Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a panel of 16 human ovarian tumours transplanted in nude mice, the expression of genes involved in cell cycle regulation and in response to drug treatment were characterised. In the 16 tumours analysed we could not detect overexpression of Erb-B2 oncogene while expression of MDR1 mRNA was not detected in 11/15 samples and was low in 4/15 tumours. Only three tumours had mutations in the p53 gene exons 5-8 and one of these mutations did not result in any amino acid alteration. The levels of mRNA for cyclins A, D1 and E were heterogeneous with some tumours expressing high levels and others not expressing them at all. The same was found for the cyclin dependent kinases (CDK) CDK2 and CDK4 and for CDK inhibitors p21/WAF1, p27/KIP1 and p16/CDKN2. Two genes belonging to the nucleotide excision repair, ERCC1 and ERCC3 were detectable in all the samples examined, as were the genes MGMT and MAG, also involved in DNA repair. The data indicate a heterogeneity in the expression of genes considered to be involved in the cellular responses to cytotoxic drug treatment and indicate the possibility of using these tumour models to test specifically molecules with a defined mechanism of action.
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PMID:Molecular characterisation of a panel of human ovarian carcinoma xenografts. 984 28

The transcription of MDR1 gene may be increased by mutation or loss of function of p53 gene. In this study, we investigated whether in osteosarcoma, the p53 status is correlated with overexpression of the MDR1 gene product P-glycoprotein. The relationship between P-glycoprotein expression and p53 status was analyzed by immunohistochemistry in 64 primary and 11 metastatic high-grade osteosarcomas. In the same series, we also assessed the nuclear accumulation of MDM2 protein, whose binding to p53 protein provides an alternative mechanism of p53 inactivation. No association was found between mutant-p53 and MDM2 nuclear accumulation either with P-glycoprotein expression or with clinical course. Only increased expression of P-glycoprotein in tumor cells was significantly associated with a poor outcome, further supporting the adverse prognostic value of this marker in osteosarcoma.
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PMID:Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma. 991 6

P-glycoprotein (Pgp) encoded by the MDR1 gene, a predictor of chemoresistance, may also serve as a prognosticator of clinical outcome in cancer patients. The mutant tumour-suppressor p53 protein has been shown to activate the MDR1 promoter, whereas the wild-type p53 represses this activity in cultured cells. We have described the differential expression of Pgp and p53 proteins in betel- and tobacco-related oral tumorigenesis in the Indian population. Herein, Pgp expression was analysed in relation to p53 protein accumulation in pre-malignant and malignant oral lesions by immunohistochemical and flow-cytometric analyses. The relationship between Pgp and p53 protein accumulation and clinicopathological parameters as well as prognosis was determined. Expression of Pgp was observed in 81% of oral squamous cell carcinomas (SCCs) and 71% of pre-malignant lesions. Sixty-five of 75 p53-positive oral SCCs and 21/24 p53-positive pre-malignant lesions showed expression of Pgp. Significant correlation between Pgp and p53 expression was found not only in oral SCCs but also in pre-malignant lesions. Co-expression of Pgp and p53 proteins was indicative of poor prognosis. Follow-up studies of 35 patients showed that 7 of 10 oral SCCs with accumulation of Pgp and p53 proteins also exhibited shorter disease-free survival (recurrence/metastases). Our findings provide clinical evidence for a significant association between Pgp and p53 protein expression in oral tumorigenesis and may account for the aggressive nature of the tumour and poor prognosis.
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PMID:P-glycoprotein is positively correlated with p53 in human oral pre-malignant and malignant lesions and is associated with poor prognosis. 998 37

To characterize the biological features of advanced breast cancer associated with poor chemotherapy response and worse prognosis, sequential tumor samples obtained from 75 patients receiving primary chemotherapy were analysed for MDR1 and TS gene expression before and after treatment. MDR1 gene expression was also analysed in 36 sequential normal samples. The levels of MDR1 and TS genes expression were determined by reverse transcription-PCR method, and examined in relation to p53 gene status, and the clinical outcome of the patients. After treatment, MDR1 expression levels were significantly enhanced in tumor (p = 0.0033) and normal (p = 0.0098) samples, whereas a significant decrease in TS expression was observed (p = 0.0054). There was no significant correlation between MDR1 or TS expressions and the presence of p53 mutations (detected in 24% of the cases), chemoresponsiveness, or survival. Only p53 mutations were associated with reduced disease-free survival (p = 0.0473). These results demonstrate that MDR1 and TS gene expressions were affected by drug exposure, but not by p53 gene status. Furthermore, the increase of MDR1 gene expression in normal and tumor tissues is in favor of an induced MDR1 expression rather than of a selection of resistant tumoral clones, which can be responsible for the absence of relationship of MDR1 expression with clinical outcome of advanced breast cancer patients.
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PMID:MDR1 and thymidylate synthase (TS) gene expressions in advanced breast cancer: relationships to drug exposure, p53 mutations, and clinical outcome of the patients. 1062 55

The long-term prognostic value of tumoural MDR1 and MRP, along with p53 and other classical parameters, was analysed on 85 node-positive breast cancer patients receiving anthracycline-based adjuvant therapy. All patients underwent tumour resection plus irradiation and adjuvant chemotherapy (the majority receiving fluorouracil-epirubicin-cyclophosphamide). Median follow-up for the 54 alive patients was 7.8 years. Mean age was 53.7 years (range 28-79) and 54 patients were post-menopausal. MDR1 and MRP expression were quantified according to an original reverse transcription polymerase chain reaction multiplex assay with colourimetric enzyme-linked immunosorbent assay detection (beta2-microglobulin as control). P53 protein was analysed using an immunoluminometric assay (Sangtec). MDR1 expression varied within an 11-fold range (mean 94, median 83), MRP within a 45-fold range (mean 315, median 242) and p53 protein from the limit of detection (0.002 ng mg(-1)) up to 35.71 ng mg(-1) (mean 1.18, median 0.13 ng mg(-1)). P53 protein was significantly higher in oestrogen receptor (ER)-negative than in ER-positive tumours (P = 0.039). The higher the p53, the lower the MDR1 expression (P = 0.015, r= -0.27). P53 was not linked to progesterone receptor (PR) status, S phase fraction, or MRP Significantly greater MDR1 expression was observed in grade I tumours (P = 0.029). No relationship was observed between MDR1 and MRP. Neither MDR1 nor MRP was linked to ER or PR status. Unlike MDR1, MRP was correlated with the S phase: the greater the MRP, the lower the S phase (P = 0.006, r = -0.42). Univariate Cox analyses revealed that MDR1, MRP, p53 and S phase had no significant influence on progression-free or specific survival. A tendency suggested that the greater the p53, the shorter the progression-free survival (P = 0.076 as continuous and 0.069 as dichotomous).
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PMID:Application of an original RT-PCR-ELISA multiplex assay for MDR1 and MRP, along with p53 determination in node-positive breast cancer patients. 1063 86

Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.
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PMID:Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts. 1081 35

Several groups have attempted to develop gene therapy strategies to treat cancer via introduction of the wild-type (wt) p53 cDNA into cancer cells. Unfortunately, these approaches do not result in regulated expression of the p53 gene and do not reduce expression of the mutant p53 that is overexpressed in cancerous cells. These shortcomings may greatly limit the utility of this gene replacement approach. We describe an alternative strategy with trans-splicing ribozymes that can simultaneously reduce mutant p53 expression and restore wt p53 activity in various human cancers. The ribozyme accomplished such conversion by repairing defective p53 mRNAs with high fidelity and specificity. The corrected transcripts were translated to produce functional p53 that can transactivate p53-responsive promoters and down-modulate expression of the multidrug resistance (MDR1) gene promoter. The level of wt p53 activity generated was significant, resulting in a 23-fold induction of a p53-responsive promoter and a 3-fold reduction in MDR1 promoter expression in transfected cancer cells. Once efficient delivery systems are developed, this strategy should prove useful for making human cancers more responsive to p53 activity and more sensitive to chemotherapeutic agents.
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PMID:Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts. 1089 Sep 10

The view that chemical or physical oncogenesis and tumor therapy resistance represent different parts of common cellular alterations gained considerable attractiveness, because it explains the inherent unreponsiveness of many tumors. Viruses are potent oncogenes and are causally linked to approximately one-fifth of all human malignancies. Whether viral oncogenesis exerts comparable effects was less clear. Recent progress in experimental research provided ample evidence that viruses affect response of tumor cells toward anti-cancer drugs and irradiation. Resistance to cytostatic drugs and radiation develops by alterations at the drug-target sites (i.e., DNA or specific target proteins), upstream (i.e., detoxification mechanisms), or downstream of them (i.e., programmed cell death). Viruses interfere with specific cellular genes at these three levels. Viral proteins induce the expression and expression of drug resistance genes, that is, MDR1, DHFR, or CAD. Viral interactions with the tumor suppressor genes (p53, pRB) abrogate cell cycle arrests and disturb DNA repair of drug- and radiation-induced DNA lesions. The readiness to commit cellular suicide (apoptosis) is also affected by viral genes. The connection between viral oncogenesis and the response of tumor cells to treatment adds a new dimension to tumor biology and may have important consequences for oncological treatment modalities in the future.
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PMID:Impact of viral oncogenesis on responses to anti-cancer drugs and irradiation. 1100 11

PKC isoenzymes were found to be involved in proliferation, antitumor drug resistance and apoptosis. Therefore, it has been tried to exploit PKC as a target for antitumor treatment. PKC alpha activity was found to be elevated, for example, in breast cancers and malignant gliomas, whereas it seems to be underexpressed in many colon cancers. So it can be expected that inhibition of PKC activity will not show similar antitumor activity in all tumors. In some tumors it seems to be essential to inhibit PKC to reduce growth. However, for inhibition of tumor proliferation it may be an advantage to induce apoptosis. In this case an activation of PKC delta should be achieved. The situation is complicated by the facts that bryostatin leads to the activation of PKC and later to a downmodulation and that the PKC inhibitors available to date are not specific for one PKC isoenzyme. For these reasons, PKC modulation led to many contradicting results. Despite these problems, PKC modulators such as miltefosine, bryostatin, safingol, CGP41251 and UCN-01 are used in the clinic or are in clinical evaluation. The question is whether PKC is the major or the only target of these compounds, because they also interfere with other targets. PKC may also be involved in apoptosis. Oncogenes and growth factors can induce cell proliferation and cell survival, however, they can also induce apoptosis, depending on the cell type or conditions in which the cells or grown. PKC participates in these signalling pathways and cross-talks. Induction of apoptosis is also dependent on many additional factors, such as p53, bcl-2, mdm2, etc. Therefore, there are also many contradicting results on PKC modulation of apoptosis. Similar controversial data have been reported about MDR1-mediated multidrug resistance. At present it seems that PKC inhibition alone without direct interaction with PGP will not lead to successful reversal of PGP-mediated drug efflux. One possibility to improve chemotherapy would be to combine established antitumor drugs with modulators of PKC. However, here also very contrasting results were obtained. Many indicate that inhibition, others, that activation of PKC enhances the antiproliferative activity of anticancer drugs. The problem is that the exact functions of the different PKC isoenzymes are not clear at present. So further investigations into the role of PKC isoenzymes in the complex and interacting signalling pathways are essential. It is a major challenge in the future to reveal whether modulation of PKC can be used for the improvement of cancer therapy.
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PMID:Modulation of protein kinase C in antitumor treatment. 1119 May 77

The expression of genes associated with apoptosis, cell proliferation and drug resistance in tumor cells was investigated in two pediatric Wilms' tumor patients (MCH-WT-1 and MCH-WT-3) for their association with cell cycle, daunorubicin accumulation and clinical data. DNA content, cell cycle and drug accumulation were analyzed immediately after surgery by flow cytometry and mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Primary cell cultures were established from tumor specimens and tumor cells in both cases showed epithelial morphology. Although cell proliferation markers (Ki67 and PCNA) were expressed in both cases, MCH-WT-3 showed higher levels of mRNA expression, which corresponded, with metastatic behavior of the tumor in the patient. While p53 and p21 mRNAs were expressed at low levels in MCH-WT1, MCH-WT-3 showed high levels of p21 mRNA only. The increased expression of cyclin kinase inhibitor (p21) in MCH-WT-3 compared to MCH-WT-1 correlated with a higher percentage of G0/G1 cell population in the tumor specimen. Despite the expression of multidrug resistance markers (MDR1 and LRP) in MCH-WT-1, flow cytometric analysis showed tumor cell populations with very low and high daunorubicin accumulation and with the absence of any effect for verapamil and dipyridamole on daunorubicin accumulation of tumor cells.
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PMID:Expression of apoptosis, cell proliferation, and drug resistance genes in pediatric Wilms' tumors. 1126 51


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