Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temsirolimus (CCI-779), a small molecule inhibitor of mTOR protein, is a water-soluble synthetic rapamycin ester that has been developed in both oral and intravenous (i.v.) formulations. PI3k/Akt/mTOR pathway activation is implicated in the pathogenesis of many cancers. Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. The drug has significant in vitro antitumor effect against a number of cancer cell lines and has demonstrated in vivo cytostatic activity in xenograft models. Flat dosing of 25 mg, 75 mg and 250 mg i.v. weekly were selected for tumor-specific phase I trials. Biological activity was observed at all these doses. However, the frequency and intensity of the toxicities increased at higher doses and more high-dose patients had to reduce the dose or discontinue the drug. Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia. Temsirolimus is farther along in clinical development than any other mTOR inhibitor in its class and has demonstrated significant activity in patients with poor-risk clear-cell renal cell carcinoma. Patients receiving temsirolimus alone achieved longer survival than those receiving interferon alone or temsirolimus plus interferon in a randomized phase III trial. Predictive biomarkers for clinical efficacy are undetermined and remain under investigation.
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PMID:Temsirolimus. 1798 19

Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. Median progression-free survival durations were 3.8 and 1.9 months, respectively, for patients treated with temsirolimus or IFN, and median overall survivals were 10.9 and 7.3 months, respectively. Exploratory analyses indicate that temsirolimus benefits those patients with metastatic RCC and multiple adverse prognostic factors regardless of tumor histology or nephrectomy status. Most adverse events that occur in patients receiving temsirolimus can be managed medically (eg, hyperglycemia, hyperlipidemia) or addressed by supportive measures (eg, stomatitis, rash). Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
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PMID:Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma. 1996 97

This report summarizes the U.S. Food and Drug Administration (FDA)'s approval of temsirolimus (Torisel), on May 30, 2007, for the treatment of advanced renal cell carcinoma (RCC). Information provided includes regulatory history, study design, study results, and literature review. A multicenter, three-arm, randomized, open-label study was conducted in previously untreated patients with poor-prognosis, advanced RCC. The study objectives were to compare overall survival (OS), progression-free survival (PFS), objective response rate, and safety in patients receiving interferon (IFN)-alpha versus those receiving temsirolimus alone or in combination with IFN-alpha. In the second planned interim analysis of the intent-to-treat population (n = 626), there was a statistically significant longer OS time in the temsirolimus (25 mg) arm than in the IFN-alpha arm (median, 10.9 months versus 7.3 months; hazard ratio [HR], 0.73; p = .0078). The combination of temsirolimus (15 mg) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone. There was also a statistically significant longer PFS time for the temsirolimus (25 mg) arm than for the IFN-alpha arm (median, 5.5 months versus 3.1 months; HR, 0.66, p = .0001). Common adverse reactions reported in patients receiving temsirolimus were rash, asthenia, and mucositis. Common laboratory abnormalities were anemia, hyperglycemia, hyperlipidemia, and hypertriglyceridemia. Serious but rare cases of interstitial lung disease, bowel perforation, and acute renal failure were observed. Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC.
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PMID:FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. 2066 70

Renal cell carcinoma (RCC) with sarcomatoid features has an aggressive course. There is no standard treatment for this histological subtype. Some authors have previously reported the use of chemotherapy, but the activity of new agents against renal carcinoma with sarcomatoid differentiation has to be formally evaluated. Temsirolimus, an inhibitor of the mammalian target or rapamycin, is active in RCC, including those tumors with non-clear histologies. We have tested the activity of this agent in three consecutive patients. A first patient showed a rapid progression, dying 2 months after the diagnosis. The second patient showed clinical improvement and a partial response to lung metastasis that was maintained for 14 months. The third patient is still alive, evaluated as stable disease after 7 months on temsirolimus. Importantly, toxicity was not a main issue during the use of temsirolimus and only grade 2 hyperglycemia, asthenia, hyperlipidemia, and pleural effusion were detected. Temsirolimus is a valid therapy in this subset of patients, with some lasting stabilizations and with manageable toxicity.
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PMID:Temsirolimus in renal cell carcinoma with sarcomatoid differentiation: a report of three cases. 2156 67