Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cell resistance against melphalan (LPAM) has been associated with increased cellular reduced glutathione (GSH) levels and glutathione S-transferase activity. Therefore, GSH conjugation of LPAM has been hypothesized to be a key factor in tumor cell resistance. In the present study, we evaluated GSH conjugation of LPAM by the perfused liver in patients with colorectal cancer metastases undergoing a Phase II study of isolated liver perfusion as well as in the rat. To evaluate whether LPAM-GSH conjugates were synthesized in the rat in vivo, LPAM was infused i.v. at a rate of 2.0 micromol/kg/min. In bile samples obtained during the infusion, two major GSH conjugates were identified by mass spectrometry: mono-hydroxy-mono-GSH-LPAM and di-GSH-LPAM. The maximum biliary excretion rate of these two conjugates accounted for only 1.3% of the LPAM infusion rate. In bile or perfusate samples from patients treated for 60 min initially with 0.3 mM LPAM in the perfusion medium via isolated liver perfusion (200 mg LPAM in approximately 2 liters perfusion medium), none of the above-mentioned conjugates were detected. When comparable rat liver perfusions were performed initially with 66 microM or 0.66 mM LPAM in the perfusion medium, bile samples did contain GSH-LPAM conjugates; the cumulative biliary excretion of the two conjugates amounted to 0.4 and 0.2% of the LPAM dose, respectively. These data suggest that both in rats and humans, hepatic GSH conjugation plays a very minor (if any) role in the elimination of LPAM and, therefore, that modulation of GSH levels is unlikely to affect the rate of elimination of this drug.
 ...
PMID:Lack of glutathione conjugation of melphalan in the isolated in situ liver perfusion in humans. 884 Sep 88

An experimental model of advanced human neuroblastoma, IGR-N-91, which is able to disseminate in the nude mouse, has been described. The present study was designed to ascertain which cell population from the IGR-N-91 primary tumour actually disseminates throughout the animals. In s.c. IGR-N-91 tumour xenografts, 3 areas, called pearly, vascularized and haemorrhagic, depending on the presence of blood vessels and haemorrhagic suffusions, were consistently observed and independently resected. Molecular analysis of tumour materials revealed a significant increase in MYCN and max gene transcript levels in the haemorrhagic area, as compared with the pearly and vascularized areas. Given the growth kinetics observed both in vitro and in vivo, and the DNA flow-cytometry profiles of tumour cells obtained from the haemorrhagic area, this transcriptional increase did not appear to be associated with enhanced proliferation. In this area of the tumours, multidrug-resistance-related genes, i.e., MDRI, MRP, GST-pi and topoisomerase II alpha were activated concomitantly with MYCN and max genes. The same observations were made, except for the topoisomerase-II alpha gene, when sub-lines derived from metastases were compared with that derived from the primary tumour. These data demonstrate that over-expression of several genes determining the multi-drug-resistance phenotype precedes the metastatic spread of IGR-N-91 NB tumour cells in the nude mouse. Data also suggest that the cell sub-population exhibiting this pleiotropic over-expression within the primary tumour undergoes selection during metastatic dissemination.
 ...
PMID:Pleiotropic over-expression of multidrug-resistance-related genes is correlated to MYCN and max mRNA accumulation during tumour progression in the IGR-N-91 human neuroblastoma model. 903 51

Our purpose was to study the role of the expression of P-glycoprotein (Pgp) and glutathione S transferase-pi (GST-pi) in predicting the response to chemotherapy, relapse-free interval, and survival of patients with synovial sarcoma (SS). Thirty-seven cases of primary SS, without regional lymph node or distant metastases, were studied. There were 17 females and 20 males, ranging in age from 7 to 81 years (median, 31 years) with tumors located in the lower extremity (n = 24) upper extremity (n = 5) and trunchus (n = 8). The cases were retrospectively studied without knowledge of clinical course to compare the immunohistochemical expression of Pgp and GST-pi, flow cytometry parameters (ploidy and % of cells in S+G2 phases), and PCNA and Ki-67 labeling of primary tumors before any therapy, with that observed in local recurrences and metastases after chemotherapy. The relationship of the aforementioned parameters with clinicopathological features (gender, age, and histo-blood group of the patients, size, location, histological subtype. TNM stage, and clinical response to chemotherapy of the tumors) was also evaluated. Results revealed that Pgp and GST-pi were expressed in 29.7% and 40.5% of the cases, respectively. In 48.6% of the tumors there was expression of a least one of the drug resistance markers. The markers were coexpressed in 25.0% of the tumors. The prevalence of Pgp expression was lower, but not significantly, in stage I-II (17.6%) than in stage III (40.0%) tumors, and also in cases without clinical progression (16.7%), than in cases with (36.0%). No such differences were observed for GST-pi expression. Pgp and GST-pi expressions were significantly associated with biphasic SS and were particularly noticeable in solid/glandular areas of biphasic SS. The expression of the drug resistance markers was not significantly associated with gender, age, and histo-blood group of the patients, dimension, location, and proliferative activity of the tumors; it was also not significantly related to relapse-free interval and survival of the patients. The expression of Pgp and GST-pi was not significantly associated either to response to chemotherapy or influenced by chemotherapy. We conclude that Pgp and GST-pi expressions are not good predictors response to of the chemotherapy in patients with localized SS. Other drug resistance mechanisms may be active in SS.
 ...
PMID:Synovial sarcoma: immunohistochemical expression of P-glycoprotein and glutathione S transferase-pi and clinical drug resistance. 911 70

The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon, referred to as biochemotherapy, has shown encouraging results in patients with advanced melanoma. Toxicity is high, however and no objective parameters exist to distinguish between patients who are likely to respond and those who are not. The purpose of this pilot study was to determine whether in vitro cisplatin-induced damage to the glutathione S-transferase-pi (GST-pi) gene in peripheral blood mononuclear cells (PBMCs) before therapy correlated with the histological response in melanoma patients with local-regional metastases who received concurrent biochemotherapy before definitive surgery. Before therapy, PBMCs from 16 patients were exposed to cisplatin at concentrations of 25, 50 or 100 microM for 3 h and the extent of damage to the GST-pi gene was quantitated by polymerase chain reaction (PCR). Patients were subsequently treated on a biochemotherapy regimen consisting of cisplatin 20 mg/m2 intravenously (i.v.) on days 1-4, vinblastine 1.5 mg/m2 i.v. on days 1-4, dacarbazine 800 mg/m2 i.v. on day 1, IL-2 9 MIU/m2 per day i.v. by continuous infusion on days 1-4 (total of 96 h), and interferon alpha2a 5 MU/m2 subcutaneously on days 1-5. The 16 patients were categorized into two groups: major responders (n = 7) and non-major responders (n = 9). Although we observed a wide interpatient variation, a statistically significant correlation existed between the histological response and the degree of DNA damage caused in the PBMCs at all three cisplatin concentrations tested (P = 0.024 for 25 microM; P = 0.036 for 50 microM; P = 0.007 for 100 microM). Our pilot study suggests that determination of in vitro cisplatin-induced DNA damage using a gene-specific PCR assay may be useful in predicting the histological response to biochemotherapy.
 ...
PMID:DNA damage in peripheral blood mononuclear cells correlates with response to biochemotherapy in melanoma. 961 Aug 67

Members of the cytochrome P450 and glutathione S-transferase supergene families are candidates for susceptibility and outcome in oral squamous cell cancer. We determined GSTM1, GSTM3, GSTT1, CYP1A1 and CYP2D6 genotypes in 100 Caucasian cases and 467 control individuals. The frequency of homozygosity for mutant CYP2D6 alleles was higher in the cases (P = 0.001, OR = 3.2, 95% CI = 1.6-6.5) than control individuals. In the cases, the frequency of homozygosity for mutant alleles was greater and that of homozygosity for wild-type CYP2D6 alleles was lower in those diagnosed at > or = 65 years (P = 0.009) than in those diagnosed at < or = 64 years. The older cases included relatively more women and patients who did not consume tobacco or alcohol. The association of CYP2D6 with outcome was assessed using the Cox's proportional hazards model. The time to first cervical node metastasis was shorter in heterozygotes and homozygotes for mutant CYP2D6 alleles compared with homozygotes for wild-type alleles after correction for age at diagnosis, gender, alcohol and tobacco consumption and tumour differentiation (P = 0.04, hazard ratio 3.6, 95% CI 1.1-12.5). The mechanism for the association of CYP2D6 alleles with susceptibility and outcome is unclear though the data are compatible with the view that homozygosity for mutant alleles confers impaired detoxication of an unknown carcinogen. No associations between GSTM1, GSTM3, GSTT1 or CYP1A1 genotypes and susceptibility or, time to node metastases were identified. We previously showed that CYP2D6 genotypes were not associated with susceptibility to squamous cell cancer in the pharynx or larynx. Therefore, the data presented suggest that susceptibility to squamous cell cancer in the various parts of the upper aerodigestive tract is associated with different genes and allelic variants.
 ...
PMID:Susceptibility and outcome in oral cancer: preliminary data showing an association with polymorphism in cytochrome P450 CYP2D6. 982 35

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.
 ...
PMID:The chemoresistance of human malignant melanoma: an update. 1033 34

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-regulation are (i) changing patterns of DNA methylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-alpha and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an important consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
Cancer Metastasis Rev
PMID:Epigenetic mechanisms for progression of prostate cancer. 1045 84

Caloric restriction has been associated with a delay in the development of both spontaneous and induced neoplasia. In contrast, cycles of fasting/refeeding were shown by us and others to enhance the incidence of early lesions during chemical carcinogenesis in rat liver. The present, long-term study was undertaken to establish whether such a diffential effect would also extend to the later phases of cancer development, until the overt appearance of neoplasia. Male Fischer 344 rats were initiated with a single dose of diethylnitrosamine (DENA, 200 mg/kg i.p.) and starting 1 week later they were either exposed to three cycles of fasting (3 days) followed by refeeding (11 days) or were fed continuously. Seven weeks after DENA administration the rats were exposed to the resistant hepatocyte model of the liver tumor promotion protocol. All animals were killed 1 year after initiation. Incidence of hepatocellular carcinoma was 2-fold higher in the fasted/refed group compared with the controls (72 versus 36%). In addition, cancers were also larger and of higher histological grade in the former group, with one animal showing metastases to the lungs, while no metastases developed in control animals. Fasting caused a decrease in total liver DNA (from 25.2 +/- 1.1 to 16.5 +/- 1.1 mg after 3 days) which was associated with a decrease in hepatocyte labeling index and mitotic activity and high levels of single cell death (apoptosis). In contrast, a sharp increase in hepatocyte proliferation was observed on day 2 of refeeding and this was more pronounced in glutathione S-transferase 7-7 positive foci compared with surrounding liver (10.2 +/- 2.3 versus 4.6 +/- 0.8%). Such a proliferative wave was associated with a sharp decline in the incidence of cell death. It is concluded that fasting/refeeding performed early after initiation accelerates the development of chemically induced hepatocellular carcinoma in the rat.
 ...
PMID:Effect of fasting/refeeding on the incidence of chemically induced hepatocellular carcinoma in the rat. 1050 14

We found that human kinin-free high-molecular-weight kininogen (kf-HK) significantly inhibited vitronectin-mediated migration (haptotaxis) and invasive potentiation (haptoinvasion) of osteosarcoma (MG-63) cells but that HK, LK, the common heavy chain of HK and LK, and the light chain (D6(H)) of HK had no inhibitory effect. Recombinant GST-D5(H) (histidine-rich region of HK) obtained from Escherichia coli. (BL21) also inhibited both haptotaxis and haptoinvasion to about 30% of the control level in a dose-dependent manner. These findings suggest that a specific region of D5(H) is responsible for the inhibition of cell haptotaxis and haptoinvasion. Among the seven synthetic peptides covering D5(H), peptide H(479)KHGHGHGKHKNKGK(493) (P-5) inhibited both haptotaxis and haptoinvasion in a dose-dependent manner, suggesting that P-5 could possibly be utilized to prevent primary and secondary metastases of tumor cells.
 ...
PMID:Inhibition of vitronectin-mediated haptotaxis and haptoinvasion of MG-63 cells by domain 5 (D5(H)) of human high-molecular-weight kininogen and identification of a minimal amino acid sequence. 1168 5

Radiotherapy is the modality of choice for the treatment of nasopharyngeal carcinoma (NPC). However, systemic chemotherapy has recently been found to play an increasing role in the treatment of advanced or metastatic disease. The status of drug resistance gene expression that has crucial impact on chemotherapy has not been fully addressed for patients with NPC. In this study, we examined the expression of multidrug resistance 1 (MDR-1) and glutathione-S-transferase-Pi (GST-Pi) in primary, recurrent, and metastatic NPC using results of immunohistochemical examinations. The results were correlated with the expression of Epstein-Barr virus (EBV) latent protein, latent membrane protein 1 (LMP1), and clinicopathologic features, including stage, histopathologic types, and survival rates. MDR-1 protein expression was detected in 18 (12.6%) of 143 patients with primary NPC, 14 (32.6%) of 43 with recurrent NPC, and O (0%) of 20 with metastatic NPC, whereas 83 (58%) of 143 patients with primary NPC, 30 (69.8%) of 43 with recurrent NPC, and 13 (65%) of 20 with metastatic NPC expressed GST-Pi. EBV-LMP1 was expressed in 59 (41.3%) of 143 patients with primary NPC, 23 (53.5%) of 43 with recurrent NPC, and 9 (45%) of 20 with metastatic NPC. Simultaneous expression of MDR1 and GST-Pi was observed in 13 (72.2%) of 18 patients with primary NPC and 12 (85.7%) of 14 with recurrent NPC. The expression of LMP1 was detected in only 6 of the 13 patients with primary NPC and 6 of the 12 with recurrent NPC. We concluded that the expression of GST-Pi was more frequent in NPC tumor tissues than the expression of MDR-1. The expression of MDR-1 correlated with clinicopathologic features of primary NPC, including the histopathologic types and survival rates, but not with disease stage. The expression of GST-Pi did not correlate with clinicopathologic features. The expression of MDR-1 and GST-Pi did not correlate with expression of EBV-LMP1 for patients with NPC.
 ...
PMID:Expression of multidrug resistance 1 and glutathione-S-transferase-Pi protein in nasopharyngeal carcinoma. 1172 64


<< Previous 1 2 3 4 Next >>