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)

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides. Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene-triamine-pentaacetate (DTPA)] can be labeled with In-111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations. The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma. The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK-B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK-B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin-related peptides, all having in common the C-terminal CCK receptor binding tetrapeptide sequence -Trp-Met-Asp-PheNH(2) or derivatives thereof, were investigated. They were members of the gastrin- or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK-B receptor subtype. Radiometal-labeled derivatives of minigastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC-bearing animals showed significant antitumor efficacy. In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK-B receptor scintigraphy was performed with (111)In-DTPA-D-Glu(1)-minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK-B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor-to-background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient-based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases. Eight patients with advanced metastatic disease were injected in a dose-escalation study with potentially therapeutic activities of a (90)Y-labeled minigastrin derivative at 4-6-weekly intervals (30-50 mCi/m(2) per injection for a maximum of four injections). Hematologic and renal were identified as the dose-limiting toxicities at the 40 and 50 mCi/m(2) levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease. These data suggest that CCK-B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK-B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved.
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PMID:Cholecystokinin-B (CCK-B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK-B receptor expressing malignancies. 1265 27

A wide variety of metabolic features of brain tumors can be imaged using PET, including glucose metabolism, blood flow, oxygen consumption, amino acid metabolism, and lipid synthesis. Currently, FDG is the most widely available PET tracer for body imaging and brain imaging. Malignant brain tumors, like many other soft tissue tumors, show increased glucose metabolism, which is reflected on FDG-PET imaging. FDG-PET imaging of brain tumors provides information on tumor grade and prognosis. Compared with other organ systems, FDG-PET imaging of the brain presents unique challenges because of the high background glucose metabolism of normal gray matter structures. Coregistration of the MRI (or CT) and FDG-PET images is essential for accurate evaluation of brain tumors and is performed routinely at the authors' institution. The heterogeneous nature of gliomas can result in significant sampling errors when patients are biopsied for primary tumor diagnosis or recurrent disease. FDG-PET can be used to define the most metabolically active targets for stereotactic biopsy. This in turn can improve diagnostic accuracy and reduce the number of biopsy samples required. FDG-PET is also useful for evaluating residual or recurrent tumor following therapy, and can be used to survey patients with low-grade brain tumors for evidence of degeneration into high-grade malignancy. In the case of suspected tumor recurrence or progression, PET can aid in defining appropriate targets for biopsy. One limitation of FDG-PET is the occasional inability to distinguish radiation necrosis from recurrent high-grade tumor. A second limitation is that FDG-PET is less sensitive than contrast-enhanced MRI for detecting intracranial metastases, and it is the authors' experience that brain studies should not be included as part of routine whole-body PET studies. Other tracers, such as 11C-methionine and FCH, also avidly accumulate in brain tumors and have the advantage of low background cortical activity. The relationship between degree of uptake of these agents and tumor grade is not established. These tracers may be useful in specific clinical situations, however, such as tumor localization for treatment planning or evaluation of low-grade tumors.
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PMID:Positron emission tomography imaging of brain tumors. 1268 15

Reactivation of hepatitis B virus (HBV) after cytotoxic chemotherapy is a serious problem, and it occurred to 41% of breast cancer patients carrying HBV. Previous studies have demonstrated that lamivudine was effective for HBV flare-up during cytotoxic chemotherapy. We aimed to monitor the HBV status of breast cancer patients undergoing chemotherapy with preemptive lamivudine over time. Six breast cancer patients carrying hepatitis B surface antigen (HBsAg) were monitored during chemotherapy, five in the adjuvant setting and one with metastatic disease. Preemptive lamivudine was given throughout the chemotherapy course. HBsAg, HBV envelope antigen (HBeAg), anti-HBV envelope antibody (HBe Ab), serial serum alanine transaminase (ALT), quantitative HBV viral DNA analysis, and HBV DNA precore promoter and precore sequence were monitored. One patient carried wild type and the other five precore mutant strain of HBV by examination of HBV sequence in precore promoter and precore region. No evident HBV reactivation developed, and all patients tolerated lamivudine well. During the 6-to-8-month follow-up after cessation of cytotoxic therapy and withdrawal of lamivudine, serum ALT remained unchanged, although an increase of HBV DNA levels in four patients was found. No emergence of the tyrosine-methionine-aspartate-aspartate (YMDD) lamivudine-selective resistant strain was observed in the six patients. Preemptive use of lamivudine can effectively prevent reactivation of HBV in breast cancer patients receiving postoperative adjuvant chemotherapy. Lamivudine can be discontinued safely without emergence of lamivudine-resistant HBV strain or rebound HBV flare-up. The candidate for the use of preemptive lamivudine in HBV carriers who need short-term chemotherapy remained to be investigated
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PMID:Preemptive use of lamivudine in breast cancer patients carrying hepatitis B virus undergoing cytotoxic chemotherapy: a longitudinal study. 1507 16

Metastasis is a leading cause of mortality and morbidity in cancer. Urokinase (uPA), only expressed by the highly invasive cancer cells, has been implicated in invasion, metastases, and angiogenesis of several malignancies including breast cancer. Because uPA expression is strongly correlated with its hypomethylated state, we utilized the uPA gene in the highly invasive MDA-231 human breast cancer cells as a model system to test the hypothesis that pharmacological reversal of the uPA promoter hypomethylation would result in its silencing and inhibition of metastasis. S-Adenosyl-l-methionine (AdoMet) has previously been shown to cause hypermethylation and inhibit demethylation. Treatment of MDA-231 cells with AdoMet, but not its unmethylated analogue S-adenosylhomocysteine, significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and metastasis in vivo. The effects of AdoMet on uPA expression were reversed by the demethylating agent 5'-azacytidine, supporting the conclusion that AdoMet effects are caused by hypermethylation. Knockdown of the methyl-binding protein 2 also causes a significant inhibition of uPA expression in vitro and tumor growth and metastasis in vivo. These treatments did not have any effects on estrogen receptor expression, suggesting that inhibition of hypomethylation will not affect genes already silenced by hypermethylation. These data are consistent with the hypothesis that hypomethylation of critical genes like uPA plays a causal role in metastasis. Inhibition of hypomethylation can thus be used as a novel therapeutic approach to silence the pro-metastatic gene uPA and block breast cancer progression into the aggressive and metastatic stages of the disease.
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PMID:Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. 1515 Feb 77

Met, the receptor for hepatocyte growth factor (HGF), is activated in human cancer by both ligand-dependent and -independent mechanisms. We engineered a soluble Met receptor (decoy Met) that interferes with both HGF binding to Met and Met homodimerization. By lentiviral vector technology, we achieved local or systemic delivery of decoy Met in mice. We provide evidence that in vivo expression of decoy Met (1) inhibits tumor cell proliferation and survival in a variety of human xenografts, (2) impairs tumor angiogenesis by preventing host vessel arborization, (3) suppresses or prevents the formation of spontaneous metastases, and (4) synergizes with radiotherapy in inducing tumor regression, without (5) affecting housekeeping physiological functions in the adult animal.
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PMID:Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. 1526 Nov 36

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Met(p+1loop)-->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thr(p+1loop) residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTK(Metp+1loop) with 2B mutation and wild-type EPH members the Thr(p+1loop) residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thr(p+1loop) residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.
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PMID:Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. 1548 8

FDG-PET has a limited role in diagnosis of prostate cancer mainly because of the low uptake of FDG in the tumor and normal excretion of FDG through urine. FDG-PET has shown some promise in the assessment of lymph nodes and bone metastases. There is a large degree of variability when FDG-PET is compared with bone scintigraphy. New C11-labeled radiotracers (acetate, choline, and methionine) have shown promising initial results but further studies are required to determine their role in such settings. These radiotracers provide a unique opportunity for dynamic, multitracer, and quantitative studies, which improve the sensitivity and specificity on PET in this population. Short half-lives and of C-11, however with the limits to their use requires an on-site cyclotron. Recent synthesis schemes with [18F]-labeling, however, may overcome this limitation. FDG-PET has a significant potential to assist with the diagnosis and management of testicular cancer. PET has been most useful in defining the presence or absence of disease in patients with residual masses. PET has shown promising results for the initial diagnosis of this cancer, but further for studies ar required to determine its role in the management of this malignancy. PET can be used in conjunction with conventional imaging techniques to diagnose retroperitoneal masses in patients with primary testicular cancer. FDG-PET has shown very encouraging results in a limited number of studies, and has also demonstrated a good sensitivity for initial staging. FDG-PET seems to be superior to conventional imaging modalities for detecting local disease and recurrence, and distant metastases.
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PMID:PET in the management of urologic malignancies. 1614 85

Prostate cancer, renal cancer, bladder, and other urothelial malignancies make up the common tumors of the male genitourinary tract. For prostate cancer, common clinical scenarios include managing the patient presenting with 1) low-risk primary cancer; 2) high-risk primary cancer; 3) prostate-specific antigen (PSA) recurrence after apparently successful primary therapy; 4) progressive metastatic disease in the noncastrate state; and 5) progressive metastatic disease in the castrate state. These clinical states dictate the appropriate choice of diagnostic imaging modalities. The role of positron emission tomography (PET) is still evolving but is likely to be most important in determining early spread of disease in patients with aggressive tumors and for monitoring response to therapy in more advanced patients. Available PET tracers for assessment of prostate cancer include FDG, 11C or 18F choline and acetate, 11C methionine, 18F fluoride, and fluorodihydrotestosterone. Proper staging of prostate cancer is particularly important in high-risk primary disease before embarking on radical prostatectomy or radiation therapy. PET with 11C choline or acetate, but not with FDG, appears promising for the assessment of nodal metastases. PSA relapse frequently is the first sign of recurrent or metastatic disease after radical prostatectomy or radiation therapy. PET with FDG can identify local recurrence and distant metastases, and the probability for a positive test increases with PSA. However, essentially all studies have shown that the sensitivity for recurrent disease detection is higher with either acetate or choline as compared with FDG. Although more data need to be gathered, it is likely that these two agents will become the PET tracers of choice for staging prostate cancer once metastatic disease is strongly suspected or documented. 18F fluoride may provide a more sensitive bone scan and will probably be most valuable when PSA is greater than 20 ng/mL in patients with high suspicion or documented osseous metastases. Several studies suggest that FDG uptake in metastatic prostate cancer lesions reflects the biologic activity of the disease. Accordingly, FDG can be used to monitor the response to chemotherapy and hormonal therapy. Androgen receptor imaging agents like fluorodihydrotestosterone are being explored to predict the biology of treatment response for progressive tumor in late stage disease in castrated patients. The assessment of renal masses and primary staging of renal cell carcinoma are the domain of helical CT. PET with FDG may be helpful in the evaluation of "equivocal findings" on conventional studies, including bone scan, and also in the differentiation between recurrence and posttreatment changes. The value of other PET tracers in renal cell carcinoma is under investigation. Few studies have addressed the role of PET in bladder cancer. Because of its renal excretion, FDG is not a useful tracer for the detection of primary bladder tumors. The few studies that investigated its role in the detection of lymph node metastases at the time of primary staging were largely disappointing. Bladder cancer imaging with 11C choline, 11C methionine, or 11C- acetate deserves further study.
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PMID:Positron emission tomography for prostate, bladder, and renal cancer. 1549 5

Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions.
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PMID:An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice. 1554 93

Identification of genes that are expressed in a cancer cell-specific manner can provide markers for detection, diagnosis, and disease progression. We have previously reported that receptor tyrosine kinase ligands in concert with ligation of alphavbeta5 integrin induce expression of Mig-7 restricted to carcinoma cells. Because of this highly specific expression, we hypothesized that Mig-7 could be used as a marker of occult tumor cells. The objective of this study was to begin to test this hypothesis by generating Mig-7 specific antisera and RT-PCR methods for detection of Mig-7 expression in tissues and blood from cancer patients as compared to those from normal subjects. By immunohistochemistry and by RT-PCR, we detected Mig-7 mRNA in lymph nodes from 7 out of 9 (77.8%) endometrial carcinoma xenograft mice but not from any of the 5 negative control animals. Mig-7 expression was more specific than Met expression, the RTK that binds Scatter factor and is used as a marker of poor progression, in endometrial carcinoma as compared to normal endometrial tissue samples. In 87.3% of tumors from various tissues including breast, lung, colon and ovary, we detected Mig-7 expression. Blood samples from untreated metastatic cancer patients also displayed Mig-7 mRNA in contrast to a lack of expression in chemotherapy treated or normal individuals. In conclusion, we report the first immunohistochemical and RT-PCR assays for Mig-7 and discuss its highly specific localization to cancer cells in contrast to an absence in normal cells. Our preliminary data indicate that Mig-7 may be a potential early marker of migrating and circulating carcinoma cells.
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PMID:Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells. 1558 99


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