http://www.olivelab.org/uploads/6/3/6/2/6362060/2004_-_cell.pdf

Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome.

The use of cisplatin in cancer chemotherapy is limited by acquired or intrinsic resistance of cells to the drug. Cisplatin enters the cells and its chloride ligands are replaced by water, forming aquated species that react with nucleophilic sites in cellular macromolecules. The presence of the cisplatin adducts in DNA is thought to trigger cell cycle arrest and apoptosis. Knowledge of the mechanism of action of cisplatin has improved our understanding of resistance. Decerased intracellular concentration due to decreased drug uptake, increased reflux or increased inactivation by sulfhydryl molecules such as glutathione can cause resistance to cisplatin. Incresed excision of the adducts from DNA by repair pathways or increased lesion bypass can also result in resistance. Finally, altered expression of regulatory proteins involved in signal transduction pathways that control the apoptotic pathway can also affect sensitivity to the drug. An improved understanding of the mechanisms of resistance operative in vivo has identified targets for intervention and may increase the utility of cisplatin for the treatment of cancer.

Mechanisms of resistance to cisplatin.

The human homologue of the mouse double minute 2 (MDM2) oncogene is overexpressed in more than forty different types of malignancies, including solid tumors, sarcomas and leukemias. Because of its prevalent expression and its interactions with p53 and other signaling molecules, MDM2 plays a central role in cancer development and progression. The expression of this oncoprotein is being studied by researchers world-wide, and the amount of data published about it is increasing exponentially. Although there are some conflicting data about the effects of MDM2 expression in individual cancers, the overall evidence is convincing, indicating that increased MDM2 expression is related to a worse clinical prognosis. There is an increased likelihood of distant metastases, as well as a decreased response to therapeutic intervention in MDM2-positive cancers. MDM2 may also serve as a diagnostic marker, not only for cancer stage, but to differentiate between similar cancers. MDM2 may also be associated with drug resistance in cancer chemotherapy. These findings make studying the oncoprotein necessary to aid in our understanding of cancer development, to identify novel cancer drug targets, and to increase the efficacy of cancer therapy.

MDM2 and Human Malignancies: Expression, Clinical Pathology, Prognostic Markers, and Implications for Chemotherapy

Cancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation-induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial-mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.

Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment

The metallothionein family is a class of low-molecular-weight, cysteine-rich proteins with high affinity for metal ions. Four major isoforms (metallothionein-1, -2, -3, and -4) have been identified in mammals, involved in many pathophysiological processes, including metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, drug and radiotherapy resistance and several aspects of the carcinogenic process. In the present review we examine the expression of metallothionein in different human tumours and its correlation with histopathological variables, tumour cell proliferation or apoptosis, resistance to radiation or chemotherapy, patient survival and prognosis. A variable profile of metallothionein and its isoforms' expression has been observed in different cancer types. Although metallothionein expression has been implicated in carcinogenic evolution, its use as a marker of tumour differentiation, cell proliferation and prognosis predictor remains unclear. Detailed studies focused on the expression of metallothionein isoforms and isotypes in different tumour types could elucidate the role of this group of proteins in the carcinogenic process, delineating its possible clinical significance for the management of patients.

Metallothionein expression in human neoplasia.

BACKGROUND: Several prior studies revealed positive p53 expression via immunohistochemistry (IHC) in a large percentage of germ cell testicular cancers (GCTTs). However, the predicting and prognostic value of this protein remains to be defined. Therefore, the aim of our study was to further clarify the role of p53 protein in GCTTs and to look for correlations between its gene expression and other disease parameters, including histological subtype, stage and clinical resistance sensitivity. Furthermore, we correlated p53 protein expression with that of MDRI gene product protein (Pgp) in order to examine the interrelationship between these two markers. PATIENTS AND METHODS: 77 untreated patients with GCTTs were investigated for their p53 expression using monoclonal antibody and immunohistochemistry in paraffin-embedded specimens. There were 34 patients with stage I, 16 with stage II, 27 with stage III disease. RESULTS: All tumor types, except differentiated teratomas, were immunoreactive for p53 to a various extent ranging from scarcely positive to homogeneously stained tumor cells. Seminomas (S) and embryonal carcinoma (EC) components showed the most positive nuclear staining. p53 expression showed a significant inverse correlation with the stage of disease (P < 0.0003). There was a significant positive relationship between p53 immunoreactivity and response to treatment (P = 0.0012), i.e. high levels of p53 expression correlated with clinical sensitivity of the tumors to chemotherapy. We could demonstrate a statistically significant opposite relationship between p53 and Pgp immunoreactivity (P < 0.0005). CONCLUSION: Our results show that p53 status in tumor cells may be a strong determinate of susceptibility to chemotherapy and that p53 overexpression has a favorable prognosis in terms of response to treatment in GCTTs. Moreover, the findings provide clinical evidence for the presense of significant relationship between p53 and MDR1/Pgp immunoreactivity. They also suggest that patients resistant to chemotherapy and lacking p53 expression might benefit from an alternative appropriately designed chemotherapeutic regimen to achieve further successful treatment in GCTTs.

Is p53 expression, detected by immunohistochemistry, an important parameter of response to treatment in testis cancer?

Backround: Although in vitro and clinical studies indicate that overexpression of P- glycoprotein (Pgp), p53, or metallothionein (MT) is involved in modulating drug resistance/sensitivity of cancer cells, the clinical relevance of the overexpression remains to be elucidated. Materials and Methods: In this paper the expression and clinical value of Pgp, p53, and MT were evaluated immunohistochemically in 77 specimens of germ cell testicular tumors (GCT). We also studied the interrelationship(s) between the investigated markers. Results: Pgp positivity correlated with cancers of advanced stages (P = 0.000). p53 and MT immunostaining does not predict a poor response to chemotherapy, but rather is correlated to a favorable clinical outcome ( P = 0.001, P = 0.00006 respectively). We obtained an inverse association between Pgp and p53 (P = 0.0005), and positive strong association between p53 and MT immunoreactivity (P = 0.0002). Conclusions: Based on our results in patients with germ cell testicular tumors we assume that the poor clinical outcome seen in certain Pgp positive tumors is the consequence of Pgp association with a more progressive malignant phenotype, rather than its role in multidrug resistance (MDR). p53 and MT immunoreactivity predicts a better response rate to chemotherapy, whereas tumors lacking or demonstrating low MT and or p53 expression show a worse prognosis.

Drug resistance and sensitivity of germ cell testicular tumors: evaluation of clinical relevance of MDR1/Pgp, p53, and metallothionein (MT) proteins.

Background. In germ cell testicular tumors (GCTT) mdm-2 gene was analyzed for amplification and transcripts but not for protein. The purpose of this study is to determine whether mdm-2 protein level is aberrant in GCTT and if so, what is the relationship between mdm-2 overexpression and other disease parameters including histologic subtypes, p53 status, metastatic potential and clinical stage. Methods. 81 testicular germ-cell tumors were screened for their mdm-2 expression at the protein levels using immunohistochemistry (IHC) and Western blot (WB) analysis. Results. Of 81 GCTTs 45 (55.55 %) showed mdm-2 nuclear immunoreactivity, 34 (41,97%) of which were strongly positive. The incidence of mdm-2 immunostaining was significantly higher (P=0.0007) in non-seminomas (NSGCT) than in seminomas (SGCT). The frequency of positive tumor was higher in tumors from metastatic patients than in tumors from metastatic-free patients (P = 0.011). mdm-2 expression was detected significantly more frequently in tumors of advanced stages, i.e. IIB, IIC and III versus tumors of early stages (I and II/A) (P = 0.0098). A significant difference between the three stages of disease as to the expression of mdm-2 (X 2 = 0.0386) could be established, namely the incidence of mdm-2 expression increased with an increase in stage. Using Western blotting 22 (68.75 %) out of 32 tumors overexpressed the mdm-2 oncoprotein of 90 kd (p90). Conclusions. mdm-2 expression as detected by immunohistochemistry may provide a reliable prognostic tool to isolate subgroups of patients with more aggressive GCTT.

mdm-2 expression in human testicular germ-cell tumors and its clinical value.

Purpose: Data on the involvement of elevated metallothionein (MT) expression in resistance to some of the commonly used anticancer treatments are scattered and conflicting. This encouraged us to examine further the contribution of metallothionein expression to the development of this resistance phenotype. Patients and methods: Formalin-fixed, paraffin-embedded blocks of primary untreated germ cell testicular tumor specimens, obtained from 77 patients following radical orchiectomy, were examined for their MT expression using monoclonal antibody and immunohistochemistry. Clinical staging, the chemotherapeutic schedule and evaluation of response to treatment (defining objective response) were performed according to UICC criteria. Results: All tumor types, including seminomas and nonseminomas, expressed MT, regardless of their histology and clinical stage. The immunoreactivity of MT showed a significant positive correlation with the clinical sensitivity of cancer to antitumor therapy (P = 0.0001). Conclusion: In patients with germ cell testicular tumors, high MT expression, as detected by immunohistochemistry, predicts a better response rate to chemotherapy whereas tumors lacking or demonstrating low MT expression show a worse prognosis. These data do not support the hypothesis that MT overexpression contributes to cisplatinum resistance, at least in this tumor type.

Do metallothioneins affect the response to treatment in testis cancers

Background The expression of a multidrug resistance associated protein (MRP) has been investigated in a variety of human tumors. However, there is a lack of data regarding its expression in germ cell testicular tumors (GCTTs). Patients and methods MRP expression was examined by immunohistochemistry (IHC) using mouse monoclonal antibody (MRPm6) against human MRP in 56 testis cancer specimens. This antigen was also correlated with the histology, metastatic behavior, clinical stage and tumor suppressor protein p53 immunostaining of GCTTs. Results All testis tumors, regardless of their histology, metastatic status and clinical stage gave positive signals. MRP was positive not only in the cytoplasm but, very interestingly, in the nuclei. Conclusion Our results suggested that ala GCTTs express high levels of MRP protein with no relation to any of clinicopathological variables investigated here. Since germ cell tumors are very sensitive to chemotherapy, the role of MRP as mediator of drug resistance seems unconvincing in this malignancy. MRP is located in the cytoplasm and the nuclei of tumor cells and may be involved in transportation and/or redistribution certain substrates from the nucleus to the cytoplasm.

MRP expression of testicular cancers and its clinical relevance.

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