Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-six patients with advanced renal cell carcinoma were treated with suramin administered by continuous infusion, with dosing determined by a nomogram. One patient achieved a partial response and five patients achieved a minor response or had stable disease for > 3 months. Toxicities included an immune-mediated thrombocytopenia in one patient and Staphylococcus sepsis that was not associated with neutropenia in five patients. Pharmacokinetic parameters were determined by the ADAPT II MAP-Bayesian parameter estimation program. Patient data were fit using a two-compartment open model and first-order rate elimination. This showed a wide interpatient variation in time to target level (median, 13.8 days), volume of distribution (median, 15.2 liters/m2), and t1/2-beta (median, 20.6 days). The patients who achieved a partial response, minor response, or stable disease had a slower elimination rate of suramin, compared to patients with progressive disease. Tumor specimens were obtained prior to therapy and were analyzed for the production of five different growth factor-specific RNA transcripts. These included transforming growth factor alpha, acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived growth factor types A and B. No difference in the pattern of growth factor expression was seen in tumors of responding and nonresponding patients. Suramin does not have significant antitumor activity in renal cell carcinoma. The wide variability in pharmacokinetics suggests that individual dosing should be used in future trials of suramin for treatment for other malignancies. Pertinent corollary studies of tumor biology and clinical pharmacology should be included whenever possible in clinical trials in patients with renal cell carcinoma.
 ...
PMID:Phase II trial of suramin in patients with advanced renal cell carcinoma: treatment results, pharmacokinetics, and tumor growth factor expression. 139 2

During the past 10 years we have studied 216 patients with renal cell carcinoma (RCC). After nephrectomy the patients were divided into two groups: one group received adjuvant acetate medroxyprogesterone therapy and the other formed our control group. The mean follow-up was 4.9 years. Survival was studied through univariate and multivariate analysis, according to Cox's multiple regression. To evaluate survival the following variables were taken into consideration: stage, grade, ploidy, sex, age, MAP therapy, Er, AR, PR receptors. The survival curves according to Kaplan and Meier were statistically significant for stage, grade, MAP therapy and DNA cellular content. The other variables were not statistically significant prognostic factors. Multivariate analysis demonstrated that only stage and MAP therapy are capable of influencing survival. A low stage has a better survival rate and in equivalent stages those who have received MAP live longer.
 ...
PMID:Hormonal therapy in carcinoma of the kidney. 165 Oct 72

TNP-470, an analogue of fumagillin, has been shown to inhibit angiogenesis in vitro and in vivo. In 1992, TNP-470 entered clinical development for cancer as an anti-angiogenic agent. It is currently in Phase I/II trials in Kaposi's sarcoma, renal cell carcinoma, brain cancer, breast cancer, cervical cancer and prostate cancer. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose limiting toxicity (DLT). Terminal half-life values are short and have shown intermittent and intrapatient variation (range: 0.05 - 1.07 h). Recently, mechanistic studies have identified cell cycle mediators and the protein methionine aminopeptidase-2 (MetAP-2) as molecular targets of TNP-470 and fumagillin. Animal studies confirm some toxic effects on normal angiogenic processes such as the female reproductive system and wound healing, which will require caution and close monitoring in the clinic. TNP-470 is one of the first anti-angiogenic compounds to enter clinical trials, making it a valuable prototype for future trials of angiogenesis inhibitors in oncology.
 ...
PMID:TNP-470: an angiogenesis inhibitor in clinical development for cancer. 1106 Jul 50

In this study, we demonstrated that thrombin activates protein kinase C (PKC), mitogen activated protein kinases (MAP kinases), transcription factor nuclear factor-kappa B (NF-kappa B), and cAMP-dependent protein kinase (PKA) in the human renal carcinoma cell line A-498. In addition, it enhanced the migratory capacity, but had no effect on the proliferation of A-498 cells. The effect of thrombin on migration could be blocked by the PKA inhibitor H-89 but was not influenced by inhibition of PKC, MAP kinases or NF-kappa B. We concluded, that thrombin acts as a regulator on human A-498 renal carcinoma cell migration including PKA.
 ...
PMID:The serine proteinase thrombin promotes migration of human renal carcinoma cells by a PKA-dependent mechanism. 1217 50

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.
 ...
PMID:Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells. 1528 72

All-trans retinoic acid (AR-t) is used for treating acute promyelocytic leukemia and renal cell carcinoma and it also has therapeutic value in several animal models of renal disease. Among its renal targets, mesangial cells have been widely studied: they have both retinoic acid receptors (RAR) and retinoid X receptors (RXR) and the cell growth is inhibited when human mesangial cells are incubated with 1-10 microM AR-t. Although his effect has been related with the antiproliferative action of AR-t, there are no studies on the involvement of apoptosis in AR-t induced cell growth when higher concentrations of retinoid are used. Our studies show that 25 microM AR-t triggers mesangial cell apoptosis assessed by light and fluorescence microscopy (Giemsa stain and acridine orange stain, respectively), DNA electrophoresis, flow cytometry (annexin-V) and immunocytochemistry (TUNEL). AR-t induced apoptosis was not inhibited by preincubation with the RXR pan-antagonist HX531 nor with the RAR pan-antagonist AGN 193109, this suggesting RAR and RXIR are not involved in AR-t induced cell death. Previous results of our group showed that ERK (extracellular regulated kinase) and INK (c-Jun kinase), two members of the MAP (mitogen activated protein) kinase family, are involved in non apoptotic effects of AR-t on mesangial cells. Therefore we focussed on the stress activated p38 kinase, the third member of the MAPK family, to investigate its involvement in AR-t induced apoptosis. The results confirmed a role of p38 since: 1) preincubation with B5203589, a p38 inhibitor, inhibited ARA induced apoptosis; 2) incubation with AR-t induced p38 phosphorilation after few minutes and p38 remained phosphorilated for at least 8 hours and 3) AR-t induced p38 phosphorilation was inhibited by SB203589. These data suggest that AR-t might have toxic side effects on the kidney but also suggest that AR-t could be an useful inhibitor of pathological mesangial cell expansion.
 ...
PMID:[All-trans retinoic acid induces apoptosis in human mesangial cells: involvement of stress activated p38 kinase]. 1591 49

The oncogene HDM2 has been implicated in the regulation of the transcription factor, hypoxia inducible factor (HIF). We show in von Hippel-Lindau (VHL)-defective renal carcinoma cells that express constitutively high levels of HIF-1 alpha and HIF-2 alpha that down-regulation of HDM2 by siRNA leads to decreased levels of both HIF-1 alpha and HIF-2 alpha protein levels. However, we show a differential regulation of HDM2 on the HIF angiogenic targets, vascular endothelial growth factor (VEGF), plasminogen activator inhibitor-1 (PAI-1), and endothelin-1 (ET-1): siRNA to HDM2 leads to increased expression of VEGF and PAI-1 proteins but decreased levels of ET-1. We show that HDM2-mediated regulation of these proteins is independent of VHL and p53 but dependent on a novel action of HDM2. Ablation of HDM2 leads to phosphorylation of extracellular-regulated kinase (ERK)1/2 in renal carcinoma cells. We show that regulation of these angiogenic factors is dependent on ERK1/2 phosphorylation, which can be reversed by addition of the MAP/ERK1/2 kinase inhibitors PD98059 and PD184352. This study identifies a novel role for the HDM2 oncoprotein in the regulation of angiogenic factors in renal cell carcinoma.
 ...
PMID:Regulation of angiogenic factors by HDM2 in renal cell carcinoma. 1819 51

We investigated the patients suffering from massive bleeding at the central surgical center, Jichi Medical University Hospital from April 2006 to March 2007. Of the 6401 patients who underwent surgical procedures, 72 patients (1%) received intraoperatively blood transfusion of more than 1400 ml (RCC-MAP Japan Red Cross). Of the 72 patients, 15 patients died within one month after surgery. Massive blood loss occurred during thoracoabdominal aortic aneurysm surgery (32 cases, 44%), major liver resections (10 cases, 14%), and surgical procedures in the pelvic organs (8 cases, 11%). Preoperative circulatory shock state affected the prognosis of the patients. The minimal hemoglobin concentration during anesthesia was significantly lower in the cases with worse prognoses than in those with recovery from illness, while amount of intraoperative blood loss, amount of blood transfusion, hemoglobin concentration before anesthesia or presence of blood coagulopathy did not influence the postoperative course of the patients.
 ...
PMID:[Investigation of massive bleeding at Jichi Medical University Hospital]. 1992 23

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.
 ...
PMID:VHL and HIF signalling in renal cell carcinogenesis. 2022 41

Renal cell carcinoma (RCC) is a highly vascular tumor associated with expression of various angiogenic growth factors. The precise process of how these growth factors are regulated in RCC is not fully understood. Recent evidence suggests that protease activated receptors (PARs), a new family of G-protein coupled receptors, play a crucial role in vascular development and tumor progression through a variety of mechanisms. However, the nature of PAR expression in human RCC tissues and its function in regulating angiogenesis in RCC are largely unknown. In this study, we investigated the expression and function of PAR-2 in RCC. RT-PCR and immunohistochemistry assays show that PAR-2 expression is significantly increased in human RCC tissue compared with the adjacent non-neoplastic kidney tissue. In RCC derived cells, PAR-2 is functional as evidenced by robust signaling through MAP kinases including ERK1/2 and JNK. Furthermore, activation of PAR-2 significantly upregulates several angiogenic cytokines, including interleukin-6 (IL-6), IL-8, monocytes chemotactic protein-1 (MCP-1) and growth-related oncogene (GRO). To our knowledge, this is the first report that characterized PAR-2 expression in RCC tissue and further demonstrated that PAR-2 has a critical role in regulating angiogenesis in RCC.
 ...
PMID:Protease-activated receptor 2 signaling upregulates angiogenic growth factors in renal cell carcinoma. 2296 Feb 71


1 2 Next >>