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

Age has important prognostic impact in acute lymphoblastic leukemia (ALL). Adults with ALL have a worse prognosis compared to children. This may be due to different, unfavorable biology, poor treatment tolerance, drug resistance, higher expression of drug resistance related proteins. The lymphoblasts from adult ALL show an increased in vitro resistance to cytotoxic drugs, including prednisolone, dexamethasone, cytosine arabinoside, daunorubicin, L-asparaginase and methotrexate. Glucocorticoid resistance may be a fundamental difference between children, adolescents and adults with ALL, which may underlie different biological aspects and also explain the difference in prognosis. It seems that in vitro resistance to prednisolone with respect to the age might be a continuous variable in ALL patients, except infants. The greater the age, the higher the in vitro resistance to prednisolone. This may be due to induction of various defense mechanisms, such as an activation of P-glycoprotein, which develops throughout the life and protect the human against xenobiotics. Among a number of various drug resistance mechanisms, only several weak differences between adults and children with ALL have been reported including higher P-glycoprotein expression, lower methotrexate polyglutamate accumulation and possibly more often p53 gene mutations in adults. Intrinsic resistance, induction of drug resistance proteins expression during chemotherapy and co-existence of various mechanisms are common phenomena in adult ALL. It seems that age itself, more than drug resistance profile, reflects factors which have direct effect on chemotherapy response in adult ALL.
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PMID:In vitro drug resistance profiles of adult acute lymphoblastic leukemia: possible explanation for difference in outcome to similar therapeutic regimens. 1199 61

Higher technetium-99m methoxyisobutylisonitrile (MIBI) uptake in non-small cell lung cancer (NSCLC) has been reported to be associated with a positive response to chemotherapy. It has previously been found that in tumour cells, P-glycoprotein (Pgp) expression is of importance for tracer uptake. However, some studies have indicated that Pgp expression does not play an important role in (99m)Tc-MIBI uptake in NSCLC; indeed, a negative correlation between (99m)Tc-MIBI uptake and Pgp expression has been reported. Against the background of conflicting results, our aim was to evaluate the relationship between (99m)Tc-MIBI uptake, prognosis and Pgp expression in NSCLC. A total of 37 patients with NSCLC underwent (99m)Tc-MIBI single-photon emission tomography (SPET) before chemotherapy. In 19 patients both Pgp and p53 expression, and in two patients only p53 expression (due to the limited biopsy material), were measured with immunohistochemical staining. (99m)Tc-MIBI uptake was significantly higher in responders than in non-responders: 3.09+/-1.14 vs 2.24+/-0.88 ( P<0.03) and 3.09+/-1.08 vs 2.37+/-1.06 ( P<0.05) for the early ratio (ER) and the delayed ratio (DR), respectively. The wash-out rate (WR) of responders was not significantly different from that of non-responders. We found no significant differences in ER, DR and WR among the groups positive or negative for Pgp and p53 status. There was a significant positive correlation between the survival rate and both ER and DR: r=0.49 ( P=0.003) and r=0.40 ( P=0.018), respectively. Patients with ER and DR values above 3 showed significantly longer survival than those with values below 3: 14.7+/-8.5 months vs 7.3+/-5.1 months ( P<0.009) and 13.2+/-8.4 months vs 7.4+/-5.3 months ( P<0.04) for ER and DR, respectively. However, interestingly, and in contrast to expectations, patients with a Pgp score of +2 showed significantly longer survival (12.9+/-6.7 months) than those with Pgp scores of +1 (4.4+/-3.0 months) or - (negative) (3.8+/-2.2 months) ( P<0.009 and P<0.02, respectively). Our results suggest that in NSCLC, patients with higher (99m)Tc-MIBI uptake tend to show a positive response to chemotherapy, and patients with ER and DR values above 3 have a significantly better prognosis. We also found that Pgp expression seems to play only a minor role in (99m)Tc-MIBI uptake. Our finding that patients with ER and DR values above 3 have a better prognosis needs to be confirmed in larger series of patients.
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PMID:99mTc-MIBI SPET in non-small cell lung cancer in relationship with Pgp and prognosis. 1211 Nov 27

Both p53 and multidrug transporters play important roles in chemoresistance. A transcriptional dependence of the Mdr1 gene promoter by p53 was first established a decade ago, and despite intense study, the p53-Mdr1 relationship still remains vague in vivo. The general model proposes that wild-type p53 down regulates, while mutant p53 up regulates, the Mdr1 promoter. Given that many studies have utilized cancer cell lines, minimal promoters and non-specific cDNA expression for in vitro experiments, we first sought to confirm the model using dermal fibroblasts isolated from the p53-knockout mice. We show that the gene products of the mouse Mdr1 homologue (Mdr1a and Mdr1b), namely P-glycoprotein (P-gp), appear upregulated at both the protein and mRNA levels in p53(-/-) mFbs compared with p53(+/+) cells. We demonstrate that transient transfection of a mouse p53(WT) expression plasmid into short-term primary p53(-/-) fibroblasts can revert P-gp overexpression. The difference in P-gp levels has functional significance in that p53(-/-) fibroblasts are more resistant to doxorubicin and vincristine treatment and this resistance can be attenuated in the presence of the P-gp inhibitor, verapamil. Furthermore, we demonstrate that in kidney, spleen and testis, P-gp expression is elevated in the absence of p53. In contrast, other organs such as heart, liver, lung, brain, thymus and skeletal muscle, show no difference in expression between p53(+/+) and p53(-/-) mice. Thus, our data shows a tissue-specific regulation of P-gp isoforms by p53 in the context of a p53-null mouse model.
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PMID:Regulation of the Mdr1 isoforms in a p53-deficient mouse model. 1237 67

Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. The present investigation presents a starting point to dissect the genes and molecular pathways involved in the tumor cells' response to CET and HHT in greater detail.
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PMID:Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. 1261 42

Localization of P-glycoprotein (P-gp) and p53 was immunohistochemically examined in 41 patients with hepatocellular carcinoma (HCC) in order to determine the relationship between the expression of P-gp and p53 and the degree of histological differentiation or cell proliferation in HCC. P-gp showed different patterns of expression between cancerous and cirrhotic liver hepatocytes, and the expression in cancerous tissue also varied according to the degree of histological differentiation. In cirrhotic liver hepatocytes, expression of P-gp was found on bile canalicular membranes. In the case of cancerous tissue, P-gp was localized on the canalicular membranes in well-differentiated HCC showing a trabecular pattern, as recognized cirrhotic liver hepatocytes. In moderately differentiated HCC showing pseudo-glandular patterns, predominant expression of P-gp was found on the luminal side of cell membranes of the glandular ducts. The P-gp expression rate was 87.5% in well-differentiated HCC, 84% in moderately differentiated HCC, and 37.5% in poorly differentiated HCC, indicating a marked decrease with decreasing degree of differentiation. On the other hand, the rate of mutation of p53, a tumor suppressor gene, was 12.5% in well-differentiated HCC, 52.0% in moderately differentiated HCC, and 85.5% in poorly differentiated HCC, showing a significant increase with decreasing degree of differentiation (P<0.005). The labeling index (LI) of proliferating cell nuclear antigen (PCNA) tended to increase with the progression of chronic liver disease, with a markedly high value of 24.0+/-1.5% in cases of HCC. The PCNA LI was 15.6+/-11.9% in well-differentiated HCC, 23.1+/-15.1% in moderately differentiated HCC, and 50.1+/-13.3% in poorly differentiated HCC, which indicated a significantly increase in poorly differentiated HCC (P<0.001). Thus, it became apparent that abnormal expressions of P-gp and p53 and the cell proliferation in HCC vary according to the degree of histological differentiation of the malignancy. This suggests that more effective chemotherapy for HCC can be potentially developed by considering the pattern and level of expression of P-gp as a mechanism of drug resistance and the extent of histological differentiation.
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PMID:Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma. 1264 52

Intrinsic or acquired drug resistance poses a major challenge to the success of chemotherapy in the clinical management of human cancers. While acquired multidrug resistance (MDR), whereby cells become refractory to multiple drugs, has been extensively investigated, the mechanistic basis for intrinsic resistance remains elusive, so that this condition is largely unmanageable in the clinical setting. To address this issue, we have assessed the effects of the anticancer agent doxorubicin (DX) on a panel of human tumor cell lines originally derived from untreated patients and tried to establish a correlation between cell response and a number of parameters, including drug accumulation and/or drug efflux; differences in expression and/or subcellular distribution of proteins involved in the apoptotic process (e.g., p53, Bcl-2, Bax) and intracellular signal transducers (PKCalpha); changes in key detoxification processes. Based on our results, 'classic' multispecific drug transporters (P-glycoprotein, MDR-related proteins) only seem to play a minor role in the intrinsically resistant phenotype, whereas LRP may contribute to resistance in non-small cell lung carcinoma (NSCLC) cells. No relationship was observed between drug response and expression and/or subcellular localization of apoptosis-related proteins; however, increased PKCalpha levels are associated with poor drug response, suggesting that one or more substrates of this enzyme may be relevant to the resistant phenotype. Finally, overactive glutathione-recycling pathways may contribute to DX resistance.
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PMID:Molecular determinants of intrinsic resistance to doxorubicin in human cancer cell lines. 1268 72

Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also being VP16 resistant. In order to explain the VP16 resistant phenotype several mechanisms where considered. The p53 status, P-glycoprotein, MRP, topoisomerase IIalpha, and Mre11 protein levels, as well as growth kinetics, provided no explanations of the observed VP16 resistance. In contrast, a significant difference in repair of both VP16- and IR-induced DSBs, together with a difference in the levels of the DSB repair proteins DNA-dependent protein kinase (DNA-PK(cs)) and RAD51 was observed. The VP16- and radioresistant 54B subline exhibited a pronounced higher repair rate of DSBs and higher protein levels of both DNA-PK(cs) and RAD51 compared with the sensitive 54A subline. We suggest, that different DSB repair rates among tumor cell subpopulations of individual SCLC tumors may be a major determinant for the variation in clinical treatment effect observed in human SCLC tumors of identical histological subtype.
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PMID:DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer. 1271 Nov 16

Mechanisms underlying multidrug resistance (MDR), one of the major causes of cancer treatment failure, are still poorly understood. We selected the osteosarcoma MDR HosDXR150 cell line by culturing Hos cells in the presence of increasing doxorubicin doses and showed that it is crossresistant to vinblastine. Similarly to the Hos parental cell line, HosDXR150 cells present mutated p53, functionally inactivated pRb/p105 and wild-type pRb2/p130. Owing to p53 mutation, MDR-1 gene, codifying for P-glycoprotein, is upregulated. Evasion of apoptosis in HosDXR150 cells is only partially explained by drug extrusion because of P-glycoprotein overexpression. Analysis of gene expression level profiles showed that parental cell line undergoes apoptosis through an E2F1/p73-dependent pathway while its resistant variant evades it. This result can be explained by the presence of distinct E2Fs-pRb2/p130 complexes on the p73 promoter. Namely, in Hos p73 transcription is activated by E2F1-Rb2/p130-p300 complexes, while in HosDXR150 it is kept repressed by E2F4-Rb2/p130-HDAC1 complexes.
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PMID:Triggering of p73-dependent apoptosis in osteosarcoma is under the control of E2Fs-pRb2/p130 complexes. 1278 60

Acute lymphoblastic leukemia (ALL) is now curable in 60-80% of children. In adults, in spite of adopting treatment protocols based on therapy for childhood ALL, the disease is still curable in 30-40% of patients only. These worse results of therapy may be due to the induction of various cell defence mechanisms, such as activation of P-glycoprotein, which protects man against xenobiotics. Among a number of various multi-drug resistance mechanisms, differences between adults and children with ALL have been found only for higher P-glycoprotein expression and possibly more often p53 gene mutations in adults. Induction of expression of drug resistance proteins during chemotherapy and co-existence of various mechanisms are common phenomena in adult ALL. Differences in resistance to different drugs might contribute to the impact of age on the outcome of ALL. The underlying mechanisms for these differences are still largely unknown; however, knowledge about drug resistance mechanisms can lead to new therapeutic options.
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PMID:Differences in significance of drug resistance mechanisms between adult and childhood acute lymphoblastic leukemia. 1280 6

The methylthioadenosine phosphorylase (MTAP) gene gained considerable interest as therapeutic target for tumors with the 9p21 deletion. This gene maps to 9p21 and loss of this chromosomal region in tumors offers an unique opportunity for chemoselective treatment, since MTAP is an important salvage enzyme for the formation of adenine that is needed for DNA synthesis. L-Alanosine, an antibiotic from Streptomyces alanosinicus, blocks the common de novo purine biosynthesis pathway and, thereby, inhibits tumor cells with MTAP deficiency. Normal cells escape the detrimental effects of L-alanosine due to their proficiency in the MTAP salvage pathway. The present analysis was undertaken to gain insights into the molecular architecture of tumor cells that determines the response to L-alanosine apart from the MTAP gene. Analysis of cell doubling times and IC(50) values for L-alanosine showed that slowly growing cell lines were more resistant to L-alanosine than rapidly growing ones. Mining the database of the National Cancer Institute (N.C.I.), for the mRNA expression of 9706 genes in 60 cell lines by means of Kendall's tau-test, false discovery rate calculation, and hierarchical cluster analysis pointed to 11 genes or expressed sequence tags whose mRNA expression correlated with the IC(50) values for L-alanosine. Furthermore, we tested L-alanosine for cross-resistance in multidrug-resistant cell lines which overexpress selectively either the P-glycoprotein/MDR1 (CEM/ADR5000), MRP1 (HL-60/AR), or BCRP (MDA-MB-231-BCRP) genes. None of the multidrug-resistant cell lines was cross-resistant to L-alanosine indicating that L-alanosine may be suitable to treat multidrug-resistant, refractory tumors in the clinic. Finally, the IC(50) values for L-alanosine of the 60 cell lines were correlated to the p53 mutational status and expression of p53 downstream genes. We found that p53 mutated cell lines were more resistant to L-alanosine than p53 wild type cell lines.
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PMID:Identification of gene expression profiles predicting tumor cell response to L-alanosine. 1290 26


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