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)

Recently initiated is a phase III randomized trial (MA.21 trial) of adjuvant chemotherapy for node-positive and high-risk node-negative, premenopausal and postmenopausal (< or = 60 years) women with breast cancer who have no distant metastases. Conducted by the National Cancer Institute of Canada-Clinical Trials Group, the trial will compare two standard therapies, CEF (cyclophosphamide [Cytoxan, Neosar], epirubicin [Ellence], fluorouracil) and AC-->T (doxorubicin [Adriamycin], cyclophosphamide, followed by paclitaxel [Taxol]), and includes a third arm consisting of a dose-dense, dose-intense EC-->T regimen (epirubicin, cyclophosphamide, followed by paclitaxel). These regimens were chosen for study based on results of previous clinical assessments of adjuvant therapies, which, taken together, suggest that CEF, FEC 100 (where 100 represents the dose in mg/m2 of epirubicin in FEC [fluorouracil, epirubicin, cyclophosphamide]), CAF (cyclophosphamide, doxorubicin, fluorouracil), and AC-->T may all be superior to standard AC or CMF (cyclophosphamide, methotrexate, fluorouracil) regimens. This article reviews trial results that support the testing of the regimens chosen for the MA.21 trial. The intent of the MA.21 study is to advance our ability to provide optimal adjuvant therapy for patients with breast cancer.
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PMID:Optimizing adjuvant breast cancer chemotherapy: rationale for the MA.21 study. 1139 66

Invasive bladder cancer is a chemotherapy-sensitive neoplasm. Historically, the development of cisplatin (Platinol)-based chemotherapy regimens has represented an important advance for patients with metastatic disease. More recently, investigations of new agents, such as gemcitabine (Gemzar) and paclitaxel (Taxol), have resulted in further options for these patients. Randomized trials comparing new regimens with cisplatin-based therapies have been initiated. The role of chemotherapy in the adjuvant and neoadjuvant settings is an area that is undergoing active investigation. The application of prognostic biological markers to risk-stratify patients has resulted in new avenues of investigation in these ongoing early disease trials.
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PMID:Recent developments in chemotherapy for bladder cancer. 1143 Feb 8

Osteoblastic metastases are common in lethal prostate cancer. Effective therapy for bone metastases is lacking. Thus, developing an appropriate in vitro screening system is critical to prioritize which of the newly developed agents should undergo additional expensive and time-consuming in vivo evaluation in bone metastases animal models. In the past, such in vitro screening evaluated the response of prostate cancer cells to chemotherapeutic agents in monoculture without the presence of osteoblasts. In such monoculture, prostate cancer cells have a high (i.e., >90%) proliferative growth fraction. In contrast, the growth fraction (i.e., mean: 7.1 +/- 0.8%; median: 3.1%) in 117 metastatic sites of prostate cancer obtained from 11 androgen ablation failing patients at "warm" autopsy was found to be >10-fold lower. To better mimic the lower growth fraction observed clinically, LNCaP human prostate cancer cells were cocultured with membrane-separated hFOB human osteoblasts. Such coculturing significantly lowered the growth fraction of the LNCaP cells (i.e., from >90 to <30%) without enhancing their low rate (i.e., <5%) of apoptosis. This lowering of the growth fraction was documented using flow cytometry, Ki-67 immunohistochemistry, and 5-bromo-2-deoxyuridine incorporation. Using RNase protection assays, it was documented that coculture with osteoblasts causes enhanced p53, p27, and p21 expression leading to a decrease in the number of LNCaP cells entering the cell cycle (i.e., enhanced number of LNCaP cells in G(0)-G(1) and a decrease in S and G(2)-M and thus the growth fraction). This osteoblast-induced enhanced G(0)-G(1) checkpoint control affected the chemosensitivity of LNCaP cells. This was documented by coculturing LNCaP cells with hFOB cells to condition the medium for 3 days to lower the growth fraction to <30% before exposing the LNCaP cells for 48 h to various concentrations of Taxol, doxorubicin, or thapsigargin (TG). In standard high (i.e., >90%) growth fraction cultures (i.e., cultures in the absence of osteoblast-conditioned medium), there was a dose-dependent and significant (P < 0.05) increase in apoptosis of LNCaP cells exposed to Taxol or doxorubicin. In contrast, even the highest dose of Taxol (1 microM) did not enhance apoptosis of lower growth fraction LNCaP cells cultured in osteoblast-conditioned medium. Similarly, only the highest concentration of doxorubicin (1 microM) enhanced apoptosis in lower growth fraction cells. In contrast, 100 nM TG induced high levels of apoptosis in both lower and high-growth fraction LNCaP cultures. These results demonstrate that the osteoblast/LNCaP coculture system is a better in vitro screen than monoculture to identify proliferation-independent agents for the treatment of prostate cancer bone metastases, and TG is such an agent.
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PMID:Therapeutic implications of enhanced G(0)/G(1) checkpoint control induced by coculture of prostate cancer cells with osteoblasts. 1152 28

Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established therapy. We describe a young woman with metastatic collecting duct carcinoma who responded to Taxol/carboplatin chemotherapy with an 80% reduction in her tumor burden, including complete regression of lymph node metastases and significant shrinkage of a renal mass. She was rendered free of disease through nephrectomy and has been without a recurrence for 20 months. This suggests that Taxol/carboplatin chemotherapy and surgery should be considered for the treatment of metastatic collecting duct carcinoma.
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PMID:Long-term remission in a patient with metastatic collecting duct carcinoma treated with taxol/carboplatin and surgery. 1174 92

Paclitaxel (Taxol) is a diterpene plant product and antineoplastic agent that promotes the assembly of microtubules as well as stabilizing their formation by preventing depolymerization. Myelosuppression was found to be dose-limiting, but peripheral neurotoxicity is also a well known side-effect. Central nervous system toxicity is rare, probably because paclitaxel does not cross the blood-brain barrier. We observed three patients who presented with acute encephalopathy within 6 h after infusion of paclitaxel at normal doses. All patients had received prior whole brain irradiation (WBI) and one patient had prior brain metastasectomy. Computer tomography and magnetic resonance imaging showed no evidence of cerebral metastases. An effect from other organ toxicities was excluded in all patients. All recovered spontaneously within 4-6 h. From this we can conclude that paclitaxel can cause severe acute transient encephalopathy, which may occur more frequently after prior WBI and/or surgery due to alteration of small vessel function.
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PMID:Acute transient encephalopathy after paclitaxel infusion: report of three cases. 1205 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

The case concerns a 56 year old male with the diagnosis of squamous cell carcinoma, which clinically presented as a rapidly increasing cardiac tamponade. The patient underwent a pericardio-centesis. Due to the expansion of the process within the bronchus, the patient underwent chemotherapy according to the Taxol + Carboplatine scheme. After 8 months of treatment the patient was hospitalized again due to a further increase in fluid in the pericardium, and symptoms of cardiac insufficiency which lead to patient death. Autopsy revealed neoplastic change within the pericardium (fibrinous-hemorrhagic pericarditis and hemopericardium). Cardiac tumors occur rarely, they may be primary or secondary. Squamous cell carcinoma metastases may be the cause of pericardial effusion, which is associated with poor prognosis.
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PMID:[Cardiac tamponade as the first clinical manifestation of squamous cell carcinoma]. 1215 50

For measuring the efficacy of new anti-metastatic drugs in preclinical models, macroscopical analysis or classical histology of secondary organs are established methods. However, macroscopical evaluation does not take into consideration intra-organ metastasis. Histological analysis is often performed in few sections of the relevant organs, and this may be misleading, since equal distribution of tumor cells within an organ is unlikely. In addition, recent studies have demonstrated that anti-tumorigenic drugs are able to promote metastasis and to change the metastatic pattern. Therefore, extensive analysis of metastasis is mandatory for the evaluation of new compounds. A feasibility study was conducted to find out if the quantification of human Alu sequences could be applied as a surrogate marker for metastasis in xenografts. Alu PCR was performed by using the LightCycler system, which allows PCR reaction and subsequent quantification of the PCR products in less than 30 min. We found that i) the equivalent of one human tumor cell in 1 x 10(6) murine cells could be detected; ii) in tumor-carrying mice, Alu signal increased over time in secondary organs; iii) this increase was more prominent using highly metastatic tumor cells; iv) Alu signal intensity in DNA extracted from tissue slides correlated with the expression of histological tumor markers; v) in three different tumor models (colon, breast and lung), treatment with Taxol or 5-fluorouracil reduced the amount of Alu in different organs. In contrast, reduction of Alu by the matrix metalloproteinase inhibitor RO 28-2653 was not significant. Taken together, quantification of Alu sequences is a fast and accurate method to evaluate the therapeutic efficacy of anti-metastatic drugs in xenografts.
Clin Exp Metastasis 2002
PMID:Quantification of human Alu sequences by real-time PCR--an improved method to measure therapeutic efficacy of anti-metastatic drugs in human xenotransplants. 1249 86

Cyclophosphamide (4 g/m2) and paclitaxel (Taxol) (175, 200 or 250 mg/m2) therapy with subsequent administration of G-CSF (10 micrograms/kg) has been used as intensification and as mobilization therapy for patients with breast cancer. This regimen was used in 19 patients, as part of adjuvant therapy in 14 and as part of therapy of metastatic disease in five. Median number of collected CD34+ cells was 17.5 x 10(6)/kg (2.9-48.1). All patients except one (94.7%) reached minimal required number of CD34+ cells (> or = 3 x 10(6)/kg). Median number of leukapheresis was two. The required number of cells (> or = 3 x 10(6)/kg) was collected in one leukapheresis in 17 out of 19 patients (89.5%) and more than five and 10 x 10(6)/kg CD34+ cells respectively were collected in 14 (73.7%) and 11 (57.9%) patients respectively. No factor significantly influencing the amount of collected cells (except the trend in favour of later year of therapy and large-volume leukapheresis) was identified. Leukopenia gr. 4 was observed in 88.9% of treated patients and febrile neutropenia developed in 46.2% patients. Although the antitumour activity of this chemotherapy was not possible to assess it seems that this intensification could be successfully used as a therapy and as very potent mobilization regimen.
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PMID:[Intensive therapy with paclitaxel (Taxol) and cyclophosphamide followed by administration of G-CSF as a mobilization regimen in patients with breast carcinoma and indications for autologous hematopoietic cell transplantation]. 1268 79

Renal cell carcinoma (RCC) frequently produces metastases to the musculoskeletal system that are a major source of morbidity in the form of pain, immobilization, fractures, neurological compromise, and a decreased ability to perform activities of daily living. Patients with metastatic RCC therefore have a dismal prognosis because there is no effective adjuvant treatment for this disease. Because the epidermal growth factor receptor (EGF-R) signaling cascade is important in the growth and metastasis of RCC, its blockade has been hypothesized to inhibit tumor growth and hence prevent resultant bone destruction. We determined whether blockade of EGF-R by the tyrosine kinase inhibitor PKI 166 inhibited the growth of RCC in bone. We use a novel cell line, RBM1-IT4, established from a human RCC bone metastasis. Protein and mRNA expression of the ligands and receptors was assessed by Western and Northern blots. The stimulation of RBM1-IT4 cells with epidermal growth factor or transforming growth factor alpha resulted in increased cellular proliferation and tyrosine kinase autophosphorylation. PKI 166 prevented these effects. First, RBM1-IT4 cells were implanted into the tibia of nude mice, where they established lytic, progressively growing lesions, after which the mice were treated with PKI 166 alone or in combination with paclitaxel (Taxol). Immunohistochemical analysis revealed that tumor cells and tumor-associated endothelial cells in control mice expressed activated EGF-R. Treatment of mice with PKI 166 alone or in combination with Taxol produced a significant decrease in the incidence and size of bone lesions as compared with the results in control or Taxol-treated mice (P < 0.001). Treatment with PKI 166 also decreased the expression of phosphorylated EGF-R by tumor cells and tumor-associated endothelial cells, and this was even more pronounced with PKI 166 plus Taxol treatment. The PKI 166 plus Taxol combination produced apoptosis of tumor cells and tumor-associated endothelial cells. Tumor cell proliferation, shown by proliferating cell nuclear antigen positivity, was decreased in all treatment groups. In addition, the integrity of the bone was maintained in mice treated with PKI 166 or PKI 166 plus Taxol, whereas massive bone destruction was seen in control and Taxol-treated mice. These results suggest that blockade of EGF-R signaling inhibits growth of RCC in the bone by its effect on tumor cells and tumor-associated endothelial cells.
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PMID:Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. 1278 1


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