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)

In order to evaluate the behaviour of N-(2-diethylaminoethyl)-4-[123I]iodobenzamide in malignant melanotic disease, we synthesized the bromo compound in a simple one-step reaction. Labelling was performed by non-isotopic bromine-iodine-123 exchange in radiochemical yields up to 60%. By means of isocratic high-performance liquid chromatography, the iodinated product could be isolated with high apparent specific activity. First clinical studies in patients with malignant melanoma using N-(2-diethylaminoethyl)-4-[123I]iodobenzamide showed moderate uptake of the tracer in the tumour and the suspected metastases in all patients. Most of the lesions were detectable with technetium-99m-diethylene triamine penta-acetic acid (DTPA) scintigraphy too, but we were able to detect additional, previously unidentified metastases with benzamide scintigraphy. This changed the therapeutic procedure in two of the five cases investigated so far.
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PMID:N-(2-diethylaminoethyl)-4-[123I]iodobenzamide as a tracer for the detection of malignant melanoma: simple synthesis, improved labelling technique and first clinical results. 846 13

The promise of cancer immunotherapy is that it will not only eradicate primary tumors but will generate systemic antitumor immunity capable of destroying distant metastases. A major problem that must first be surmounted relates to the immune resistance of large tumors. Here we reveal that immune resistance can be overcome by combining immunotherapy with a concerted attack on the tumor vasculature. The functionally related antitumor drugs 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone acetic acid (FAA), which cause tumor vasculature collapse and tumor necrosis, were used to attack the tumor vasculature, whereas the T-cell costimulator B7.1 (CD80), which costimulates T-cell proliferation via the CD28 pathway, was used to stimulate antitumor immunity. The injection of cDNA (60-180 microg) encoding B7.1 into large EL-4 tumors (0.8 cm in diameter) established in C57BL/6 mice, followed 24 h later by i.p. administration of either DMXAA (25 mg/kg) or FAA (300 mg/kg), resulted in complete tumor eradication within 2-6 weeks. In contrast, monotherapies were ineffective. Both vascular attack and B7.1 immunotherapy led to up-regulation of heat shock protein 70 on stressed and dying tumor cells, potentially augmenting immunotherapy. Remarkably, large tumors took on the appearance of a wound that rapidly ameliorated, leaving perfectly healed skin. Combined therapy was mediated by CD8+ T cells and natural killer cells, accompanied by heightened and prolonged antitumor cytolytic activity (P < 0.001), and by a marked increase in tumor cell apoptosis. Cured animals completely rejected a challenge of 1 x 10(7) parental EL-4 tumor cells but not a challenge of 1 x 10(4) Lewis lung carcinoma cells, demonstrating that antitumor immunity was tumor specific. Adoptive transfer of 2 x 10(8) splenocytes from treated mice into recipients bearing established (0.8 cm in diameter) tumors resulted in rapid and complete tumor rejection within 3 weeks. Although DMXAA and B7.1 monotherapies are complicated by a narrow range of effective doses, combined therapy was less dosage dependent. Thus, a broad range of amounts of B7.1 cDNA were effective in combination with 25 mg/kg DMXAA. In contrast, DMXAA, which has a very narrow range of high active doses, was effective at a low dose (18 mg/kg) when administered with a large amount (180 microg) of B7.1 cDNA. Importantly, combinational therapy generated heightened antitumor immunity, such that gene transfer of B7.1 into one tumor, followed by systemic DMXAA treatment, led to the complete rejection of multiple untreated tumor nodules established in the opposing flank. These findings have important implications for the future direction and utility of cancer immunotherapies aimed at harnessing patients' immune responses to their own tumors.
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PMID:Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci. 1128 Jul 51

Hepatic artery embolization (HAE) has been utilized for treatment of advanced hepatic carcinoid metastases, with promising symptom palliation and tumor control. Our institution employs transcatheter HAE using Lipiodol/Gelfoam for treatment of carcinoid hepatic metastases, and this report presents our experience with twenty-four patients, examining symptom control, quality-of-life, octreotide dependence, and tumor progression. Twenty-four (11 male, 13 female, mean age = 59.4 +/- 2.5 yr) patients with carcinoid and unresectable hepatic metastases, confirmed by urinary 5-hydroxyindole acetic acid (5-HIAA) measurement and biopsy, were treated with Lipiodol/Gelfoam HAE from 1993-2001. Median follow-up was 35.0 months. Before HAE, 14 patients (58.3%) had malignant carcinoid syndrome, with symptoms quantified using our previously reported Carcinoid Symptom Severity Score, and 13 patients (54.2%) required octreotide for symptom palliation. Following treatment, symptom severity, octreotide dose, and tumor response were measured. Asymptomatic patients did not develop symptoms or require following treatment. Hepatic metastases remained stable (n = 4) or decreased (n = 19) in 23 patients (95.8%). Mean pretreatment Symptom Severity Scores (3.8 +/- 0.2), decreased to 1.4 +/- 0.1 post-treatment (P < 0.00001), with 64.3% of patients becoming asymptomatic. Mean pretreatment octreotide dosages (679.6 +/- 73.0 microg/d), decreased to 262.9 +/- 92.7 microg/d (P = 0.0024) post-treatment, with 46.2% of patients discontinuing octreotide. There were no treatment-related serious complications or deaths. This study demonstrates that Lipiodol/Gelfoam HAE produces excellent control of malignant carcinoid syndrome, allowing patients to decrease or eliminate use of octreotide, while controlling hepatic tumor burden.
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PMID:Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. 1239 54

The exact staging of prostate cancer is mandatory to allow selection of the appropriate primary therapy. In addition, if the PSA level rises again it is extremely important to find the site(s) of local recurrence or metastatic spread as soon as possible. However, with the morphological and metabolic imaging techniques currently available it is often not possible to answer these questions with adequate sensitivity and specificity, since small metastases < or = 1 cm in diameter are likely to remain undetected by them. In the last few years new radioactive labelled tracers have been introduced for use in positron emission tomography (PET), and it is hoped that the shortcomings in the diagnostic procedures used for prostate carcinoma might be compensated by their use. Besides 11C- or 18F-labelled choline, [11C]Acetate is also attracting attention as a promising PET tracer. In this paper we review the various PET tracers available and evaluate the advantages and the drawbacks of [11C]Acetate in three case studies by comparing [11C]Acetate-PET with histology and with other imaging techniques. The use of [11C]Acetate appears to be feasible and helpful in the diagnosis of prostate carcinoma. However, its final value relative to other imaging techniques needs further investigation, with special reference to initial lymph node involvement, early localisation of recurrence and possible noninvasive differentiation between prostate cancer, prostatis and benign hyperplasia of the prostate.
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PMID:[The (11C) acetate positron emission tomography in prostatic carcinoma. New prospects in metabolic imaging]. 1252 44

Angiogenic activity and formation of a vascular network facilitate tumor perfusion and play a critical role in tumor growth and metastasis. Tumor vasculature may be visualized by means of parametric imaging of specific morphological and physiological characteristics that collectively describe its properties. In this review, we describe advanced magnetic resonance imaging (MRI) techniques that have been developed in order to image and quantify the distribution of tumor vasculature throughout the tumor and characterize its function. These techniques have been used to monitor changes in the magnetic resonance signal intensity of tissue water hydrogens generated by intrinsic effects, as well as by exogenous contrast agents administered into the blood circulation. We further describe specific applications of magnetic resonance imaging using a contrast agent, gadolinium diethylene triamine penta-acetic acid (GdDTPA), which has long been approved for clinical use. Examples include studies of the vascular properties of breast cancer tumors and metastases in animal models, as well as of breast cancer vasculature in patients. We also discuss the use of MRI to improve breast cancer diagnosis in humans by quantifying the permeability of the tumor vasculature. By maximizing the spatial resolution of the images in both animal and human studies, the capacity of magnetic resonance imaging to enhance our understanding of the processes regulating tumor angiogenesis, and improve the diagnosis of cancer, could be clearly demonstrated.
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PMID:Magnetic resonance imaging of tumor vasculature. 1254 Sep 50

A nonhydrolyzable ether analogue of RRR-alpha-tocopherol, 2,5,7,8-tetramethyl-2R-(4R, 8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid, called RRR-alpha-tocopheryloxyacetic acid or RRR-alpha-tocopherol ether-linked acetic acid analogue (alpha-TEA), exhibits antitumor activity in vitro and in vivo using a syngeneic BALB/c mouse mammary tumor model (line 66 clone 4 stably transfected with green fluorescent protein). Treatment of cells with 5, 10, and 20 micro g/ml alpha-TEA for 3 days produced 6, 34, and 50% apoptosis, respectively, and treatment of cells with 10 micro g/ml for 2, 3, 4, and 5 days produced 20, 35, 47, and 58% apoptosis, respectively. A liposomal formulation of alpha-TEA administered by aerosol reduced s.c. tumor growth and lung metastasis. Alpha-TEA-treated animals showed a significant decrease in tumor volumes over 17 days of aerosol treatment (P < 0.001). Forty percent of aerosol as well as untreated control mice had visible, macroscopic lung metastases versus none (0%) of the alpha-TEA-treated mice. On the basis of fluorescence microscopic examination of the surface (top and bottom) of flattened whole left lung lobes, an average of 60 +/- 15 and 102 +/- 17 versus 11 +/- 4 fluorescent microscopic metastases was observed in aerosol control and untreated control versus alpha-TEA-treated animals, respectively. Alpha-TEA formulated in ethanol + peanut oil (5 mg/mouse/day) delivered by gavage did not reduce s.c. primary tumor burden; however, fluorescent microscopic lung metastases were significantly reduced (P < 0.0021). In summary, alpha-TEA formulated in liposomes and delivered by aerosol is a potent antitumor agent and reduces lung metastasis.
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PMID:Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. 1274 5

A novel nonhydrolyzable ether-linked acetic acid analog of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (alpha-TEA) in combination with cisplatin, reduces tumor burden of A2780/cp70 (cp70) cisplatin-resistant human ovarian cancer cells xenografted into immune compromised nude mice. Two xenograft studies were conducted using cp70 cells stably expressing green fluorescent protein (cp70-GFP) subcutaneously transplanted into NU/NU mice. For studies 1 and 2, alpha-TEA was formulated in liposomes and delivered by aerosol such that approximately 36 microg and 72 microg of alpha-TEA were deposited in the respiratory tract of each mouse each day, respectively. Cisplatin at 5 mg/kg was administered by intraperitoneal injections once weekly for the first 3 weeks in Study 1 and on the third and 10th days following treatment initiation in Study 2. The combination alpha-TEA + cisplatin treatment reduced tumor burden and metastasis of cp70-GFP cells in comparison to control mice or mice treated with alpha-TEA or cisplatin singly. A significant reduction (P < 0.001) in growth of subcutaneous transplanted tumors was obtained with alpha-TEA + cisplatin for both studies. Visible metastases were observed in the lungs of animals from control and cisplatin-treated groups but not in animals from the alpha-TEA- or alpha-TEA + cisplatin-treated groups. The alpha-TEA + cisplatin significantly reduced the total number of lung and axillary lymph node micrometastasis (P < 0.03 and P < 0.0001, respectively). Analyses of tumor sections showed the alpha-TEA + cisplatin treatment group, in comparison to control, to have a significantly lower level of cell proliferation (Ki-67 staining; P < 0.0001) and a significantly higher level of apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling [TUNEL]; P < 0.0001). In summary, combinations of alpha-TEA + cisplatin significantly reduced tumor burden and metastases in a xenograft model of cisplatin-resistant human ovarian cancer cells. These data show promise for combination alpha-TEA + cisplatin chemotherapy for ovarian cancer.
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PMID:Alpha-TEA plus cisplatin reduces human cisplatin-resistant ovarian cancer cell tumor burden and metastasis. 1585 95

Gene therapy of cancer offers the possibility of a targeted treatment that destroys tumors and metastases, but not normal tissues. In gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, the gene encoding an enzyme is delivered to tumor cells, followed by administration of a prodrug, which is converted locally to a cytotoxin by the enzyme. The producer cells as well as surrounding bystanders are subsequently killed. Promising results have meant that suicide gene therapy has reached multicenter phase III clinical trials. This review will discuss the development, efficiency, mode of action and pharmacokinetics of seven GDEPT systems in vitro and in vivo. We will review the latest data of those systems in clinical trials (herpes simplex virus thymidine kinase/gancyclovir, bacterial cytosine deaminase/5-fluorocytosine, bacterial nitroreductase/CB1954 and cytochrome P450/cyclophosphamide), as well as the development of more recent and experimental systems which are not yet in clinical trials (P450 reductase/tirapazamine, carboxypeptidase/CMDA, horseradish peroxidase/indole-3-acetic acid or paracetamol and others).
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PMID:From bench to bedside for gene-directed enzyme prodrug therapy of cancer. 1574 71

During the last decade, there has been a significant advancement in imaging of urologic diseases. Transrectal ultrasound (TRUS), computerized tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) are still experiencing new developments in urology. Despite these many technological advances, the initial diagnostic procedure for a patient with suspected prostate cancer (PC) is multiple site blind prostate biopsies. There is a need for a noninvasive metabolic imaging modality to direct the site of biopsy to decrease the sampling error. MRS seems promising but as it is a costly and more time-consuming test, further studies are needed to evaluate its clinical utility. Currently, PET does not play any role to direct biopsy. Acetate and choline appear to be better tracers than FDG for the detection of a prostate lesion, however, further well-organized studies are needed before any of these agents can be used clinically. Incidental detection of intense focal uptake in the prostate during whole body PET scanning should be evaluated with prostate-specific antigen (PSA) and TRUS-guided biopsy. Although FDG is inferior to other tracers for primary staging, it may be useful in selected patients with suspected high-grade cancer. The role of ProstaScint scan is still controversial for detection of recurrent PC. This study may be helpful for evaluating nodal metastases when PSA is elevated and bone scan is negative. Bone scan remains the study of choice when bone metastases are suspected (PSA>15-20 ng/mL+/-bone pain). Acetate and choline provide better accuracy than FDG in the detection of local soft tissue disease, nodal involvement, and distant metastases. High FDG uptake may be indicative of more aggressive and possibly androgen-independent disease. PET/CT with any of the above PET tracers will most likely be preferred to the PET scan alone due to better localization of a hot lesion in PET/CT. Nuclear medicine studies also have been used to evaluate acute scrotum and testicular neoplasms. Scrotal scintigraphy has lost its popularity to Doppler ultrasound in the evaluation of the acute scrotum. In testicular tumors, FDG-PET appears to be superior to conventional imaging modalities in initial staging, detection of residual/recurrence, and monitoring treatment response. Tumor markers after treatment occasionally are elevated and cannot locate the site of recurrence, FDG-PET can play a very important role in this regard. Nuclear medicine studies also have been used to evaluate diseases of the urinary bladder. Radionuclide cystography is more sensitive and has less than 1/20 the radiation exposure of the conventional contrast enhanced micturating cystourethrogram (MCU). However, the utility of FDG-PET in the evaluation of bladder cancer seems to be limited to the evaluation of distant metastases. 11C-Methionine and choline may be a better option for local and nodal disease due to their negligible excretion in the urine.
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PMID:Nuclear medicine studies of the prostate, testes, and bladder. 1635 96

Carcinoid tumors are rare, often insidious neoplasms arising from neuroendocrine cells. The majority arise in the gastrointestinal system, and are often incidentally found during investigation, although some may present as an emergency bleed or perforation. The prosaic symptoms of flushing, diarrhea, and sweating are often overlooked; thus, the diagnosis is usually much delayed and the tumor is advanced at presentation. This diagnostic delay renders effective management difficult and adversely affects outcome. This overview provides a current assessment of the evolution of the diagnostic techniques available to establish an accurate biochemical (5-hydroxyindole-3-acetic acid and chromogranin A) and topographic diagnosis (octreoscan, radio-labeled metaidobenzylguanidine, computerized tomography, magnetic resonance imaging, positron emission tomography, enteroclysis, endoscopic ultrasound, enteroscopy, capsule endoscopy, and angiography) of carcinoid tumors. The utility and shortcomings of the respective modalities available are evaluated. Although considerable advances have been made in establishing the diagnosis of carcinoid tumors and in defining the topography of metastatic disease, the major limitation is the inability to establish an early and timely diagnosis before the advent of metastatic disease.
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PMID:Gastrointestinal carcinoids: the evolution of diagnostic strategies. 1691 96


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