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

Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.
 ...
PMID:Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats. 1105 Dec 69

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.
 ...
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.
 ...
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.
 ...
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.
 ...
PMID:The treatment of brain metastases from malignant melanoma. 1240 17

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.
 ...
PMID:The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. 1530 60

About 40% of patients with advanced cancer develop metastases in the central nervous system (CNS), mainly from primary tumors of lung, breast and melanoma. In most of cases there are multiple CNS metastases, making surgery or localized radiosurgery not feasible. The current standard of care for these patients is radiation therapy, which can improve neurologic symptoms but does not have any impact on the patient's overall survival. Temozolomide, capecitabine and gefitinib are safe and active in the treatment of CNS metastases from melanoma/recurrent gliomas, breast carcinoma and lung cancer, respectively. New, orally administered drugs hold a great potential for patients with CNS metastases.
 ...
PMID:Innovative therapy for patients with brain metastases: oral treatments. 1567 90

Temozolomide is a rapidly absorbed chemotherapeutic agent, achieving significant central nervous system penetration. Previous clinical trials suggested that temozolomide in sequence with low-dose recombinant human interleukin-2 might be an efficacious and relatively non-toxic chemo-immunotherapeutic treatment, which may synergistically eliminate tumours. The primary objective was to determine the safety and tolerance of temozolomide administered orally 200 mg/m days 1-5, in sequential combination with subcutaneous injections of 4.5x10 IU recombinant human interleukin-2 on days 8-11, 15-18 and 22-25 in patients with measurable, progressive metastatic malignant melanoma without radiological signs of central nervous system metastases. The secondary objectives were to determine tumour response and time to progression. Twenty-seven patients were included, of which four were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to the World Health Organization (WHO) scale. Three patients suspended the treatment because of WHO grade 3 side effects already during the first 3 days of the first course of temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. Two patients had complete responses, three partial responses and two stable disease at the end of the four cycles defined by the protocol and they continued the treatment until signs of relapse or a maximum of 21 courses. Five of these patients are still alive. Thrombocytopenia was significantly more pronounced in patients with objective response and stable disease than in non-responders to therapy. The median time to progression for all patients was 3.1 months and for responding and stable disease patients was 15 months. Five of 23 treated patients (22%) developed brain metastases during follow-up. Temozolomide in combination with recombinant human interleukin-2 is a well-tolerated regimen for outpatient treatment and the bio-chemotherapy combination induced durable clinical responses. Thrombocytopenia might be a positive predictive factor for response to therapy.
 ...
PMID:Alternating chemo-immunotherapy with temozolomide and low-dose interleukin-2 in patients with metastatic melanoma. 1684 32

Temozolomide is an oral alkylating agent used in the treatment of metastatic melanoma. Commonly reported adverse effects of the drug include nausea and vomiting, constipation, headache, and fatigue, as well as myelosuppression, which may be dose limiting. Few reports have described dermatologic adverse effects such as rash and pruritus, and, to our knowledge, none have discussed the seriousness or extensiveness of the rash. We describe a 37-year-old woman who was receiving temozolomide for treatment of metastatic melanoma. After 6 weeks of therapy, the patient developed an unexplained fever. The drug was discontinued, and the fever resolved within 2 days. Temozolomide was restarted 2 months later; the patient again developed a fever. This time the fever was accompanied by a diffuse erythematous skin rash that progressed to an extensive, full-body, desquamative skin rash. The rash was treated with moisturizing cream along with intravenous and topical corticosteroids and antibiotics. Due to the severity of the rash, temozolomide was permanently discontinued. Even after its discontinuation, the patient experienced the rash on a long-term basis, with periodic exacerbations. However, none were as severe as the first rash. The patient's metastatic disease remained stable for the next 2 years. According to the Naranjo adverse drug reaction probability scale, the likelihood that temozolomide was responsible for the adverse drug reaction of fever was probable (score of 6). Clinicians should be aware that an erythematous and exfoliative rash may be induced by temozolomide, and be familiar with the pharmacologic and supportive measures necessary for its treatment.
 ...
PMID:Temozolomide-induced desquamative skin rash in a patient with metastatic melanoma. 1829 21

A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.
 ...
PMID:A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood. 1849 27


1 2 Next >>