used to introduce multiple copies of segments of the Leishmania major H region into wild-type L. major promastigotes. Only constructs bearing a segment of L. major DNA containing the P-glycoprotein lmpgpA conferred arsenite resistance. Deletional analysis of the arsenite-resistant construct mapped resistance to the lmpgpA protein coding region. Lines expressing lmpgpA showed resistance to arsenite and trivalent antimonials, but not to pentavalent antimonials, zinc, cadmium, or the typical multidrug-resistant P-glycoprotein substrates vinblastine and puromycin. Transfection of the Leishmania tarentolae P-glycoprotein homologue ltpgpA resulted in a similar resistance profile. Thus, these pgpAs represent a functionally distinct group of P-glycoproteins which exhibit a substrate specificity similar to prokaryotic heavy metal pumps. Additionally, several arguments suggest that pgpAs may play a role in the susceptibility of Leishmania to clinically utilized antimonials.
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PMID:Heavy metal resistance: a new role for P-glycoproteins in Leishmania. 168 Aug 61

One strategy to overcome multidrug resistance in neoplasia is to inhibit the gp170 glycoprotein (relative molecular mass, 170,000) that functions as a plasma membrane, energy-dependent, drug-efflux pump. The human colon cancer cell line HT-29, which grows as an ascitic tumor in athymic NCr-nu/nu nude mice, was made multidrug resistant by infection with an MDR1 (also known as PGY1) retrovirus. Referred to as HT-29mdr1, it was used to study reversal of drug resistance in vivo by the anti-P-glycoprotein monoclonal antibody MRK-16. Flow cytometry and radioimmunoassay demonstrated a marked increase in MRK-16 reactivity on HT-29mdr1 cells as compared with its reactivity on the parental, uninfected cell line (HT-29par). The 50% inhibitory concentrations (IC50) of vincristine on HT-29par and HT-29mdr1 cells were 2.5 and 15 ng/mL, respectively. The MRK-16 monoclonal antibody did not affect the vincristine sensitivity of the HT-29par cells. Pretreatment of HT-29mdr1 cells with 10 micrograms/mL MRK-16 in tissue culture partially restored the vincristine sensitivity (IC50 = 7 ng/mL). This modulation of vincristine sensitivity by MRK-16 was then tested in vivo. The median survival times of mice given intraperitoneal transplants of 5 x 10(6) HT-29par or HT-29mdr1 were 37 and 39 days, respectively. Treatment of mice with 1 mg/kg vincristine weekly for 3 weeks, beginning 10 days after tumor injection, resulted in a significant increase in the median survival time of the HT-29par tumor-bearing mice (68 days, P less than .0001), but it had no effect on the HT-29mdr1 tumor-bearing mice. However, treatment of mice bearing the HT-29mdr1 tumor with MRK-16 before vincristine therapy reversed the resistance to the drug (median survival time = 64 days, P less than .0001). The MRK-16 monoclonal antibody alone had no effect on the median survival time of mice given an injection of either HT-29par or HT-29mdr1 cells. These results suggest that strategies employing monoclonal antibody against gp170 may be clinically useful to reverse multidrug resistance.
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PMID:Reversal of drug resistance in a human colon cancer xenograft expressing MDR1 complementary DNA by in vivo administration of MRK-16 monoclonal antibody. 168 Nov 10


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