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 mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.
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PMID:Targeted approaches for treating advanced clear cell renal carcinoma. 1697 18

Due to the chemoresistance of renal cell cancer, cytokine-based therapeutic approaches were considered the standard treatment for patients with metastatic disease. At present, data that are available from a few phase II/III studies, dealing both with the first- and second-line treatment of patients suffering from systemic progression of RCC, indicate the significantly higher clinical efficacy of multikinase inhibitors when compared with cytokine-based therapeutic regimens. In this context, sorafenib (Nexavar, BAY 43-9006) and sunitinib (Sutent, SU 011248) are the most frequently applied and most intensively investigated substances. In Germany, with regard to a phase III study reported at the ASCO congress in 2006, sunitinib received approval for the first-line therapy of metastatic RCC. The application of multikinase inhibitors follows the principle of targeting such mediators that are considered to be substantially involved in the pathogenesis and particularly progression of renal cell cancer within relatively well-defined molecular pathways. The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding the therapeutic efficacy of kinase inhibitors during the treatment of metastatic RCC.
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PMID:[Efficacy of multikinase inhibitors in the treatment of advanced renal cell cancer. A snapshot]. 1743 75

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
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PMID:Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. 1765 13

One of the most serious problems of urology as specialized surgery is the oncological diseases. A large part of the scientific research is dedicated to their basic research, diagnostics and treatment as the results are then presented at the big international forums each year. The new achievements in the investigations of urological diseases excite special interest and mark the stages of the actual progress of the respective science. The overview is a panorama of the newest and at the same time most significant achievements of the science of urology in this field in 2006 presented at the biggest international congresses - the Congress of the European Association of Urology, the Annual Meeting of the American urologists and the Congress of the American Society of Clinical Oncology - ASCO. What is typical is the existence of the large number of researches of the carcinoma of the prostate - an issue on which the urological society focuses its attention quite often. Without any revolutionary breakthroughs being made new scientific proof has been added which considerably enriches our knowledge about this disease and places special focus on the real value and interpretation of the levels of the Prostate Specific Antigen (PSA). What is especially impressive in bladder cancer research is the discovery of a protein element called "survivin", which is of the family of the inhibitors of apoptosis and its level is connected with qualities of the tumors like aggressiveness, recurrence and progression of the disease and mortality rate. The weight of the scientific research in the field of kidney tumors is placed on the basic research of their oncogenesis. After quite a few years of standstill in the area of chemotherapy new drugs like Sunitinib, Sorafenib and Temserolimus are being introduced, some of which even have independent antitumor effect. As far as the testicle tumors are concerned, the necessity of an extensive lymphadenectomy is confirmed. The increased possibilities of conservative treatment of the lymph node metastases are stressed though radiation therapy and chemotherapy, especially in the cases of seminoma tumors. In the case of penis cancer the weight is placed on the timely diagnostics and treatment allowing organ-preserving operations. The summarized messages of the achievements that are part of the development of the oncourology have also been pointed out.
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PMID:[Current progress and problems in oncourology]. 1843 12

Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.
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PMID:Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress? 1847 14

Angiogenesis is an important factor for cancer development and progression in humans. Hereditary and sporadic renal cell carcinoma are characterized by inactivation of the Von-Hippel Lindau (VHL) gene, which results in hyperactivity of the hypoxia-inducible factor-a (HIFa). As a consequence, there is a production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, growth, and metastatic potential of renal-cell carcinoma. These data indicate that angiogenic factors are the promising therapeutic targets in this disease. Surgery can cure the patients with renal cancer if disease is diagnosed at an early stage. On the contrary, inoperable or metastatic disease is not curable. Until recently, the only drugs approved for the treatment of advanced disease were the cytokines, interferon, and interleukin. Nevertheless, only a minority of patients (about 15%) would benefited from this treatment, while the toxicity was considerable. During the last 5 years a new era of biological agents, with considerable activity has been developed and tested in clinical trials and (some of them) have been approved in USA and Europe. These agents are: Sunitinib, Bevacizumab, Sorafenib and Temserolimus. Bevacizumab is an anti-VEGF monoclonal antibody, Sunitinib and Sorafenib are multi- tyrosine kinase inhibitors (TKIs), while Temserolimus is a mTOR inhibitor. The common these in their development is the inhibition of angiogenesis, which may explain their significant activity in renal-cell carcinoma. All the agents have been proven more effective than the interferon as first or second-line treatment. This review will focus in these recent developments and the intense continuing clinical research in this field.
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PMID:Targeting angiogenesis in renal cell carcinoma. 1869 Aug 41

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.
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PMID:Sorafenib for the treatment of unresectable hepatocellular carcinoma. 1970 58

Treatment of metastatic renal cell cancer (RCC) has entered a new paradigm since the development of tyrosine kinase inhibitors such as sorafenib (Nexavar) and sunitinib (Sutent). Despite these advances, immunotherapy, the traditional mainstay of treatment, is not yet obsolete. Immunotherapy offers the possibility of a complete response for a small number of patients with favorable disease factors. However, immunotherapy is a toxic treatment, with a significant impact on quality of life in comparison with a relatively modest survival advantage for most. As such, the search for a biomarker to select patients for immunotherapy and to monitor their progress still remains a clinical and research goal for those involved in treating patients with metastatic renal cancer. At present, performance status and a number of prognostic scores incorporating performance status and laboratory variables are the most widely used indicators of suitability for immunotherapy. More recently, the histological expression of carbonic anhydrase IX has been reported as a biomarker of response to interleukin (IL)-2 immunotherapy. C-reactive protein (CRP) is an acute-phase protein synthesized as part of the systemic inflammatory response. It is readily measured by standardized assays and is reliable, without variability for age, sex, or bodyweight. The presence of an elevated CRP is a prognostic indicator in a number of solid tumors, both in localized and metastatic disease. In advanced renal cancer, the Glasgow Prognostic Score, which is based on elevated CRP and low albumin, has shown prognostic value. CRP is also superior to the widely used performance status in predicting survival for patients treated with either interferon (IFN)-alpha or IL-2. As such, CRP is an increasingly exciting biomarker for predicting outcomes in immunotherapy. Currently, no other biomarker has been applicable for use in both IFNalpha and IL-2 immunotherapy. More recently, changes in CRP kinetics have shown promise as a predictive tool, although more research is required. Use of CRP as a biomarker can improve stratification of patients with metastatic renal cancer, allowing the patients less likely to benefit from immunotherapy to avoid a potentially toxic treatment. The ongoing selection of patients based on biomarkers should enable continued research on the optimum dose and timing of immunotherapy while managing toxicity and optimizing outcomes.
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PMID:The role of the systemic inflammatory response as a biomarker in immunotherapy for renal cell cancer. 1979 32

Metastatic renal cell carcinoma (mRCC) is a highly vascularized tumor with a generally poor prognosis. It is largely resistant to conventional cancer treatment, including most schemes of hormonal and cytokine therapy as well as to modern chemotherapy. Although IFN-alpha has been the first choice in mRCC treatment strategies for more than a decade, recent recommendations of the European Association of Urology focus on so-called molecular-targeted therapies, with multikinase inhibitors, such as sorafenib and sunitinib, blocking the progression of cell proliferation and tumor angiogenesis, as preferential therapy. Sorafenib targets the VEGF receptor, the PDGF receptor beta and, finally, Raf kinase, and is approved for patients who have either received cytokines or are unsuitable for such a therapy. Although targeted therapies reveal superior efficacy compared with previous cytokine-based approaches, they do not cure patients with metastatic disease. Therefore, following tumor progression, most patients require a second-line or sequential therapy during the further progress of the disease. Owing to the fact that optimal sequencing of these new agents has not been fully elucidated, some recent mainly retrospective studies compared the sequence of sorafenib and sunitinib in order to assess the best clinical benefit in mRCC patients. Apparently, no cross-resistance could be observed in any trial, and most results demonstrated a superior efficacy of a sequence strategy when sorafenib was applied as first-line treatment. Regarding current investigations, the aim of the present article is to address and critically discuss the clinical data concerning the efficacy of sorafenib as part of a sequential treatment of mRCC.
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PMID:Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer. 1982 3

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable beta-subunit human choriogonadotropin (beta-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.
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PMID:Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma. 2023 20


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