metallothionein and Carcinoma

Metallothioneins (MTs) are low weight proteins involved in several key cellular processes such as metal ions homeostasis, detoxification and scavenging of free radicals. Four groups of MTs are distinguished: MT-1, MT-2, MT-3 and MT-4. Regardless of the type, MTs are characterized by high content of cysteine, responsible for their biological properties such as binding of relevant zinc and copper ions, as well as toxic ions such as lead and cadmium. MTs were additionally shown to protect cells against oxidative stress damage and participate in differentiation, proliferation and/or apoptosis of normal and cancer cells. Many studies of different neoplasms showed association of elevated MTs levels with occurrence of chemo- and radiotherapy resistance and poor patients' outcome. In this review, we summarize and discuss the potential mechanism of action of metallotioneins in lung physiology and pathology.

Topics: Animals; Biomarkers, Tumor; Carcinoma; Humans; Lung Neoplasms; Metallothionein

Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, waf 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immuno-peroxidase complex method.

Topics: Animals; Antioxidants; Biomarkers, Tumor; Carcinoma; Gene Expression Regulation, Neoplastic; Humans; Liver; Liver Neoplasms; Metabolic Detoxication, Phase I; Metallothionein; Mice

Carcinoma of the gallbladder has a very unusual geographical distribution with pockets of high incidence seen in Chile, Poland, India, Japan and Israel; it occurs rarely in the rest of the world. It is a common malignancy in the Western Bihar and Eastern Uttar Pradesh regions of India. Patients present with extremes of clinical symptoms, indicating benign biliary diseases on the one hand and incurable malignant disease on the other. Laboratory and roentgenographic data tend to confirm the clinical diagnosis of the advanced incurable disease at presentation, in most cases. Various aetiopathological agents have been proposed but none has stood the test of time. In this article, we have reviewed the aetiopathological agents proposed from time to time over the past two centuries, with special emphasis on the developments made in the last 25 years.

Topics: Carcinogens; Carcinoma; Cholelithiasis; Diet; Ethnicity; Gallbladder Neoplasms; Humans; Incidence; Infections; Life Style; Lipid Peroxidation; Metallothionein; Metals, Heavy; Neoplasm Staging; Occupational Exposure; Racial Groups; Risk Factors

Clear-cell renal cell carcinoma (ccRCC) appears as the most common type of kidney cancer, the carcinogenesis of which has not been fully elucidated. Tumor heterogeneity plays a crucial role in cancer progression, which could be largely deciphered by the implement of scRNA-seq. The bulk and single-cell RNA expression profile is obtained from TCGA and study conducted by Young et al. We utilized UMAP, TSNE, and clustering algorithm Louvain for dimensionality reduction and FindAllMarkers function for determining the DEGs. Monocle2 was utilized to perform pseudo-time series analysis. SCENIC was implemented for transcription factor analysis of each cell subgroup. A series of WB, CFA, CCK-8, and EDU analysis was utilized for the validation of the role of MT2A in ccRCC carcinogenesis. We observed higher infiltration of T/NK and B cells in tumorous tissues, indicating the role of immune cells in ccRCC carcinogenesis. Transcription factor analysis revealed the activation of EOMES and ETS1 in CD8 + T cells, while CAFs were divided into myo-CAFs and i-CAFs, with i-CAFs showing distinct enrichment of ATF3, JUND, JUNB, EGR1, and XBP1. Through cell trajectory analysis, we discerned three distinct stages of cellular evolution, where State2 symbolizes normal renal tubular cells that underwent transitions into State1 and State3 as the CNV score ascended. Functional enrichment examination revealed an amplification of interferon gamma and inflammatory response pathways within tumor cells. The consensus clustering algorithm yielded two molecular subtypes, with cluster 2 being associated with advanced tumor stages and an abundance of infiltrated immune cells. We identified 17 prognostic genes through Cox and LASSO regression models and used them to construct a prognostic model, the efficacy of which was verified in multiple cohorts. Furthermore, we investigated the role of MT2A, one of our hub genes, in ccRCC carcinogenesis, and found it to regulate proliferation and migration of malignant cells. We depicted a detailed single-cell landscape of ccRCC, with special focus on CAFs, endothelial cells, and renal tubular cells. A prognostic model of high stability and accuracy was constructed based on the DEGs. MT2A was found to be actively implicated in ccRCC carcinogenesis, regulating proliferation and migration of the malignant cells.

Topics: Carcinogenesis; Carcinoma; Carcinoma, Renal Cell; Endothelial Cells; Humans; Kidney Neoplasms; Metallothionein; Single-Cell Gene Expression Analysis

Therapeutic efficacy of cisplatin-based treatment of late stage urothelial carcinoma (UC) is limited by chemoresistance. To elucidate underlying mechanisms and to develop new approaches for overcoming resistance, we generated long-term cisplatin treated (LTT) UC cell lines, characterised their cisplatin response, and determined the expression of molecules involved in cisplatin transport and detoxification, DNA repair, and apoptosis. Inhibitors of metallothioneins and Survivin were applied to investigate their ability to sensitise towards cisplatin. Cell growth, proliferation, and clonogenicity were examined after cisplatin treatment by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, EdU (5-ethynyl-2'-deoxyuridine) incorporation assay, and Giemsa staining, respectively. Cell cycle distribution and apoptosis were quantified by flow cytometry. mRNA and protein expressions were measured by real-time quantitative (qRT)-PCR, western blot, or immunofluorescence staining. LTTs recovered rapidly from cisplatin stress compared to parental cells. In LTTs, to various extents, cisplatin exporters and metallothioneins were induced, cisplatin adduct levels and DNA damage were decreased, whereas expression of DNA repair factors and specific anti-apoptotic factors was elevated. Pharmacological inhibition of Survivin, but not of metallothioneins, sensitised LTTs to cisplatin, in an additive manner. LTTs minimise cisplatin-induced DNA damage and evade apoptosis by increased expression of anti-apoptotic factors. The observed diversity among the four LTTs highlights the complexity of cisplatin resistance mechanisms even within one tumour entity, explaining heterogeneity in patient responses to chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Cycle; Cell Line, Tumor; Cisplatin; DNA Damage; Drug Resistance, Neoplasm; Humans; Metallothionein; Urinary Bladder Neoplasms; Urothelium

Metallothioneins (MTs) are involved in numerous cell processes such as binding and transport of zinc and copper ions, differentiation, proliferation and apoptosis, therefore contributing to carcinogenesis. Scarce data exist on their expression in benign and malignant lesions of the thyroid.. mRNA expression of functional isoforms of MT genes (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1X, MT2A, MT4) was studied in 17 nodular goiters (NG), 12 follicular adenomas (FA) and 26 papillary thyroid carcinomas (PTC).. One-way ANOVA revealed significant differences in mRNA expression levels of MT1A (p<0.05), MT1E (p<0.005), MT1F (p<0.0001), MT1G (p<0.005), MT1X (p<0.0005) and MT2A (p<0.005) in the analyzed samples. Post hoc analysis confirmed a significantly lower expression of MT1A mRNA in PTC compared to NG (p<0.05). Significant down-regulation was also noted for other MT isoforms in PTC in comparison to NG: MT1E (p<0.05), MT1F (p<0.0001), MT1G (p<0.005), MT1X (p<0.0005) and MT2A (p<0.05). In addition, significant down-regulation of MT1F and MT1G in FA compared to NG was observed (p<0.005 and p<0.05, respectively).. Expression of functional MT isoforms may contribute to thyroid carcinogenesis and potentially serve as a diagnostic marker in distinguishing benign and malignant lesions.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Carcinoma; Carcinoma, Papillary; Female; Gene Expression Regulation, Neoplastic; Goiter, Nodular; Humans; Male; Metallothionein; Middle Aged; Protein Isoforms; RNA, Messenger; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

Hypoxia inducible factor-1α (HIF-1α) is upregulated by hypoxia, and involved in tumor growth and metastasis in many malignant tumors including papillary thyroid carcinoma (PTC). Metallothionein (MT) is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. SLUG is a member of SNAIL superfamily of zinc finger transcriptional factors implicated in epithelial-mesenchymal transition (EMT). The purpose of this study was to examine HIF-1α, MT and SLUG expression in PTC and assess association of their expression with clinicopathological indicators. HIF-1α, MT and SLUG protein expression in 129 PTCs, 61 nodular hyperplasia and 118 normal thyroid tissue specimens were analyzed using immunohistochemistry. The protein expression levels of these three molecules were up-regulated in PTCs. High protein expression of HIF-1α, MT and SLUG was significantly correlated with high TNM stage (P=0.003, 0.002, 0.024, respectively) and lymph node metastasis (LNM) (P<0.001 for all three molecules). Furthermore, HIF-1α, MT and SLUG protein expression were correlated with one another. Concomitant high expression of any two of these three molecules had stronger correlation with high TNM stage (P≤0.001 for HIF-1α/MT, MT/SLUG and HIF-1α/SLUG) and LNM (P=0.008, 0.002, 0.019 for HIF-1α/MT, MT/SLUG and HIF-1α/SLUG, respectively) than did each alone, and concomitant high expression of all these three molecules is significantly associated with high TNM stage and LNM as compared with cases not showing such expression (P<0.001). These results demonstrated that the evaluation of HIF-1α, MT and SLUG expression in PTC may be useful in predicting the risk of LNM and high TNM stage.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lymphatic Metastasis; Male; Metallothionein; Middle Aged; Neoplasm Staging; Snail Family Transcription Factors; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tissue Array Analysis; Transcription Factors; Up-Regulation

Metallothioneins (MT1, MT2, MT3, and MT4) are regarded as modulators regulating a number of biological processes including cell proliferation, differentiation, and invasion. We determined the effects of androgen, cadmium, and arsenic on MT1/2 and MT3 in prostate carcinoma cells, and evaluated the functional effects of MT3 on cell proliferation, invasion, and tumorigenesis.. We determined the expression of MT1/2 and MT3 in prostate carcinoma cells by immunoblotting assays or real-time reverse transcription-polymerase chain reactions. The effects of ectopic MT3 overexpression or MT3-knockdown on cell proliferation, invasion, and tumorigenesis were determined by (3) H-thymidine incorporation, matrigel invasion, and murine xenograft studies. The effects of androgen, cadmium, and arsenic on target genes were assessed using immunoblotting and reporter assays.. Androgen, cadmium, and arsenic treatments enhanced gene expression of MT1/2 and MT3 in prostate carcinoma LNCaP cells. Results of immunohistochemical staining indicated MT3 overexpression was found predominantly in the nuclear areas of PC-3 cells overexpressing MT3. Overexpression of MT3 significantly increased cell proliferation, invasion, and tumorigenic activities in PC-3 cells in vitro and in vivo. MT3 overexpression downregulated the gene expressions of N-myc downstream regulated gene 1 (Ndrg1) and maspin, and attenuated blocking effects of doxorubicin in PC-3 cells on cell proliferation. MT3-knockdown enhanced Ndrg1 and maspin expressions in LNCaP cells.. The experiments indicate that MT3 is an androgen-upregulated gene, and promotes tumorigenesis of prostate carcinoma cells. The downregulation of Ndrg1 and maspin gene expressions appears to account for the enhancement of proliferative and invasive functions of MT3 in PC-3 cells.

Topics: Androgens; Animals; Arsenic; Cadmium; Carcinogenesis; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; Genetic Enhancement; Humans; Intracellular Signaling Peptides and Proteins; Male; Metallothionein; Metallothionein 3; Mice; Prostatic Neoplasms; Serpins; Signal Transduction; Up-Regulation

To investigate anticancer effect and potential mechanism of tanshinone II(A) (Tan II(A)) on human nasopharyngeal carcinoma cell line CNE cells.. Antiproliferative effect of Tan II(A) on CNE cells was evaluated by morphological examination, cell growth curves, colonial assay and MTT assay. Apoptosis detection was carried out using Hoechest 33258 and PI double-dyeing method. Intracellular Ca2+ concentration and mitochondria membrane potential were detected by fluorospectrophotometer. Bad and MT-1A transcript analysis in CNE cells was analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).. Tan II(A) could inhibit CNE cells proliferation in dose- and time-dependent manner. 50% inhibiting concentration of Tan II(A) on CNE cells in 24, 48, 72 h was 45.7, 24.8, 3.3 mg x L(-2), respectively. Typical apoptotic morphology such as chromatin aggregation was observed in CNE cells with Tan II(A) treated for 24 h, and the apoptotic inducing effect was in a dose-dependent manner. After treated with Tan II(A), intracellular Ca2+ concentration of CNE cells was increased, mitochondria membrane potential of the cells was decreased, relative mRNA level of Bad and MT-1A was up-regulated.. Tan II(A) had anticancer effect on CNE cells through apoptosis via calcineurin-dependent pathway and MT-1A downregulation.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-Associated Death Protein; Calcium; Carcinoma; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Metallothionein; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Signal Transduction

Ovarian cancer is primarily treated with platinum-based chemotherapy, with ROS generation implicated in cytotoxicity. We examined redox protein expression in ovarian tumors, focusing on the thioredoxin system, to determine the role it might play in mediating response to therapy. Nuclear and cytoplasmic expression of thioredoxin, thioredoxin reductase, thioredoxin-interacting protein, metallothionein, and glutathione S-transferase Pi was assessed, using standard immunohistochemical techniques, on a tissue microarray of 154 primary ovarian carcinomas obtained from patients subsequently treated with adjuvant platinum-based chemotherapy. Low cytoplasmic expression of thioredoxin (p=0.032) and negative nuclear expression of metallothionein (p=0.04) significantly correlated with better progression-free survival. When nuclear and cytoplasmic expression patterns were combined those patients with tumors with low cytoplasmic but high nuclear expression of thioredoxin exhibited better progression-free (p=0.003) and overall survival (p=0.004). This combination was, using multivariate analysis, an independent predictive factor for overall survival (p=0.034). Improved progression-free survival was also seen with negative expression of metallothionein, cytoplasmic and nuclear (p=0.038), and was independent of other clinical parameters (p=0.048). Such results support the suitability of using redox protein expression to predict response and, potentially, to alter treatment options accordingly.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Nucleus; Disease-Free Survival; Female; Follow-Up Studies; Glutathione S-Transferase pi; Humans; Metallothionein; Microarray Analysis; Middle Aged; Ovarian Neoplasms; Platinum Compounds; Prognosis; Survival Analysis; Thioredoxins

Cadmium is discussed as being involved in the development of transitional cell carcinoma (TCC) of the bladder and can be observed in urine of these patients. Investigations of urinary samples from bladder cancer patients and normal controls were carried out with special emphasis on metallothionein (MT)-bound cadmium. Compounds that are constituents of urine were separated in urine samples by means of size exclusion chromatography and cadmium was monitored continuously with a hyphenated inductively coupled plasma mass spectrometry (ICP-MS) system. MT-bound cadmium was quantified by peak area integration, taking into account the intensity of the rhodium signal which was added continuously before ICP-MS detection. The obtained results show that urinary cadmium is predominantly bound to the observed MT-fraction. The median of the MT-bound cadmium concentration in the control group was found to be 0.8 microgL(-1) whereas the cancer group has a median of 1.8 microgL(-1). The variance of the data in the cancer group is much higher than in the controls. However, the urinary MT-bound cadmium is significantly elevated in the cancer group; odds-ratio test: 7.11 (95% C.I.: 1.89-26.80), taking into account the total protein content. Due to the fact that only one main cadmium-containing fraction was observed, there is no necessity to separate the MT-fraction before cadmium determination in urine samples in future studies.

Topics: Adult; Aged; Aged, 80 and over; Animals; Cadmium; Carcinoma; Chromatography, Gel; Female; Humans; Male; Mass Spectrometry; Metallothionein; Middle Aged; Probability; Rabbits; Urinary Bladder Neoplasms

Previous studies have provided some evidence of a possible association between cancer and metallothioneins. Whether this relates to an exposure to carcinogenic metals remains unclear.. In order to examine the association between the expression of metallothioneins and bladder tumors, and to compare the levels of arsenic, cadmium, chromium, lead and nickel in animals with bladder tumors and animals without bladder tumors, 37 cases of bovine bladder tumors and 17 controls were collected. The detection and quantification of metallothioneins in bladder tissue of both cases and controls was performed by immunohistochemistry. And the quantification of metals in tissue and hair was assessed by inductively coupled plasma - mass spectrometry.. Increased expression of metallothioneins was associated with bladder tumors when compared with non-tumoral bladder tissue (OR = 9.3, 95% CI: 1.0 - 480). The concentrations of cadmium, chromium, lead and nickel in hair of cases were significantly higher than those of controls. However, as for the concentration of metals in bladder tissue, the differences were not significant.. Though the sample size was small, the present study shows an association between bladder tumors and metallothioneins. Moreover, it shows that concentrations of metals such as cadmium, chromium, lead and nickel in hair may be used as a biomarker of exposure.

Topics: Adenoma; Animals; Carcinoma; Cattle; Cattle Diseases; Gene Expression Regulation, Neoplastic; Hair; Hemangioma; Metallothionein; Metals; Papilloma; Risk Factors; Trace Elements; Urinary Bladder Neoplasms

The molecular pathogenesis of tumors arising from the thyroid follicular epithelial cells, including papillary (PTC) and follicular thyroid carcinoma (FTC), is only partially understood, and the role of tumor suppressor genes has not yet been assessed. The metallothionein (MT) gene family encodes a class of metal-binding proteins involved in several cellular processes, and their expression is often deregulated in human tumors. Recently, downregulation of MT gene expression in PTC has been reported, suggesting a possible oncosuppressor role of this gene family in the pathogenesis of thyroid tumors. To further explore this possibility, we performed expression and functional studies. Analysis of microarray data of thyroid tumors of different histologic types showed that several MT genes were downregulated with respect to normal tissue. The microarray data were corroborated by quantitative PCR experiments, showing downregulation of MTs in PTC and FTC, but to a greater extent in papillary carcinoma. The expression of MTs was also investigated at the protein level by immunohistochemistry; the results were consistent with the microarray data, showing general downregulation in tumor samples, which was more evident in PTC. The functional consequence of MT downregulation was addressed employing an experimental model made of the PTC-derived K1 cell line in which MT1G expression is repressed by promoter methylation. Restoration of MT1G expression by cDNA transfection affected growth rate and in vivo tumorigenicity of K1 cells, indicating an oncosuppressor role for MT1G in thyroid papillary tumorigenesis.

Topics: Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; DNA Methylation; DNA, Complementary; Down-Regulation; Gene Expression; Humans; Immunohistochemistry; Metallothionein; Microarray Analysis; Promoter Regions, Genetic; Thyroid Neoplasms; Transfection; Tumor Suppressor Proteins

Metallothioneins (MTs) are a family of cystein-rich metal-binding proteins, which are expressed in normal cells during fetal and postnatal life but also in a variety of human neoplasms. MT expression in human tumors has been linked to resistance to anticancer drugs and differentiation and progression in some types of tumors. This study examined the immunohistochemical expression of MTs in benign, borderline and malignant tumors of ovarian surface epithelium and the possible correlations with clinicopathological parameters and survival. A total of 87 cases with diagnosis of ovarian surface epithelial tumors were included. Specifically, 21 cases of benign cystadenomas (11 serous and 10 mucinous), 14 borderline (low malignant potential tumors, 8 mucinous and 6 serous) and 52 cases of ovarian cancer were analysed. Immunohistochemical expression of MT (cut-off level > 10% of tumor cells) was clearly associated with malignancy. A statistically significant correlation was found between the expression of MT in cancer cases and benign tumors (p < 0.0001) and cancer cases and borderline tumors p = 0.003. In cancer cases a difference was observed between grade I and III (p = 0.002). There was no correlation of MT overexpression with survival in the small number of ovarian carcinoma patients where it was analysed. MT constitutes a marker that characterizes aggressiveness and a high malignant potential in ovarian epithelial tumors. In diagnostic problems MT may help distinguish between benign, borderline and malignant tumors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma; Cell Differentiation; Cell Proliferation; Cystadenoma, Mucinous; Cystadenoma, Serous; Diagnosis, Differential; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Metallothionein; Middle Aged; Ovarian Neoplasms; Tumor Suppressor Protein p53

Studies indicate that smoking is significantly related to breast cancer mortality. One hypothesis is that this association is due to the elevated expression of proteins associated with resistance to cancer therapies. The metallothioneins (MTs) are a family of proteins that appear to play a role in conferring resistance to certain cancer therapies. This study was carried out to assess whether smoking was associated with MT expression in breast carcinomas. Archival breast tissues with accompanying clinical and epidemiological information were collected from three different cancer centers for 123 women diagnosed with invasive breast cancer. MT expression was assessed using immunohistochemical procedures and semi-quantified using an immunoreactivity score that was obtained by multiplying the percentage of MT-positive tumor cells by MT staining intensity. The results showed that 27.6% of the women were current smokers. Among women whose tissues were collected at the cancer center where enrolled women had primarily early stage, low grade breast cancer, smokers had increased odds, although not significantly, of having a MT-positive tumor compared to non-smokers, independent of cancer stage. This association was not observed among the women whose tissues were collected from the other cancer centers. These findings suggest that among specific groups of women, smoking at the time of breast cancer diagnosis may be associated with an increase in breast tissue MT.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Metallothionein; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Retrospective Studies; Smoking

The expression of metallothionein (MT), an intracellular ubiquitous low molecular weight protein thiol with antioxidant properties, was studied in nasopharyngeal cancer (NPC) and correlated with the apoptotic index. Immunohistochemical staining of randomly selected, formalin-fixed and paraffin-embedded normal and malignant nasopharyngeal tissues were analysed for the expression of MT using the commercially available E9 antibody directed against MT I and MT II isoforms. The corresponding apoptosis labelling indices were evaluated by the TUNEL method. Localization of MT at the ultrastructural level was studied by immunogold labelling. All the tumour sections (17 specimens) showed MT-immunopositivity. A direct correlation between the percentage of MT-positive cells and the staining intensity was noted (P < 0.001; Pearson's r = 0.95). There was absence of cytoplasmic staining and only nuclear staining (with localization in the nucleoplasm) was demonstrated in the tumour cells. In normal epithelium of the nasopharynx, the basal layer was stained. An inverse relationship was observed between the level of MT expression and the apoptotic index in the NPC tissues (P = 0.0059; Pearson's r = -0.6380). The results suggest that overexpression of MT in NPC may protect the tumour cells from entering into the apoptotic process and thereby contribute to tumour expansion. Preferential localization of MT in the nuclei of NPC cells may possibly enhance radioresistance since radiotherapy is known to eradicate tumour cells by free radical-induced apoptosis.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Carcinoma; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Metallothionein; Middle Aged; Nasopharyngeal Neoplasms; Radiation Tolerance; Regression Analysis

Metallothionein (MT) is a metal-binding protein with functional roles in cell growth, repair and differentiation. MT is reported to be differentially expressed in lymphocytes of malignant gastrointestinal lesions. The level of MT protein was examined by immunohistochemical analysis at light microscopic and ultrastructural level in infiltrating lymphocytes from 20 cases of undifferentiated nasopharyngeal carcinoma (NPC). MT expression was found to be absent in the infiltrating lymphocytes of NPC and in reactive lymphocytes of lymphoid hyperplasia in nasopharyngeal tissues. Ultrastructural examination confirmed the absence of MT immunoreactivity in the lymphoid infiltrate of NPC. On the other hand, malignant lymphoblasts of diffuse large cell lymphoma, showed MT-immunopositivity by immunoelectron microscopy. This study demonstrates a lack of MT expression in the lymphoid stroma of undifferentiated NPC, a further characteristic of its non-neoplastic nature.

Topics: Adult; Aged; Carcinoma; Female; Humans; Immunohistochemistry; Lymphocytes, Tumor-Infiltrating; Lymphoma, B-Cell; Male; Metallothionein; Microscopy, Electron; Microscopy, Immunoelectron; Middle Aged; Nasopharyngeal Neoplasms

Cellular drug resistance and increased metastatic potential are the major obstacles in the successful treatment of cancer with chemotherapy. The aim of this study was to investigate whether the immunohistochemical expression of two proteins implicated in drug resistance (P-glycoprotein and metallothionein) and the product of the suppressor gene nm23 could be related to prognosis in breast cancer. Seventy-two patients with palpable or occult breast carcinoma, not treated with chemotherapy or endocrine therapy, were examined. Immunohistochemical methods were used to determine the expression of P-glycoprotein (PG), metallothionein (MT), nm23, as well as the estrogen receptor (ER), the p53 status, and the Ki67 index. The results were correlated with clinical and morphological features. Cytoplasmic and membrane-specific immunostainings of PG were seen exclusively in tumor cells and identified in 14 of 72 cases (19.4%). Only a statistically significant association with metastases, (p = 0.06) and recurrences (p = 0.1) was observed. MT-positive reaction was identified in the cytoplasm of the tumor cells in 47 (65.3%) cases. Statistical significance was associated with metastases (p = 0.07), but not with death or recurrences. Specific immunostaining of nm23 protein was seen only in the cytoplasm of tumor cells. A positive reaction was observed in 55 of 72 (89.3%) cases. Although a significant association between nm23 protein expression and other morphologic and immunohistochemical variables did not exist, we observed a higher morbidity in patients with the MT-positive/nm23-negative tumor phenotype. Univariate analysis for survival selected the following variables: histologic grade (p = 0.001), ER (p = 0.002), mitotic index (p = 0.005), Ki 67 index (p = 0.068), MT (p = 0.046) and PG (p = 0.085). The Cox model provided the following independent variables: histologic grade (p = 0.021) and metallothionein (p = 0.03). These data confirm the prognosis observed in patients with PG or metallothionein expression as well as the independence of these two variables. It also suggests that nm23 is not necessarily involved in the development of an invasive phenotype.

Topics: Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Metallothionein; Middle Aged; Monomeric GTP-Binding Proteins; NM23 Nucleoside Diphosphate Kinases; Nucleoside-Diphosphate Kinase; Prognosis; Survival Analysis; Transcription Factors

Utilising a specific monoclonal mouse antibody (E9), metallothionein (MT) expression has been immunohistochemically investigated in 112 formalin-fixed paraffin-embedded surgical gastric samples, 38 of which were early carcinomas (EGC) and 74 advanced ones (AGC); clinico-pathological details and follow-up data (ranging from 3 to 197 months, mean 60.5 months) were available. Eighty-nine portions of gastric mucosa adjacent to examined carcinomas (transitional mucosa) were also analysed; in addition, 22 biopsies of normal gastric mucosa were studied as tissue control. The MT immunoreactivity was evaluated by staining and intensity-distribution scores. A various MT positivity was appreciable in the cytoplasm and nucleus of antrum or body gastric epithelial cells in 100% of normal control biopsies. 75/112 (67%) gastric carcinomas showed MT immunoreactivity with a significant lower expression in AGC. No relationships were encountered between MT immunostaining and clinico-pathological data; in addition, no difference in the Kaplan-Meier survival curves of patients with various MT expression was achieved. When the transitional mucosa was examined, 84/89 (94%) samples were stained although the immunoreaction was not always concordant with that encountered in adjacent carcinomatous elements. The significant statistical decrease of MT scores observed by us moving from normal to neoplastic gastric mucosa allows us to exclude the hypothesis of an overexpression of MT in gastric carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Cell Nucleus; Cytoplasm; Female; Gastric Mucosa; Humans; Immunohistochemistry; Male; Metallothionein; Middle Aged; Prognosis; Stomach Neoplasms; Survival Analysis

Metallothionein (MT) is a cysteine-rich protein with pleiotropic functions and a high binding affinity for heavy metals. The present study was designed to examine the relationship between MT expression and tissue zinc levels in conjunction with cell proliferation in nasopharyngeal cancer (NPC). Proliferative activity in NPC was quantified by Ki67 immunolabelling and MT expression was determined by immunohistochemistry. Total zinc and subcellular zinc fractions were analysed by flame atomic absorption spectrometry. MT immunostaining was observed in the nuclei of NPC cells, with the percentage MT immunopositivity ranging from 3.0 to 59.7%. Thirteen tumours displayed weak MT staining and the remaining 11 showed moderate to strong immunostaining. There was a significant positive correlation between MT and Ki67 positivity (P = 0.0127). Tissue zinc levels were higher in NPC as compared with benign nasopharyngeal tissues (4.800 +/- 0.4610 versus 2.889 +/- 0.4045 microgram/g dry wt tissue, respectively; P = 0.0122). Nuclear zinc levels in NPC were significantly higher than levels in membrane and cytosolic fractions (mean zinc levels 1.4840 +/- 0.1489, 0.6286 +/- 0.0789 and 0.3014 +/- 0.0250 microgram/mg protein, respectively). A linear relationship was also observed between nuclear zinc levels and MT immunostaining (P = 0.0024) as well as with Ki67 immunopositivity (P = 0.0123). Our results show that MT and zinc are correlated with proliferative activity in NPC, providing further insights into the biology of this enigmatic and aggressive tumour.

Topics: Carcinoma; Cell Division; Cell Nucleus; Humans; Immunohistochemistry; Ki-67 Antigen; Metallothionein; Nasopharyngeal Neoplasms; Zinc

Regimens containing platinum drugs continue to be amongst the most effective therapies for ovarian cancer. However, despite high initial response rates most patients relapse and die of their disease. Elevation of metallothionein has been implicated as a mechanism by which tumour cells become resistant to platinum anticancer drugs, although most of these studies have been carried out in vitro. This study was carried out to determine whether metallothionein expression was associated with response or survival in patients with epithelial ovarian cancer.. Metallothionein was determined by radioimmune assay using frozen ovarian tumour tissue taken either before or following cytotoxic chemotherapy.. An increase in expression of metallothionein was seen in tumour tissue from patients who had undergone cytotoxic chemotherapy, although this did not attain significance. However, a preliminary study using biopsy material from the same patient, taken both before and after chemotherapy, showed a statistically significant increase in metallothionein. An analysis of these data showed that the level of metallothionein expression was not associated with survival or response.. These data do not support the hypothesis that metallothionein expression is a determinant of response in ovarian cancer. There is some preliminary evidence from the study of paired samples which indicates that cytotoxic chemotherapy may increase metallothionein expression. An increase in metallothionein was also seen in the study using unmatched biopsies although this did not attain statistical significance, due in part to the large inter-patient variability in expression of this protein.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma; Disease-Free Survival; Female; Frozen Sections; Gene Expression Regulation, Neoplastic; Humans; Metallothionein; Middle Aged; Ovarian Neoplasms; Platinum Compounds; Predictive Value of Tests; Prognosis; Radioimmunoassay; Reoperation; Risk Factors; Survival Analysis; Treatment Outcome

Immunocytochemical demonstration of metallothionein (MT) has been reported as a useful prognostic tool in human breast cancer. The aim of this study was to determine the immunohistochemical location of MT in canine mammary tumours and its possible correlation with the morphologic characteristics of these tumours. Surgical specimens from spontaneous malignant (n = 20) and benign mammary neoplasms (n = 20) were processed for routine histological examination and immunohistochemical study. An indirect immunoperoxidase technique, using monoclonal antibody E9 against horse MT was employed. Intensity of the stain, the percentage of immunoreactive tumour cells and immunohistochemical overexpression of MT was estimated for each case. Metallothionein over-expression, defined as those cases with more than 10% immunopositive cells, was detected in both benign and malignant mammary tumours. However, strong immunostaining intensity was seen in benign tumours, whereas in malignant tumours immunopositive cells stained weakly. Positive MT immunostaining occurred in neoplastic epithelial cells, and some chondrocytes present in mixed mammary tumours. However, staining intensity was variable in immunopositive cells. Differences in staining intensity between the primary malignant mammary tumour, tumour emboli and metastatic cells within a lymph node were also noted. Myoepithelial cells and connective tissue did not stain for MT. We concluded that metallothionein immunostaining cannot be used as a diagnostic or prognostic tool in canine mammary neoplasms. However, results of this study support the hypothesis that MT has a role in tumour proliferation and tumour progression.

Topics: Adenocarcinoma; Adenoma; Animals; Biomarkers, Tumor; Carcinoma; Dogs; Female; Immunoenzyme Techniques; Mammary Neoplasms, Animal; Metallothionein; Mixed Tumor, Malignant; Neoplasms, Complex and Mixed; Neoplasms, Glandular and Epithelial

Metallothioneins (MT) are sulphur-rich, low molecular-weight, intracellular metal-binding proteins with a possible role in carcinogenesis of some human tumours. Metallothionein expression in gallbladder cancer has not been studied previously.. Immunohistochemical expression of metallothionein was studied in 42 gallbladders (27 cases of carcinoma of the gallbladder, eight chronic cholecystitis and seven cases of normal gallbladder). Metallothionein expression was significantly higher in cases with carcinoma of the gallbladder (70.37%) as compared to chronic cholecystitis (25%) and normal gallbladders (0%). There was a trend suggestive of increasing MT expression with increasing histological dedifferentiation of carcinoma of the gallbladder.. The increased expression of MT in cases of carcinoma of the gallbladder may represent an increased exposure to heavy metals, which are known carcinogens, and may have a role in gallbladder carcinogenesis. Metallothionein over-expression in carcinoma of the gallbladder may be relevant to the poor prognosis and chemoresistance seen in these cases.

Topics: Adult; Aged; Carcinoma; Cholecystitis; Female; Gallbladder; Gallbladder Neoplasms; Humans; Immunohistochemistry; Male; Metallothionein; Middle Aged

Megestrol acetate (MGA) is being widely used for the improvement of appetite and performance status in patients receiving chemotherapy, especially cisplatin-containing therapy. However, little is known about whether MGA has an effect on cisplatin cytotoxicity. We have investigated this using two transitional carcinoma cell lines, i.e. the cisplatin-sensitive parental line NTUB1 and the resistant daughter line NTUB1/P. Combined effects of MGA and cisplatin were assayed with a microculture chemosensitivity method. We explored the level changes of several cisplatin detoxification mechanisms, including metallothionein (MT), glutathione S-transferase-pi (GST-pi) and glutathione (GSH) levels in cells treated with or without MGA. After treatment with 10 microns MGA for 24 h, the cisplatin IC50s of NTUB1 and NTUB1/P increased 1.4- (p = 0.03) and 1.6- (p = 0.02) fold, respectively. By median effect analysis, the combinations of MGA and cisplatin in the two cells appeared to produce an antagonistic interaction. By Northern analysis, MT transcript levels in both cells were significantly upregulated after treatment with MGA, as compared to those without treatment. Exposure to MGA in either sensitive or resistant cells did not alter GST-pi levels as shown by immunoblotting analysis. Cellular GSH content was increased only in NTUB1/P (p = 0.0036) but remained unchanged in NTUB1 cells (p = 0.29) after MGA exposure. In conclusion, MGA may antagonize cisplatin cytotoxicity by upregulating cellular MT and GSH levels. Use of MGA in cisplatin-containing chemotherapy may impair tumor response by antagonizing cisplatin antitumor activity.

Topics: Antineoplastic Agents; Appetite Stimulants; Carcinoma; Cisplatin; Glutathione; Glutathione Transferase; Humans; Megestrol Acetate; Metallothionein; Tumor Cells, Cultured

Expression of metallothionein (MT) in 75 cases of salivary gland tumors was studied by immunohistochemistry. All tumors containing myoepithelial cells were positive for MT immunostaining. In the tumors composed of both adenoepithelial cells and myoepithelial cells, only myoepithelial cells were MT positive. A rather large portion of cells was noted MT positive in myoepithelial carcinoma and myoepithelioma. Compared with S-100 and smooth muscle actin (SMA) antibodies, the effect of staining by MT antibody for myoepithelial cells was more satisfactory. The results indicate that MT may be a better marker for neoplastic myoepithelial cells and useful in the differential diagnosis of salivary gland tumors.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Adenoid Cystic; Humans; Metallothionein; Myoepithelioma; Salivary Gland Neoplasms

Metallothioneins (MTs) are low-molecular-weight proteins with specific binding for group II metal ions. MTs are involved in the detoxification of metals, but can also play a role in protection of the cell against certain anticancer agents and from damage of irradiation. High expression of MTs in primary breast carcinomas has been found to be associated with poorer prognosis. Expression of MT (MT) was examined immunohistochemically in 160 breast carcinomas and their concomitant lymph node metastases. The immunoreactivity appeared to be independent of the length of fixation when the section was microwaved before incubation with the primary antibody, a monoclonal antibody E-9. The findings were correlated with various histopathological factors, disease-free survival and over-all survival. Patients were divided into two groups, those with MT over-expression (above 10% of positive tumour cells), and those with low MT expression (below 10% positive). MT over-expression was found to be correlated with postmenopausal status and inversely with positive progesterone receptor status (PgR). MT over-expression showed statistically significant correlation with poor over-all survival. No differences in survival were seen between pre- and postmenopausal patients. PgR was in univariate analysis a poor prognostic parameter. In one fourth of the patients, the lymph node metastases showed increased MT expression compared with the primary tumour. These patients had a poorer, but not statistically significant different survival. MT expression was not correlated to chemo- or radiation therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Breast Neoplasms; Carcinoma; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Metallothionein; Neoplasm Proteins; Survival Rate

Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypical lobular hyperplasia, lobular carcinoma in situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductal in situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression. In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.

Topics: Breast; Breast Neoplasms; Carcinoid Tumor; Carcinoma; Carcinoma, Ductal, Breast; Epithelial Cells; Epithelium; Female; Fibrocystic Breast Disease; Humans; Immunohistochemistry; Metallothionein; Papilloma, Intraductal; Reference Values; Risk Factors

Metallothionein (MT) is a cysteine-rich, low molecular weight protein that binds zinc, copper, and cadmium. It is present in a number of normal cells including hepatocytes particularly during fetal and early postnatal life. It has been suggested that developmental profile of MT is similar to other oncofetal gene products and hence, it could be used as a marker for aggressive tumour behaviour. In order to test that hypothesis, we used a monoclonal antibody to MT and immunohistochemically evaluated formalin-fixed, paraffin-embedded tissues from 79 breast carcinomas. In non-neoplastic breast tissue, a strong nuclear and cytoplasmic staining was observed in myoepithelial cells. Positive staining for MT was present in 35 (44%) of breast carcinomas. In most positive cases, nuclear, or both nuclear and cytoplasmic staining was seen. All positive tumours were invasive ductal carcinomas, including a medullary and a metaplastic carcinoma. None of the mucinous, lobular, or intraductal papillary carcinomas reacted for MT. A statistically significant association was found between MT immunostaining and histological grade (P < 0.01) as well as with nuclear grade (P < 0.01). We also observed an inverse relationship between MT staining and oestrogen receptor content of tumours (P < 0.01). Similarly, a statistically significant association was found between moderate and strong MT immunostaining and decreased overall survival and shorter disease-free survival (P < 0.01). MT immunostaining was also predictive of a worse prognosis in the subgroup of lymph node negative (P < 0.001) and oestrogen receptor negative patients (P < 0.01). No statistically significant association was found between MT staining and size of tumour or the presence of lymph node metastasis. We conclude that MT staining may be a useful marker of less differentiated and more aggressive carcinomas of the breast.

Topics: Breast Neoplasms; Carcinoma; Humans; Immunohistochemistry; Lymphatic Metastasis; Metallothionein; Receptors, Estrogen

This study reports the structure and expression rates of genes of the transforming growth factor-alpha (TGF-alpha) signal transduction pathway (TGF-alpha, epidermal growth factor receptor [EGF-R], jun, myc, and metallothionein [MT]) in 47 specimens of ovarian cancer and 21 nonmalignant tissues. The objective was to establish a direct correlation between the genetic activities and the malignant phenotype of the ovarian cancer. The Southern blot technique identified four samples with myc amplification and two with rearranged EGF-R genes. By using the S1 nuclease assay, the analysis of myc transcription showed a similar use of both promotors. Although the size of the investigated transcripts was unaltered, significant differences in the transcription rates were noticed in malignant tissue probes (using northern blot analysis and RNAase protection assay). The following results of messenger RNA analysis in ovarian cancer were observed: EGF-R, negative in 25%, low in 65%, and strongly positive in 10%; TGF-alpha, negative in 34%, low in 36%, and strongly positive in 30%; myc, negative in 8%, low in 64%, and strongly positive in 28%; jun, negative in 4%, low in 58%, and strong in 38%; and MT, low in 80% and strongly positive in 20%. In most nonmalignant tissues studied, no or only a low expression of TGF-alpha, EGF-R, and myc. was found. A comparison of these messenger RNA results with the clinical data from tumors showed four different subgroups of ovarian carcinomas. The results of chemotherapy were known in 32 cases. Tumors with negative or low expression rates of all investigated genes did not respond to chemotherapy; 13 of 18 tumors with high expression rates did respond. Additional signal transduction chains distinct from the TGF-alpha pathway, however, are likely to influence both the expression and activity of transcription factors and MT.

Topics: Adult; Aged; Blotting, Northern; Carcinoma; ErbB Receptors; Female; Gene Expression; Genes, jun; Genes, myc; Humans; Metallothionein; Middle Aged; Ovarian Neoplasms; Phenotype; RNA, Messenger; Transforming Growth Factor alpha

A single topical treatment of mouse skin with the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) results in transient inductions of a variety of genes. Based on the time courses of their inductions, these genes can be classified into two main groups: "early" response genes whose mRNA expression reaches a maximum 0.5-2 h after TPA treatment and "secondary" response genes whose mRNA expression is maximal 4 h or more after treatment. The nuclear oncogenes c-fos, c-myc, and c-jun belong to the early response group, whereas the metallothionein, osteopontin, and urokinase genes belong to the secondary response group. The steady-state expressions of these early and secondary response genes are all very low in normal skin, except that of c-jun, which is relatively high. Steady-state levels of expression and inducibility of these genes by TPA were not altered in initiated skin or in apparently normal skin during tumor promotion. We examined the expressions of these genes in papillomas and carcinomas produced by two-stage (initiator-promoter) and three-stage (initiator-promoter-initiator) protocols in mouse skin. Steady-state expression of the early responding nuclear oncogenes in papillomas and carcinomas was found to remain at the same low level as in normal skin. However, all the secondary responding genes were found to be expressed constitutively at high levels in these tumors. Elevated expressions of the genes for transforming growth factor alpha and beta were also observed in papillomas and to varying extents in carcinomas. These observations suggest that the regulatory machinery for transcription by the protein kinase C-mediated pathway through nuclear oncogenes is altered during the processes of tumor promotion and progression. The genes whose expression is elevated may be associated directly or indirectly with tumor promotion and progression.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Blotting, Northern; Carcinogens; Carcinoma; Female; Gene Expression; Metallothionein; Methylnitronitrosoguanidine; Mice; Mice, Inbred Strains; Osteopontin; Papilloma; Proto-Oncogene Proteins; RNA, Messenger; Sialoglycoproteins; Skin; Skin Neoplasms; Skin Physiological Phenomena; Tetradecanoylphorbol Acetate; Transforming Growth Factors; Tubulin; Urokinase-Type Plasminogen Activator

We have determined the ability of two human ovarian carcinoma cells to over-express metallothioneins (MTs) and the subsequent effect this elevation has on DDP cytotoxicity. Cells of 2008 and COLO 316 human ovarian carcinomas that were resistant to CdCl2 were obtained by stepwise selection and chronic culture in CdCl2 and ZnCl2. The 2008/MT cells were 3.2-fold resistant to CdCl2 and 4.1-fold resistant to DDP; they had 23-fold elevated MTs. The COLO/MT cells were 1.2-fold resistant to CdCl2 and 3.3-fold resistant to DDP, and they had 9-fold elevated MTs. Glutathione (GSH) was also elevated in the Cd-resistant sublines. However, four times more intracellular thiols were contributed by the MTs than by the GSH. 2008 and 2008/MT cells were examined in more detail to elucidate the mechanism of DDP resistance. Depletion of GSH with D,L-buthionine-S,R-sulfoximine (BSO) had no effect on the sensitivity of these cells to either CdCl2 or DDP. Uptake of [195m Pt]DDP in 2008 and 2008/MT cells was identical. Fractionation of the cytosol from [195mPt]DDP-exposed cells on Sephadex G-75 revealed that 17% of the total cellular Pt in 2008/MT cells was associated with the MT fraction, as against 4% in the parent 2008 cells. This increase corresponded to a concomitant loss of Pt from the particulate fraction. Fractionation of 2008 cells selected with DDP (2008/DDP cells) indicated that elevated MTs did not contribute to the DDP resistance of these cells. Only 2% of the total cellular Pt was in the MT fraction in 2008/DDP cells. These results showed that elevation of MTs may be one mechanism of DDP resistance in ovarian carcinoma; however, in vitro selection with DDP does not trigger this mechanism.

Topics: Cadmium; Carcinoma; Cell Compartmentation; Cells, Cultured; Cisplatin; Drug Resistance; Female; Glutathione; Humans; Metallothionein; Ovarian Neoplasms; Platinum; Zinc

Topics: Adult; Carcinoma; Cell Compartmentation; Child; Crohn Disease; Humans; Immunoenzyme Techniques; Intestinal Mucosa; Intestine, Small; Liver; Liver Cirrhosis; Metallothionein; Steroids

Topics: Cadmium; Carcinoma; Cell Line; Cell Survival; Cisplatin; Drug Resistance; Female; Glutathione; Humans; Metallothionein; Ovarian Neoplasms