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)

A hybrid toxin targeted to melanotropin receptors and selectively cytotoxic to melanoma cell lines in vitro has recently been developed. The toxin, a recombinant fusion protein (designated DAB389-MSH), contains the peptide sequences of alpha-melanocyte-stimulating hormone (alpha-MSH) and the catalytic (cytotoxic; Fragment A) and lipophilic (part of Fragment B) domains of diphtheria toxin. In the present study, binding of DAB389-MSH to melanotropin receptors in biopsy specimens of human and mouse melanoma metastases was assessed by measuring its ability to inhibit binding of a radiolabeled, superpotent analogue of alpha-MSH (125I-[Nle4,D-Phe7]-alpha-MSH; 125I-NDP-MSH) and comparing its potency in this system with those of the established ligands NDP-MSH and alpha-MSH. Radioligand binding to tissue sections in vitro was localized and quantified by autoradiography and image analysis. DAB389-MSH inhibited binding of 125I-NDP-MSH to experimental murine B16-F1C23 melanoma metastasis tissue and to melanoma metastases of three patients. In both mouse and human melanoma tissues, concentration-response relationships for DAB389-MSH-mediated inhibition of 125I-NDP-MSH binding were parallel, and its maximal effects were comparable in magnitude, to those of NDP-MSH and alpha-MSH. Half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 0.63 nM; alpha-MSH, 3.14 nM; and DAB389-MSH, 10.1 nM. In human melanoma tissues, the respective half-maximal peptide concentrations for inhibition of 125I-NDP-MSH binding to mouse melanoma tissue sections were: NDP-MSH, 1.80 nM; alpha-MSH, 2.43 nM; and DAB389-MSH, 11.9 nM. Taken together, these results suggest that NDP-MSH, alpha-MSH, and DAB389-MSH bind to a common melanotropin receptor in human metastatic melanoma cells. Since previous work has shown that melanotropin receptors are detectable in melanoma metastases of about 80% of human patients, malignant melanoma cells of many patients may be susceptible to killing by the melanotropin receptor-targeted cytotoxin DAB389-MSH.
 ...
PMID:Interaction of an alpha-melanocyte-stimulating hormone-diphtheria toxin fusion protein with melanotropin receptors in human melanoma metastases. 131 97

Restriction fragment length polymorphisms at 61 autosomal and 7 X-linked loci were screened for heterozygosity in cell lines derived from 6 independent metastases and autologous B-cells from a patient with melanoma. Segregations resulting in the loss of heterozygosity were detected in the tumor cells at 8 of 16 autosomes with at least 1 informative locus and at the 3 informative X-linked loci. With a single exception, karyotypic abnormalities were not detected in the region of loci where loss of heterozygosity had been detected. Three patterns of loss were identified: unique segregations in cells from a single metastasis; segregation of the same alleles in different subsets of metastases; and identical segregations in all 6 metastases. The monoclonal derivation of the 6 metastases is supported by the inactivation of the same X-chromosome and the presence of identical segregation at loci on chromosomes 9 and X. Analysis of the patterns of segregation in the metastatic tumor cells permitted the development of a genealogy of tumor progression in this patient and the development of a model of tumor progression which describes the accumulation of selectively neutral and advantageous segregations in metastatic tumor cells.
 ...
PMID:Loss of heterozygosity at autosomal and X-linked loci during tumor progression in a patient with melanoma. 288 13

A neurofibroma, a fibroma, a primary neurofibrosarcoma, and four neurofibrosarcoma metastases from a woman with hereditary neurofibromatosis who was heterozygous (GdB/GdA-) for the X-linked enzyme glucose-6-phosphate dehydrogenase were studied to determine the number of cells from which the tumors developed. Both enzyme types were observed in the benign tumors in proportions similar to those present in seven different normal tissues studied. These findings indicated that the benign tumors arose from many cells. In marked contrast, only type A activity was detected in the primary neurofibrosarcoma and in all of the metastases. Two or more steps probably were involved in the development of neurofibrosarcoma in this patient: the inherited genetic mutation producing neurofibromatosis and a rare event or combination of events that permitted a single cell to undergo malignant proliferation.
 ...
PMID:Probable clonal origin of neurofibrosarcoma in a patient with hereditary neurofibromatosis. 681 62

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.
 ...
PMID:Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability. 1062 Jan 9

A 32yr-old nonsmoking male, diagnosed as having X-linked agamma-globulinemia, presented with fever, cough with purulent sputum, a very intense back pain and a mass of 10 centimetres in lower left lobe. Diagnostic evaluation revealed a squamous cell carcinoma with very aggressive metastases at L3. Malignancies are the second leading cause of death in children and adults with congenital immunodeficiency disorders, mostly non-Hodgkin lymphomas and gastric and colon adenocarcinomas, but this is the first report of lung cancer in a patient with X-linked agammaglobulinemia. Lung cancer incidence has been reported to be higher in patients with other diseases of the lung, however, there is no clear evidence of the role of bronchiectasis in developing lung cancer. It is possible that a longer survival for patients with X-LA recently diagnosed, and an association of chronic bronchial infection, could favour the development of pulmonary neoplasm.
 ...
PMID:X-linked agammaglobulinaemia and squamous lung cancer. 1140 38

Fibroadenoma and phyllodes tumour of the breast are both fibroepithelial tumours. Although progression to epithelial malignancy has been described, the behaviour of most fibroadenomas is benign. Phyllodes tumours, on the other hand, can display locally destructive growth and can even metastasize. A relationship between the two tumours has been suggested in the literature. This study investigated the clonality of both the stroma and the epithelium of these fibroepithelial tumours and attempted to construct a model in which fibroadenoma can progress in both an epithelial and a stromal direction. Fibroadenomas (n=25) and phyllodes tumours (n=12) were selected for analysis. Tissue was microdissected and analysed for clonality using a polymerase chain reaction (PCR)-based assay targeted at an X-linked polymorphic marker, the human androgen receptor gene (HUMARA). Nineteen fibroadenomas and nine phyllodes tumours could be analysed. Normal-appearing epithelium, hyperplastic epithelium, and stroma removed from fibroadenomas were polyclonal. As expected, carcinoma in situ (CIS) removed from four fibroadenomas was monoclonal. Three areas of apparent stromal expansion within fibroadenoma were monoclonal, suggesting stromal progression. Mostly, the stroma of phyllodes tumours was monoclonal and the epithelium polyclonal. In two cases, however, the epithelium seemed to be monoclonal, whereas in three other cases the stromal component was polyclonal. These findings indicate that fibroadenoma can progress in an epithelial direction to CIS and in a stromal direction to phyllodes tumour.
 ...
PMID:Analysis of the progression of fibroepithelial tumours of the breast by PCR-based clonality assay. 1221 75

A 61-year-old male patient had esophageal carcinoma with multiple mediastinal and right supraclavicular lymph node metastases. Chemotherapy consisting of infusion of nedaplatin and continuous infusion of 5-fluorouracil was performed. After three courses of the chemotherapy, the patient was treated with a combination of cisplatin and 5-FU and radiotherapy. However, only radiotherapy was performed after 18 Gy because of grade 3 leukocytonenia during the chemoradiotherapy. The patient achieved a partial response (nearly complete response) for 9 months after the initiation of the treatment. In conclusion, chemotherapy with NDP and 5-FU followed by chemoradiotherapy is effective and safe for patients with esophageal carcinoma with multiple lymph node metastases.
 ...
PMID:[A case of advanced esophageal cancer with multiple lymph node metastases successfully treated with induction chemotherapy consisting of nedaplatin and 5-FU followed by chemoradiotherapy]. 1221 70

Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiopharmaceuticals. Because both melanotic and amelanotic melanomas overexpress melanocortin-1 receptors (MC1R), radiolabeled analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) are potential candidates for melanoma diagnosis. Here, we report the in vivo performance of a newly designed octapeptide analogue, [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(OCT)), which was conjugated through its N-terminal amino group to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable incorporation of radiometals (e.g., indium-111) into the peptide. DOTA-MSH(OCT) displayed high in vitro MC1R affinity (IC(50) 9.21 nM). In vivo [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumorbearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]-DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly for the amount of radioactivity taken up by nonmalignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) is a promising melanoma imaging agent.
 ...
PMID:DOTA alpha-melanocyte-stimulating hormone analogues for imaging metastatic melanoma lesions. 1285 39

Following the first synthesis of tritiated alpha-melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin) in 1974 by Medzihradszky et al., several alpha-MSH analogs were designed containing between 2 and 12 tritium atoms, the latter of which displayed a specific radioactivity of 12.21 GBq/micromol (330 Ci/mmol). Similarly, radioiodinated alpha-MSH analogs of high purity, full biological activity and a specific radioactivity of approximately 140 GBq/micromol were obtained. Although tritiated and radioiodinated alpha-MSH became indispensable tools as tracer molecules for numerous in vitro and in vivo studies, above all for receptor identification and characterization as well as for structure-activity studies, they did not fulfill the criteria required for therapeutic in vivo targeting of metastatic melanoma. Therefore, we recently developed alpha-MSH analogs containing the universal metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) in different positions of the molecule. As DOTA can equally well incorporate diagnostic (e.g. (111)In, (67,68)Ga) and therapeutic (e.g. (90)Y, (67)Cu) radionuclides, DOTA-MSH compounds may serve for both melanoma scintigraphy and therapy. The analog DOTA-[betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (DOTA-MSH(OCT)), which contains the metal chelator at its N-terminal end, displayed good in vitro MC1R affinity (IC(50) 9.21 nm). In vivo, [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumor-bearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly with respect to the amount of radioactivity taken up by non-malignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) specifically targets melanoma metastases and represents a lead compound for the development of therapeutic DOTA-MSH analogs.
 ...
PMID:Radiolabeled alpha-melanocyte-stimulating hormone analogs for receptor-mediated targeting of melanoma: from tritium to indium. 1452 36

Synchronous tumors of the ovary and endometrium are a well-known phenomenon. There are histological criteria for defining double primary tumors or metastasis from one organ to another, but in some cases a precise diagnosis is difficult. In this study we reviewed 17 cases of synchronous ovarian and endometrial adenocarcinoma by previously reported histological criteria and performed a microsatellite analysis, combined with X-linked clonality analysis. We also analyzed 8 cases of endometrial adenocarcinoma with pelvic lymph node metastasis as a control. Five dinucleotide microsatellite markers were selected, and microsatellite analysis was performed by a high-resolution method using fluorescence-labeled polymerase chain reaction and laser scanning. In synchronous tumors, 11 ovarian carcinomas (65%) and 10 endometrial carcinomas (59%)demonstrated microsatellite instability (MSI). In total, 13 of the 17 patients demonstrated MSI in the ovarian tumor, the endometrial tumor, or both. Four cases of endometrial carcinoma with pelvic lymph nodes metastases displayed MSI, and MSI findings of the endometrial tumor and lymph node metastasis were same in all cases. Based on these findings, we considered that similar MSI findings indicate metastatic tumors. According to the MSI findings, 13 of the 17 patients (76%) had single or double clonal tumors, 11 (67%) with double primary tumors and 2 (13%) with metastatic tumors. Using X-linked clonality analysis, 3 patients were diagnosed with double primary tumors. The molecular diagnosis corresponded with the histological criteria in all but 1 case. In conclusion, using both MSI and X-linked clonality analysis, most patients (82%) could be diagnosed as having single or double clonal tumors. The histological criteria are accurate and useful in most cases; however, in some cases where the relationship between the 2 tumors is difficult to determine, high-resolution MSI analysis may be helpful.
 ...
PMID:Frequent microsatellite instability in synchronous ovarian and endometrial adenocarcinoma and its usefulness for differential diagnosis. 1561 7


1 2 Next >>