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)

Thirty-two patients with high-risk gestational trophoblastic disease (GTD), defined as metastases to the brain or liver (regardless of hCG level or duration of disease) or prior unsuccessful chemotherapy are reviewed. In this classification, an antecedent term pregnancy is not considered to be an independent high-risk factor. Initial chemotherapy in 15 (46.8%) patients consisted of methotrexate, actinomycin D, and chlorambucil (MAC), actinomycin D alone in seven (21.8%), etoposide, methotrexate, actinomycin D, cytoxan on covin (EMACO) EMACO in three (9.4%), ITMA (hydroxyurea, vincristine, methotrexate, folinic acid, cyclophosphamide, actinomycin D, adriamycin, and melphalan) in three (9.4%). The remaining patients were treated with actinomycin D and 6-mercaptopurine (1), CHAMOCA (1), carboplatin and Taxol (1), and methotrexate (1). All patients with brain metastases were treated with cranial radiotherapy. Overall complete remission was achieved in 14 of 32 (43.7%) patients. Five of 9 (55.5%) patients whose disease followed a term pregnancy survived compared to nine of 23 (39.1%) patients whose disease followed other types of pregnancies. The data analyzed according to the clinical classification of 'high-risk' indicates that an overall survival rate of 70% was achieved. The Memorial Hospital classification therefore identifies patients who need primary chemotherapy more aggressive than MAC and similar to the WHO scoring system is a better predictor of survival than the clinical classification.
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PMID:Management of high-risk gestational trophoblastic disease--the Memorial Hospital experience. 1279 1

Pancreatic adenocarcinoma is a common disease that is rarely cured. Surgical resection remains the only treatment modality that has a curative potential, although the majority of patients are unsuitable for resection at the time of diagnosis. Chemoradiation therapy prior to a pancreaticoduodenectomy ensures that a patient who undergoes a complete resection multimodality therapy, avoids a resection in patients who have a rapidly progressive disease, and allows radiation therapy to be given to well oxygenated cells before, surgical devasculation. This permits the chance of resection of an unresectable pancreatic cancer by downstaging. A patient with cytologic proof of localized adenocarcinoma of the pancreatic head received an intravenously chemoradiation (Taxol, 50 mg/m2 intravenously for 3 hours week on 5 cycles, of Gemcytabine 1000 mg/m2/day intravenously for 3 days week on 2 cycles, of 4500 cGy) with the intention of proceeding to a resection operation, restaging was performed by computed tomography, magnetic resonance imaging from 5 weeks every months due to ongoing decreasing of tumor size after the chemoradiation. At laparotomy, the patient didn't have suspected metastatic disease, the tumor size was 2 X 3 cm on the pancreas head and was infiltrating into the portal vein for about 3 cm length on right side. A pancreaticoduodenectomy along with a portal vein and superior mesenteric vein resection was done and then reconstruction of a vascular anastomosis by using the right side of the internal jugular vein. Perioperative complications didn't occur. In conclusion, preoperative chemoradiation of a localized advanced pancreatic tumor has no added risk to the operative complications and the prospects for resectability are enhanced.
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PMID:Preoperative chemoradiation and pancreaticoduodenectomy with portal vein resection for localized advanced pancreatic cancer. 1283 99

Following resection of colorectal carcinoma, a considerable local recurrence rate within the previous tumor bed or at the peritoneal site remains an unsolved problem. Currently, there are no established protocols for the treatment or prevention of peritoneal carcinomatosis. Taxol showed benefit in patients with advanced tumor growth, in particular, gynecological carcinomas. Taxol was used to test whether it can either prevent or treat peritoneal tumor growth derived from colon carcinoma. In rats divided in 3 groups, peritoneal carcinomatosis was induced by tumor cell transfer: Taxol (170 mg/m(2)) was given i). directly (group A); ii). on days 5, 10, 15 postoperatively (representing early administration; group B), or iii). as late intraperitoneal (i.p.) chemotherapy (15, 20, 25 days following surgery; aiming for reduction of a manifest peritoneal carcinomatosis; group C) into the abdominal cavity. Tumor growth was quantified by tumor weight of the greater omentum and the mesenteric site, number of detectable tumor lesions, occurrence of hepatic and pulmonary metastases and the amount of ascites. Taxol was highly effective in preventing or reducing i.p. tumor spread when the drug was given directly or within a short time interval after tumor cell implantation (groups A and B), whereas no significant antineoplastic potential was found in the treatment of an established peritoneal carcinomatosis. In conclusion, Taxol appears to be a promising chemotherapeutic agent to be investigated in further detail with possible potential for a later human phase-I trial in peritoneal carcinomatosis.
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PMID:Intraperitoneal treatment using taxol is effective for experimental peritoneal carcinomatosis in a rat model. 1453 98

An in vivo melanoma spontaneous metastases model was adopted to study the molecular mechanisms of the anti-metastatic effect of Taxol. The morphology of melanoma cells in the melanoma tissue lesions was examined by hematoxylin/eosin (H&E) staining and electron microscopy. The in situ programmed cell death was tested by TUNEL analysis. Vascular endothelial growth factor (VEGF) and E-cadherin expression were detected by immunohistochemistry. The metastases suppressor gene nm23 mRNA expression level was analyzed by in situ hybridization. The results showed that i.p. injection of Taxol at 5 mg/kg per day for three weeks significantly inhibited metastases formation in the pulmonary of mice. Taxol induced melanogenesis and apoptosis in the melanoma cells, inhibited angiogenesis in melanoma tissue lesions, and reduced the expression of VEGF. Conversely, Taxol increased the expression of E-cadherin and nm23. In conclusion, administration of Taxol in the early stage of melanoma metastases can significantly inhibit melanoma metastases. This effect was possibly related to apoptosis induction, tumor angiogenesis inhibition, and restoration of the metastasis suppression ability.
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PMID:Taxol inhibits melanoma metastases through apoptosis induction, angiogenesis inhibition, and restoration of E-cadherin and nm23 expression. 1457 88

ABI 007 [Abraxane] is an albumin-stabilised nanoparticle formulation of paclitaxel designed to overcome insolubility problems encountered with paclitaxel. This then eliminates the need for toxic solvents like cremophor, which limits the dose of paclitaxel that can be administered and hence affect overall drug efficacy. Studies have shown that the albumin receptor-mediated paclitaxel-transport mechanism is analogous to the opening of a 'trapdoor' on the endothelial cell wall within blood vessels. This facilitates the passage of ABI 007 from the bloodstream via the blood vessels to the underlying tumour tissue. ABI 007 is being developed for the treatment of a variety of tumour types by American Pharmaceutical Partners. In addition to the standard infusion formulation of ABI 007, oral and pulmonary delivery formulations are also being investigated. American Pharmaceutical Partners, a subsidiary of American BioScience, secured exclusive North American marketing and manufacturing rights to ABI 007 from American BioScience in November 2001. In anticipation of product launch within the fourth quarter of 2004, the company formed Abraxis Oncology and recruited an experienced sales and marketing team. The company has also accumulated approximately 28 million US dollars of paclitaxel inventory. As such, American Pharmaceutical Partners anticipates pre-launch expenses to cost approximately 40 million US dollars, incurred over 2004. In addition, the company expects to make two milestone payments worth 10 million US dollars as well as 15 million US dollars, based upon US FDA acceptance of NDA filing in the second quarter of 2004 and subsequent US FDA approval, respectively. The milestone for US FDA approval would be capitalised and amortised over the estimated life of the product.Previously, American Pharmaceutical Partners reported that its rolling NDA submission for ABI 007 commenced in May 2003. In July 2003, the company announced that this was progressing on schedule and expected to have completed its entire NDA submission by the end of 2003. The company also began preparations to form a sales and marketing group in anticipation of product launch. In addition, production of commercial quantities of ABI 007 was expected to begin in the second half of 2003. The US FDA granted fast-track status to ABI 007 for this indication in January 2003. The decision for NDA filing was based on the successful completion of a phase III trial evaluating ABI 007 versus standard paclitaxel among 460 patients with metastatic breast cancer in the US. In September 2003, American Pharmaceutical Partners and American BioScience jointly announced positive interim results from the trial, which shows that the primary efficacy objective had been exceeded. American BioScience completed this phase III trial in early 2003 with the results unblinded in mid-2003. The phase III study directly compared the efficacy of ABI 007 260 mg/m(2) versus paclitaxel 175 mg/m(2). Both agents were administered every 3 weeks. ABI 007 was administered as a 30-minute infusion without steroid pretreatment. Paclitaxel-treated patients received steroid pretreatment and the drug was administered over 3 hours. Enrollment was completed in December 2002 with 460 first- and second-line metastatic breast cancer patients enrolled. A Data Monitoring Committee concluded in October 2002 that a sample-size adjustment of the phase III trial was not required and that the study could be continued to completion. A phase II trial of ABI 007 was also underway in metastatic breast cancer patients who have failed taxane therapy. The trial was evaluating a weekly rather than 3-weekly regimen of ABI 007. Also in February 2004, American BioScience initiated a multicentre phase II trial in patients with metastatic melanoma. The trial will evaluate both chemotherapy-naive patients (at a dose of 150 mg/m(2) administered weekly) and patients who have previously received chemotherapy (at a dose of 100 mg/m(2) administered weekly) as treatment for metastatic disease. In May 2003, American Pharmaceutical Partners reported that ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. Phase I/II trials have also been conducted in other solid tumours, including squamous cell cancer of the head and neck, and pelvis. Phase I trials have also been conducted in patients with solid tumours to evaluate the administration of ABI 007 on a weekly schedule. In September 2003, American BioScience was issued US patent No. 6,506,405, which has 89 claims covering compositions of matter and unit dosage forms. In addition, the patent covers methods of use without the requirement for pretreatment with steroid therapy or growth factor support. In July 2003, the US Court of Appeals for the Federal Circuit in Washington DC unanimously ruled that American BioScience is the true and rightful owner of patent No. 5,780,653. This patent covers three next-generation taxane anticancer compounds. This ruling overturned a lower court decision in a lawsuit brought in 1998 by Florida State University (FSU) and FSU Prof. Robert Holton's privately held company, Taxolog. In the lawsuit, FSU and Taxolog alleged that Prof. Holton and others at FSU were the true inventors of the compounds claimed under American BioScience's patent.
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PMID:ABI 007. 1513 76

This Phase II trial was designed to evaluate the overall objective response rate, complete response rate, efficacy, and safety of weekly paclitaxel (Taxol) and carboplatin (Paraplatin) in the treatment of advanced urothelial carcinoma. Thirty-three patients with measurable, unresectable, stage III-IV carcinoma of the urothelium were enrolled. Paclitaxel (135 mg/m2) and carboplatin (AUC=2) were given by intravenous (IV) infusion weekly x 6 followed by two weeks rest. Patients were premedicated with oral dexamethasone, diphenhydramine, and cimetadine (or equivalent). Patient characteristics included an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 (36%), one (36%), two (28%); median age 70 years (37-83); 29 (88%) male, four (12%) female; 16 (48%) patients had prior chemotherapy [eight postoperative (adjuvant), five neoadjuvant, three for metastatic disease] and eight (24%) had prior radiation therapy. Eight patients (24%) achieved objective responses, three complete responses (CR) and five partial responses (PR); one patient was not evaluable (patient died prior to first dose). The median duration of response was 13 months (range, 2-29). Nine patients (27%) had stable disease (SD) and 15 patients (45%) had progressive disease (PD). Median time to progression was 3.6 months (range, < 1-29) and median survival was 10.3 months (range, < 1-33). Grade 3 and 4 toxicities included: asthenia (46%), neutropenia (36%), leukopenia (15%), thromboembolism (12%), diarrhea (9%), nausea and vomiting (9%), hyperglycemia (7%), and neuropathy (6%). Two patients died of sepsis, one death was treatment-related. Weekly paclitaxel plus carboplatin shows promising activity; however in the current study, efficacy may have been limited by the toxicities associated with this dose-intensive regimen in an elderly, pretreated patient population with poor performance status. This regimen warrants further study, perhaps as a three out of four week regimen or at reduced doses.
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PMID:A phase II evaluation of weekly paclitaxel plus carboplatin in advanced urothelial cancer. 1549 58

Paclitaxel (Taxol) is formulated in 50% Cremophor EL (CrEL)/absolute ethanol for clinical use. In order to reduce vehicle-related side effects, Genetaxyl was developed to have paclitaxel formulated in a solution containing lesser amounts of CrEL and ethanol plus 2 other solvents. The purpose of the study was to evaluate the efficacy and safety of Genetaxyl as first-line therapy to treat breast cancer patients. Patients with newly diagnosed stage III (N = 8) or IV (N = 10), or recurrent (N = 11) breast cancer received single-agent Genetaxyl at 175 mg/m(2) administered in a 3-h infusion every 3 weeks for 3-6 cycles. A total of 148 cycles were delivered to 29 patients. The overall response rate was 41.4% (95% confidence interval, 23.4 to 59.2%), and that of patients with metastatic disease (N = 20) was 30%. Median survival for all patients was 32.4 months and 24.3 months for patients having metastatic disease. The toxicity profile seems favorable, especially regarding myelosuppression and myalgia/arthralgia. No severe hypersensitivity reaction occurred. These phase II trial results demonstrate that a 60% reduction of CrEL by Genetaxyl's formulation does not affect the activity of paclitaxel and could allow for better control of several CrEL-related toxicities.
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PMID:Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast cancer: a phase II trial. 1574 94

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.
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PMID:Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group. 1598 Sep 85

Breast cancer is the most common malignancy in women, accounting for about 18% of female cancers, and over half a million new cases are diagnosed worldwide each year. Its incidence increases with age and is currently rising. Although the increased availability of screening programs has allowed earlier detection and treatment of primary breast cancers, many patients relapse with metastases after apparently successful treatment of their primary tumor and over 15,000 women in the UK and about 50,000 in the USA die from advanced disease each year. The natural course of breast cancer is very variable even after the development of metastases, and depends on a variety of tumor characteristics and prognostic factors. This is reflected in the large number of treatments currently employed. However, despite this wide choice and considerable research over the years, treatment of metastatic breast cancer (MBC) prolongs average survival times only slightly. Current therapy is aimed at achieving a balance between producing maximal tumor shrinkage to produce the most effective possible palliation of symptoms, and minimizing adverse effects. Anticancer chemotherapy is the preferred option in patients who do not respond to hormones, those with hormone-independent tumors, those with aggressive breast cancer subtypes. A variety of anticancer chemotherapy regimens, using both single and combined agents, have been shown to be effective in achieving tumor regression in MBC. Anthracyclines (doxorubicin, epirubicin) are the most active of the established monotherapies, typically producing response rates of 50-60% during initial (first-line) treatment for metastatic disease, but being effective in fewer than 25% of patients requiring second-line therapy. The drawbacks of anthracyclines include dose-limiting cumulative cardiotoxicity and the development of resistant tumor clones after the use of anthracyclines for adjuvant or first-line therapy, especially if subsequent courses are required within a year. The success of these established chemotherapeutic agents depends greatly on the number and location of metastatic sites. Lymph node and soft tissue secondaries tend to respond well, while visceral metastases (especially in the liver) carry a particularly poor prognosis despite treatment. The outlook for patients with metastases involving more than two organ systems is also bleak. Although some patients can live for years with metastatic disease, the average survival time in patients with MBC is 18-24 months, while in those with liver metastases, life expectancy averages only 6 months. High-dose anticancer chemotherapy with granulocyte-colony stimulating factor (G-CSF) or autologous bone marrow transplantation has allowed the dose intensity of anthracyclines to be increased, and has improved the response rate to about 70% in selected patients with MBC. However, this approach has not been proven to improve survival, involves the risk of greater toxicity and drug-related mortality, and patients with reduced clearance of anthracyclines due to hepatic dysfunction from liver metastases may not be suitable candidates. A number of new anticancer agents have also recently been introduced in an attempt to improve on the performance and avoid the tolerability problems associated with anthracyclines. Among these, antitubulin agents (taxoids and vinorelbine) have shown highly promising activity in MBC. This paper reviews the preclinical, phase I and phase II data for one taxoid, docetaxel. Docetaxel (Taxotere) belongs to the taxoid class of cytotoxic agents, the development of which began more than 20 years ago. In 1971, paclitaxel (Taxol) was identified as the active compound of the crude extract of the bark of the Pacific Yew tree Taxus brevifolia. However, at that time the development of paclitaxel was hampered because of the limited source of the drug and difficulties with isolation, extraction and formulation. The second active taxoid, docetaxel, was isolated by Potier et al. in 1986. Docetaxel is prepared from a non-cytotoxic precursor, extracted from the needles of the European Yew tree Taxus baccata, that is condensed with a chemically-synthesized side-chain. As the docetaxel precursor is freely available because of the regenerating capacity of the needles the development of docetaxel has thus been rapid.
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PMID:Docetaxel: a new active agent in the therapy of metastatic breast cancer. 1598 86

Gene-expression profiling can help distinguish between patients at high risk and those at low risk for developing distant metastases, and so identify patients for adjuvant therapy. For several years, the Netherlands Cancer Institute has been working on gene-expression profiling of breast cancer using a microarray platform containing 25,000 genes. Using supervised classification, a prognostic classifier consisting of 70 genes could be identified. In addition to providing prognostic information, gene profiling should also enable us to detect patients who are likely to respond to particular adjuvant interventions. Well-known predictors for response to systemic therapy include estrogen receptor status HER-2 status, c-kit mutation, and epidermal growth factor receptor mutation. Because of the long periods required for predicting responsiveness in the adjuvant setting, neoadjuvant trials promise far quicker results. Several neoadjuvant studies are under way or planned to investigate gene-expression profiling as a means of predicting the therapeutic response to docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), cyclophosphamide, and doxorubicin (Adriamycin; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) in breast cancer patients. It is expected that in the coming years an increasing number of novel prognostic and predictive tests will help in guiding the adjuvant systemic treatment of breast cancer and other malignancies.
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PMID:Gene-expression profiling and the future of adjuvant therapy. 1627 57


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