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

The aim of our present study was to explore a potential use of 125I-labeled murine monoclonal antibody M75 that recognizes carbonic anhydrase IX (CA IX) in the immunotargeting of human cervical carcinoma xenografts in nude mice. CA IX is a hypoxia-inducible antigen, whose expression is significantly associated with carcinomas of the uterine cervix, whereas normal cervical tissue does not express CA IX protein. M75 monoclonal antibody was labeled with 125I and used to quantify hypoxic induction of CA IX expression in vitro in HeLa human cervical carcinoma cells by immunoradiometric assay. HeLa cells showed inducible expression of CA IX in vitro by hypoxia (0.1% O2) and various hypoxia mimicking agents (Co2+, Ni2+, Mn2+, desferrioxamine, o-phenanthroline and Na2S2O4). CA IX expression was also upregulated in the centre of HeLa multicellular clusters (spheroids) corresponding to the conditions of chronic hypoxia. For the immunotargeting study, 125I-M75 was intravenously injected into immunodeficient mice bearing HeLa cervical carcinoma xenografts. Biodistribution profile showed selective and preferential accumulation of 125I-M75 mAb in CA IX expressing HeLa xenografts in comparison with control unreactive 125I-T111 antibody. Specificity was also confirmed by low uptake in CA IX negative C33A xenografts. In addition, CA IX expression in cervical carcinoma xenografts was analyzed by immunohistochemistry with M75. Detailed immunohistochemical analysis of HeLa xenograft sections revealed perinecrotically intensified expression of CA IX. These results indicate that M75 mAb, recognizing CA IX antigen, has targeting properties which could be potentially useful in radioimmunodetection or radioimmunotherapy of human cervical carcinomas and derived metastases.
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PMID:Immunotargeting of human cervical carcinoma xenograft expressing CA IX tumor-associated antigen by 125I-labeled M75 monoclonal antibody. 1268 73

Glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX) are regulated by hypoxia inducible factor-1 (HIF-1) and have been studied as putative intrinsic cellular markers for hypoxia. This study directly compares CAIX and GLUT1 with pimonidazole binding in a prospective series of bladder cancer patients and also studies the prognostic significance of the markers, in combination with vascularity and proliferation, in a retrospective series of bladder cancer patients treated in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON). A total of 21 patients with a diagnosis of transitional cell carcinoma of the bladder received 0.5 g m(-2) pimonidazole. Serial tumour sections were stained for pimonidazole, GLUT1 and CAIX and compared. Tissue sections obtained from a series of 64 patients previously treated for invasive bladder cancer using ARCON were stained for GLUT1 and CAIX together with Ki-67 and CD31/34. There was a good geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients; correlation coefficients were 0.82 (P=0.0001) for GLUT1 and 0.74 (P<0.0001) for CAIX. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident in the retrospective study. In univariate and multivariate analyses, GLUT1 and CAIX were independent predictors for overall and cause specific survival. The hypoxia markers did not predict for local control or metastases-free survival although higher Ki-67 indices showed a trend towards local failure. The data suggest that both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer.
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PMID:GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. 1452 Apr 62

The aim of the study was to compare the angiogenic status, potential qualitative differences in microvessels and carbonic anhydrase IX expression in bone-marrow (BM) metastases and different haematological tumours at time of diagnosis. The microvessel density (MVD), endothelial-cell proliferation (ECP) and carbonic anhydrase IX (CA IX) immunoreactivity were determined on 210 trephine biopsies from 57 patients with multiple myeloma (MM), 13 with acute myeloid leukaemia (AML), 48 with chronic myeloproliferative syndrome (CMPS), 26 with chronic lymphocytic leukaemia (CLL), 25 with epithelial BM metastases, 18 with monoclonal gammopathy of undetermined significance (MGUS) and from a control group composed of 23 patients without haematological neoplasm. There was an increased MVD and ECP in epithelial BM metastases, MM, AML, CMPS and in a part of CLL. While an ECP greater than 0 was detected in 72% of MM, 75% of CMPS and 92% of AML, it was invariably observed (100%) in the BM metastases. The absence of ECP together with a MVD comparable with the control group in our MGUS cases supports the view that MGUS is a pre-angiogenic condition. Qualitative differences in microvessels were associated with growth patterns in MM and CLL and were observed between the different entities of CMPS. In one-third of the epithelial BM metastases, there was a focal CA IX immunoreactivity, which was never observed in the haematological diseases.
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PMID:Microvessel density, endothelial-cell proliferation and carbonic anhydrase IX expression in haematological malignancies, bone-marrow metastases and monoclonal gammopathy of undetermined significance. 1516 17

Renal cell carcinoma (RCC) still represents a therapeutic challenge when patients have advanced or metastatic disease. Treatment using IL-2 and IFN-alpha continues to be the standard of care in patients who are able to tolerate such regimens. Targeted therapy may become the first-line treatment for patients resistant or intolerant to cytokines as new emerging drugs continue to be investigated. Understanding the genetic abnormalities related to the development of RCC (e.g., VHL gene abnormalities) and identifying molecular targets (e.g., epidermal growth factor, vascular endothelial growth factor and carbonic anhydrase IX) are playing a major role in the emergence of these novel agents for the treatment of this malignancy. Overall, these drugs are better tolerated and more acceptable to use by patients than the traditional cytokine-based regimens. The use of oral drugs to treat various malignancies including RCC seems to be the new paradigm of the future. Further understanding of their mechanisms of action and confirmation of their benefits on the clinical outcome is needed.
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PMID:Emerging drugs for renal cell carcinoma. 1626 62

Novel approaches for the early detection of urogenital cancers are urgently needed. Metastatic renal cell carcinoma (RCC) has a poor prognosis and unpredictable course and to date there are no molecular markers that reliably protect RCC outcome. A novel kidney cancer marker, carbonic anhydrase IX (CA IX), was investigated as an independent prognostic factor for survival for patients with metastatic RCC. In patients with non-metastatic RCC low CAIX predicted a worse outcome similar to patients with metastatic disease and overall CAIX expression decreased with development of metastasis. CAIX reflects significant changes in tumour biology, which may be used to predict clinical outcome and identify high-risk patients for adjuvant-targeted therapies. With regard to prostate cancer there are a number of putative biomarkers, although there are limited studies providing clinical correlations in humans. Potential biomarkers include caveolin-1, p-Akt, p27, the met oncogene, Ki67 (MIB-1), 8q24 over-expression, polycomb protein EZH2, plasma TGF-B1 and IL-6 among others. The laboratory has concentrated on the Prostate Stem Cell Antigen (PSCA) which is increased in patients with more aggressive features, that is higher Gleason grade and higher stage. Highest expression is seen in metastatic lesions to bone and staining for PSCA may predict for disease progression or recurrence. Also promising is the finding reported by the group that expression of p27 in radical prostatectomy specimens correlates with biochemical recurrence. Loss of p27 (defined as absent expression in more than 70% of the specimen) is an independent predictor of recurrence among all patients and among the sub-set with organ confined and extra-capsular disease. The data also shows that p27 can predict outcome among patients with positive surgical resection margins. As with other biomarkers, major questions still to be addressed is the requirement for universal application with uniform scoring and the need for prospective studies in randomized clinical trials.
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PMID:Biomarker discovery in urogenital cancer. 1629 16

Most solid tumors contain hypoxic regions. Hypoxia affects a variety of tumor cell properties such as cell growth rate, neovascularization, metastasis and sensitivity to treatment. Breast 3cancer is the second most common cause of death in women. Nearly half of breast cancer patients treated for localized disease develop metastases and often combinations of local and systemic therapy are not curative. Tissue oxygenation measurements in human breast carcinomas have shown large areas of hypoxic tissue and immunolocalized signals of the hypoxic markers, CAIX and HIF-1 alpha, in breast cancer tissue show strong staining around necrotic regions. A wide range of genes associated with breast cancer metastasis have been reported to be upregulated under hypoxic conditions and hypoxic gene signatures are associated with poorer outcome in breast cancer. An understanding of the molecular pathways in hypoxia-induced breast cancer metastasis promises potential useful prognostic and therapeutic information.
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PMID:Hypoxia and metastasis in breast cancer. 1747 65

A hallmark of renal cell carcinoma is its variable prognosis. Surgical resection of primary renal cell carcinoma can be curative when the disease is localized. However, approximately 20% of patients with early stages of localized renal cell carcinomas subsequently develop metastasis after the primary tumor is removed. The median survival for patients with metastatic disease is approximately 13 months. Therefore, there is a great need for biomarkers to predict metastasis and prognosis. Many prognostic biomarkers were studied in the past decade. In recent years, several promising biomarkers, including CAIX, B7-H1 and IMP3, have also been identified by large retrospective studies. Further validation of these biomarkers is essential to transfer the research data into clinical practice. Eventually, an outcome prediction model with biomarkers, staging system and other risk factors will identify high-risk patients with likelihood of progression and formulate different follow-up protocols or systematic treatments for these patients.
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PMID:Prognostic biomarkers in renal cell carcinoma. 1748 36

Renal cell carcinoma (RCC) is a radio- and chemotherapy resistant tumor, which has a very high morbidity and mortality when metastasized. The current treatment options demonstrate limited efficacy and severe side-effects. Therefore, there is a need for new therapeutic strategies for RCC. As for other malignancies, monoclonal antibodies (mAbs) targeting tumor-associated antigens have been developed for RCC. One of these, mAb G250, targets the MN/CAIX/G250 antigen, which is ubiquitously expressed in clear cell RCC (ccRCC). ccRCC is the most common form of RCC with a prevalence of 80%. Expression of G250 in normal tissue is restricted to the gastrointestinal mucosa and related structures, thereby making it a suitable candidate for targeting ccRCC. In several clinical studies the efficient accumulation of mAb G250 in ccRCC has been demonstrated, resulting in high contrast images. G250-imaging could prove to be a valuable tool in diagnosing metastases in patients with a G250-antigen positive primary tumor and/or in the differential diagnosis of suspect kidney lesions. Furthermore, the therapeutic efficacy of radiolabeled G250 has been investigated in a series of studies. Thus far, most efforts have been devoted to G250 labeled with high doses of 131I. Other radionuclides which may enhance the therapeutic index of this radiolabeled mAb are currently under investigation. In our institution, an activity dose escalation study is currently ongoing to investigate the therapeutic potential of 177Lu-labeled G250 in metastatic ccRCC patients. In this review, the current status of the diagnostic and therapeutic properties of radiolabeled antibodies in RCC is described.
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PMID:Radiolabeled antibodies in renal cell carcinoma. 1805 91

We attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival.
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PMID:Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. 1846 92

The aim of the study was to identify the impact on prognosis of hypoxia-inducible factor-1 genetic program in colorectal carcinomas and to develop an experimental procedure that would allow a reliable quantitative gene expression analysis in formalin-fixed and paraffin-embedded tissue. The expression of hypoxia-inducible factor-1alpha and 13 hypoxia-inducible factor-1 target genes (AMF, CAIX, VEGF, VEGFR1, VEGFR2, HGF, MET, TGFalpha, EGFR, IGF2, MMP2, PLAUR, NIX) was quantified by real-time polymerase chain reaction in 18 colorectal, poorly differentiated neuroendocrine carcinomas and in 60 invasive colorectal carcinomas. Moreover, hypoxia-inducible factor-1alpha protein expression was evaluated by immunohistochemistry. High levels of hypoxia-inducible factor-1alpha were positively associated with poorly differentiated neuroendocrine carcinoma histology (P < .005), poor differentiation (P < .025), presence of necrosis, and presence of microsatellite instability (P < .05). AMF, TGFalpha, IGF2, NIX, VEGF, and VEGFR2 transcripts were significantly higher in the very aggressive poorly differentiated neuroendocrine carcinomas than in exocrine colorectal carcinomas and TGFalpha expression was significantly associated with presence of lymph nodal metastases (P < .05). High levels of TGFalpha and NIX were significantly associated with decreased overall survival (P < .001; P < .01). The multivariate analysis showed that advanced stage, presence of lymph node metastases, and high TGFalpha expression had an independent effect on survival (P < .006; P < .01; P < .0006). Our study suggests an up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas. hypoxia-inducible factor-1alpha overexpression alone, has no impact on the prognosis of colorectal carcinomas likely because the consequences of hypoxia-inducible factor-1alpha expression/stabilization strongly depend on the genetic background of the transformed cells. Mechanisms leading to increased synthesis of hypoxia-inducible factor-1alpha mRNA via autocrine growth factor loops may play a crucial role in invasive growth in this site.
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PMID:Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas. 1861 49


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