Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we examined the effect of interleukin-2 (IL-2) gene transfer into multidrug resistance (MDR) cancer cells on the therapeutic efficacy of MRK16. Human MDR ovarian cancer cells, AD10, were transduced with a bicistronic IL-2 retrovirus, Ha-IL2-IRES-Neo. The G418-resistant population, IL2-AD10, secreted IL-2 into the culture supernatant and did not form a tumor mass in nude mice. The IL2-AD10 cells were more susceptible to the cytotoxicity of murine spleen cells than AD10 cells in vitro. For examination of the effect of IL-2 gene transfer on the antitumor activity of MRK16 against P-glycoprotein-positive tumors, IL2-AD10 cells were co-transplanted s.c. with AD10 cells into nude mice in a ratio of 1:3, and the mice were treated with MRK16 on days 2 and 7. MRK16 markedly inhibited the growth of AD10 cells mixed with IL2-AD10 cells under conditions (0.3-1 microgram/body) where it showed only marginal effects on the growth of AD10 tumors. These findings suggest that IL-2 gene transfer potentiates the antitumor activity of MRK16 against MDR tumors.
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PMID:Combination therapy with antibody and interleukin-2 gene transfer against multidrug-resistant cancer cells. 943 86

We obtained a full-length cDNA fragment encoding human O(6)-methylguanine-DNA-methyltransferase (MGMT) from the liver tissue of a patient with cholelithiasis by RT-PCR and confirmed by DNA sequencing. The polycistronic retrovirus vector G1Na-MGMT-Neo(r)-IRES-MDR1 was constructed and verified by restriction endonuclease analysis and DNA sequencing. The vector was transfected into packaging cells GP+E86 and PA317 by the LipofectAMINE method. Cord blood CD34+ cells were transfected with the supernatant of retrovirus containing human MGMT and MDR1cDNA under stimulation of hematopoietic growth factors. PCR, RT-PCR, Southern Blot, Western Blot, FACS and MTT analyses showed that dual drug resistance genes have been integrated into the genomic DNA of cord blood CD34+ cells and expressed efficiently. The transgene cord blood CD34+ cells conferred 5.8-6.3-fold stronger resistance to P-glycoprotein effluxed drugs and 5-fold to BCNU than untransduced cells. The polycistronic retrovirus vector mediated transfer of two different types of drug resistance genes into human cord blood CD34+ cells and co-expression provided an experimental foundation for improving combination chemotherapy tolerance in clinical practice.
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PMID:Improvement of combination chemotherapy tolerance by introduction of polycistronic retroviral vector drug resistance genes MGMT and MDR1 into human umbilical cord blood CD34+ cells. 1179 17

Studies in patients have indicated that the oral absorption of thalidomide is considerably variable at high doses (>200 mg/day). The aim of this study was to investigate the transport of racemic thalidomide using human colon cancer cell line (Caco-2) monolayers, which have been widely used to investigate drug permeability. A typical 21-day protocol was used to prepare Caco-2 monolayers. Thalidomide was determined by a validated high performance liquid chromatography method with ultraviolet detection. The integrity of Caco-2 monolayer was confirmed when the transepithelial electrical resistance (TEER) exceeded 300 Ohmz . cm2, and the leakage of 14C-manitol was <1% per hour. Uptake of thalidomide by Caco-2 cells was very limited (up to 2.1%). The transport of thalidomide appeared to be linear up to 1 hr. Our study indicated that the permeability coefficients (Papp) of thalidomide at 2.5-300 microM from the apical (AP) to basolateral (BL) and from BL to AP side was 2-6 x 10(-5) cm/sec, with a marked decrease in Papp values from AP to BL at increased thalidomide concentration. The transport of thalidomide was sodium-, temperature- and pH-dependent, as replacement of extracellular sodium chloride or reducing temperature and apical pH can result in significant decreases in the Papp values. Additional data indicated that transport of thalidomide is energy-dependent, as it was significantly (P < 0.05) inhibited by the ATP inhibitors, sodium azide and 2,4-dinitrophenol. In addition, DL-glutamic acid, cytidine, diprodomole, papaverine, quinidine, and cyclophosphamide significantly (P < 0.05) inhibited the transport of thalidomide, while the P-glycoprotein inhibitor verapamil and other nucleosides and nucleotides such as thymidine and guanine had no effect. These results indicated that thalidomide was rapidly transported by Caco-2 monolayers, and this might involve a saturable energy-dependent transporter.
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PMID:Transport of thalidomide by the human intestinal caco-2 monolayers. 1601 Aug 62

Dose-limiting diarrhea and myelosuppression compromise the success of irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin) (CPT-11)-based chemotherapy. A recent pilot study indicates that thalidomide attenuates the toxicity of CPT-11 in cancer patients. This study aimed to investigate whether coadministered thalidomide modulated the toxicities of CPT-11 and the underlying mechanisms using several in vivo and in vitro models. Diarrhea, intestinal lesions, cytokine expression, and intestinal epithelial apoptosis were monitored. Coadministered thalidomide (100 mg/kg i.p. for 8 days) significantly attenuated body weight loss, myelosuppression, diarrhea, and intestinal histological lesions caused by CPT-11 (60 mg/kg i.v. for 4 days). This was accompanied by inhibition of tumor necrosis factor-alpha, interleukins 1 and 6 and interferon-gamma, and intestinal epithelial apoptosis. Coadministered thalidomide also significantly increased the systemic exposure of CPT-11 but decreased that of SN-38 (7-ethyl-10-hydroxycampothecin). It significantly reduced the biliary excretion and cecal exposure of CPT-11, SN-38, and SN-38 glucuronide. Thalidomide hydrolytic products inhibited hydrolysis of CPT-11 in rat liver microsomes but not in primary rat hepatocytes. In addition, thalidomide and its major hydrolytic products, such as phthaloyl glutamic acid (PGA), increased the intracellular accumulation of CPT-11 and SN-38 in primary rat hepatocytes. They also significantly decreased the transport of CPT-11 and SN-38 in Caco-2 and parental MDCKII cells. Thalidomide and PGA also significantly inhibited P-glycoprotein (PgP/MDR1), multidrug resistance-associated protein (MRP1)- and MRP2-mediated CPT-11 and SN-38 transport in MDCKII cells. These results provide insights into the pharmacodynamic and pharmacokinetic mechanisms for the protective effects of thalidomide against CPT-11-induced intestinal toxicity.
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PMID:A mechanistic study on reduced toxicity of irinotecan by coadministered thalidomide, a tumor necrosis factor-alpha inhibitor. 1681 71

The drug efflux transporter P-glycoprotein (P-gp) is an active component of the placental barrier which protects the fetus against maternal xenobiotics. The goal of the study was to compare species difference between human and rat in terms of susceptibility to drugs at the level of the placental barrier using in vitro models in order to improve translation from rat to human. Effects of selected drugs (Aspirin, Methadone, a Cardiovascular Proprietary Compound, Thalidomide) on cytotoxicity and P-gp expression and activity were compared using human and rat trophoblast cultures. No direct cytotoxicity of drugs on trophoblasts was noted in both invitro models, but for Thalidomide a proliferative effect on human trophoblast primocultures was observed. All tested drugs induced changes towards P-gp; for each drug the same profile was noted in both human and rat trophoblast models except for Thalidomide. Observation of this similar response between these two in vitro trophoblast models is promising for assessment between P-gp expression and activity of drugs towards placental function.
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PMID:Comparative effects of drugs on P-glycoprotein expression and activity using rat and human trophoblast models. 1984 Aug 43