Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As a part of a pilot clinical study, a high-performance reversed-phase liquid chromatography analysis was developed to quantify temozolomide in plasma and urine of patients undergoing a chemotherapy cycle with temozolomide. All samples were immediately stabilized with 1 M HCl (1 + 10 of biological sample), frozen and stored at -20 degrees C prior to analysis. The clean-up procedure involved a solid-phase extraction (SPE) of clinical sample (100 microliters) on a 100-mg C18-endcapped cartridge. Matrix components were eliminated with 750 microliters of 0.5% acetic acid (AcOH). Temozolomide was subsequently eluted with 1250 microliters of methanol (MeOH). The resulting eluate was evaporated under nitrogen at RT and reconstituted in 200 microliters of 0.5% AcOH and subjected to HPLC analysis on an ODS-column (MeOH-0.5% AcOH, 10:90) with UV detection at 330 nm. The calibration curves were linear over the concentration range 0.4-20 micrograms/ml and 2-150 micrograms/ml for plasma and urine, respectively. The extraction recovery of temozolomide was 86-90% from plasma and 103-105% from urine over the range of concentrations considered. The stability of temozolomide was studied in vitro in buffered solutions at RT, and in plasma and urine at 37 degrees C. An acidic pH (< 5-6) should be maintained throughout the collection, the processing and the analysis of the sample to preserve the integrity of the drug. The method reported here was validated for use in a clinical study of temozolomide for the treatment of metastatic melanoma and high grade glioma.
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PMID:Determination of temozolomide in human plasma and urine by high-performance liquid chromatography after solid-phase extraction. 766 2

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m(-2) day(-1). Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for phase II studies.
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PMID:Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. 1057 60

Temozolomide (TMZ) is the first new chemotherapy agent to be approved for the treatment of high-grade malignant gliomas in more than 20 years. This novel oral alkylating agent has demonstrated promising activity not only in brain tumors, but in a variety of solid tumors, including malignant melanoma. TMZ is 100% bioavailable when taken orally and, because of its small size and lipophilic properties, it is able to cross the blood-brain barrier. Concentrations in the central nervous system are approximately 30% of plasma concentrations. Once it has entered the central nervous system, TMZ can be spontaneously converted to the active metabolite. These pharmacologic properties make it an ideal agent for treating central nervous system malignancies. In patients with advanced metastatic melanoma, brain metastases are a major cause of treatment failure. In this setting, TMZ has been shown to be as effective as dacarbazine, with a similar safety profile. More importantly, there is evidence to suggest that TMZ-treated patients have a lower incidence of central nervous system relapse compared with dacarbazine-treated patients. Therefore, TMZ is actively being investigated for the treatment and prevention of brain metastases in melanoma patients. TMZ may become an important part of treatment regimens for advanced metastatic melanoma.
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PMID:Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. 1079 5

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5-8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas and other difficult-to-treat tumors. Temozolomide, a p.o. imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. An overview of the mechanism of action of temozolomide and a summary of results from clinical trials in malignant glioma are presented here.
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PMID:Temozolomide and treatment of malignant glioma. 1091 98

Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
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PMID:Future directions for temozolomide therapy. 1155 Jan 38

Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma.
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PMID:Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. 1193 Jan 15

The overall survival for patients with metastatic melanoma ranges from 4.7 to 11 months, with a median survival of 8.5 months. Standard treatment for patients with metastatic melanoma has not been defined. The range of treatment options includes close observation, surgical resection of isolated metastases, therapy with dacarbazine, combination chemotherapy, and participation in clinical trials. Numerous chemotherapeutic agents have shown activity in the treatment of malignant melanoma. Dacarbazine (DTIC-Dome; Bayer Corporation, West Haven, CT) has a response rate of 15% to 20% and remains the reference agent for the treatment of metastatic disease. Additional agents with single-agent activity include cisplatin, (Platinol-AQ; Bristol-Myers Oncology, Princeton, NJ); carmustine (BiCNU; Bristol-Myers Oncology, Princeton, NJ); paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ); and docetaxel (Taxotere; Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, PA). Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ), which is essentially an oral form of dacarbazine but with greater central nervous system penetrance, is associated with a response rate of 20%. Combination chemotherapy with or without tamoxifen has been extensively evaluated in patients with metastatic melanoma. Although the initial results with the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) were associated with overall response rates of 50% to 55% in single-institution studies, results from larger multicenter studies reveal responses rates ranging from 10% to 20%. Based on the results of several clinical trials, there is no evidence that the addition of tamoxifen improves the response rate. Another combination regimen is cisplatin, vinblastine, and dacarbazine (CVD), which is associated with a 20% to 25% response rate. There has been widespread interest in developing immunotherapies against metastatic melanoma. Interferon (IFN)-alfa and interleukin (IL)-2 as single agents have produced response rates in the 15% to 20% range. Biochemotherapy, which is a combination of immunotherapy and cytotoxic chemotherapy, has been studied in patients with metastatic melanoma. Multiple phase II studies have demonstrated high response rates but unclear impact on overall survival. Therapy is associated with significant toxicity. Ongoing randomized clinical trials will clarify the role of biochemotherapy in patients with metastatic melanoma. Ongoing new approaches to treatment include the therapeutic use of vaccines alone or in combination with cytokines.
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PMID:Metastatic melanoma. 1205 19

Temozolomide is an imidazotetrazine with a mechanism of action and efficacy similar to dacarbazine (DTIC). However, it differs from DTIC in that it can be taken orally, degrades spontaneously to an active metabolite and penetrates the blood-brain barrier. It is well tolerated, making it a suitable candidate for combination chemotherapy. Trials to date have focussed on its activity in advanced metastatic melanoma and high-grade malignant glioma. Investigations into other indications, in particular solid tumors with central nervous system metastases, are ongoing. Studies of new drug schedules and of drugs to ameliorate temozolomide resistance offer the prospect of increased efficacy.
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PMID:Temozolomide: a novel oral alkylating agent. 1211 20

The survival of patients affected by cutaneous melanoma has improved dramatically in the last 10 years, because of earlier diagnosis. Despite this, the therapeutic results obtained in metastatic melanoma (MM) are very disappointing due to its poor responsiveness to cytotoxic agents. In this type of solid tumor, tumor chemosensitivity assays have been suggested to be an important tool to predict clinical responsiveness to therapy. Metastatic melanoma cells (MMCs) were obtained from subcutaneous melanoma metastases of five patients and cultured for several consecutive passages. An immunofluorescence and an electron microscopic study were performed in order to establish the ultrastructural and physiopathological features of MMCs. A sulphorodamine-B test was used to measure in vitro sensitivity of MMCs to temozolomide, cisplatin, vindesine, taxol and interpheron alpha-2a. Following a 72 h exposure, maximum activity was obtained with vindesine (median inhibitory concentration, IC(50), 0.23 nM) and taxol (median IC(50) 0.31 nM). Cisplatin median IC(50) values were higher (4.6 microM) than taxol and vindesine, but still in the range of clinically achievable plasma concentrations. Temozolomide inhibited cell proliferation only at very high concentrations (median IC(50) 228 microM). No significant cell growth inhibitory effects (<or=25%) were observed with interferon alpha-2a concentrations up to 8000 IU/ml. MMCs expressed progression markers typical of cutaneous metastatic melanoma and showed poor sensitivity in vitro to most anticancer drugs tested, including temozolomide.
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PMID:Immunophenotypical markers, ultrastructure and chemosensitivity profile of metastatic melanoma cells. 1221 88

Metastasis to the CNS develops in nearly half of patients with advanced melanoma; in 15% to 20% of these patients, the CNS is the first site of relapse. While systemic therapy for metastatic melanoma produces objective responses in 15% to 50% of patients, the available drugs do not penetrate well into the CNS, and these patients rarely benefit from systemic therapy. Although brain metastasis may be treated with surgery and/or stereotactic radiosurgery (SRS) when disease is limited to approximately one to three lesions, treatment for patients with large or multiple metastases is limited to whole brain irradiation (WBRT). While formal response and survival analyses of the impact of WBRT in melanoma have not been reported, the estimated median survival time for unselected patients with CNS metastases is only 2 to 4 months, with 1-year survival rates of less than 13%. In a selected population of patients with limited CNS involvement, surgical resection alone or in combination with WBRT appears to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports of patients with melanoma CNS metastases, treatment with surgical resection alone or in combination with WBRT has been demonstrated to prolong median survival. More recently, SRS has been shown to be an effective local treatment for selected patients with brain metastases. In several retrospective reports, patients with CNS metastases from melanoma treated with a combination of WBRT plus SRS or SRS alone had median survivals and rates of control in the CNS superior to published reports for traditional WBRT. Most of these patients died from progressive extracranial disease with locally controlled CNS disease. Investigation of the contribution of newer systemic agents to the control of melanoma metastatic to the CNS has been based on the identification of drugs that have antitumor activity and the ability to cross the blood-brain barrier. Fotemustine is a nitrosourea that produced similar activity in CNS metastasis as in systemic disease, with a response rate of about 25%. Temozolomide (TMZ) is an oral alkylating agent that acts via the same mechanism as dacarbazine (DTIC), the most active single agent in melanoma. TMZ, which is highly active in brain tumors, has also been associated with activity in systemic and CNS metastases in melanoma patients, also in the 25% range. Efforts are underway to assess the additive benefit of TMZ and other drugs to WBRT or focused radiotherapy in this disease.
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PMID:The treatment of brain metastases from malignant melanoma. 1240 17


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