Dietary glycine inhibits the growth of B16 melanoma tumors in mice.
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Dietary glycine inhibited hepatocyte proliferation in response to the carcinogen WY-14,643. Since increased cell replication is associated with hepatic cancer caused by WY-14,643, glycine may have anti-cancer properties. Therefore, these experiments were designed to test the hypothesis that dietary glycine would inhibit the growth of tumors arising from B16 melanoma cells implanted subcutaneously in mice. C57BL/6 mice were fed diet supplemented with 5% glycine and 15% casein or control diet (20% casein) for 3 days prior to subcutaneous implantation of B16 tumor cells. Tumor volume was estimated from tumor diameter for 14 days. Tumors were excised, weighed and sectioned for histology post-mortem. B16 cells and endothelial cells were cultured in vitro to assess effects of glycine on cell growth. Statistical tests were two-sided and a P-value of 0.05 was defined as a significant difference between groups. Weight gain did not differ between mice fed control and glycine-containing diets. B16 tumors grew rapidly in mice fed control diet; however, in mice fed glycine diet, tumor size was 50-75% less. At the time of death, tumors from glycine-fed mice weighed nearly 65% less than tumors from mice fed control diet (P < 0.05). Glycine (0.01-10 mM) did not effect growth rates of B16 cells in vitro. Moreover, tumor volume and mitotic index of B16 tumors in vivo did not differ 2 days after implantation when tumors were small enough to be independent of vascularization. After 14 days, tumors from mice fed dietary glycine had 70% fewer arteries (P < 0.05). Furthermore, glycine (0.01-10 mM) inhibited the growth of endothelial cells in vitro in a dose-dependent manner (P < 0.05; IC50 = 0.05 mM). These data support the hypothesis that dietary glycine prevents tumor growth in vivo by inhibiting angiogenesis through mechanisms involving inhibition of endothelial cell proliferation. (+info)
Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy.
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PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma. (+info)
Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen.
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In an effort to identify tumor-specific antigens recognized by CD4(+) T cells, an approach was developed that allows the screening of an invariant chain-complementary DNA fusion library in a genetically engineered cell line expressing the essential components of the major histocompatibility complex (MHC) class II processing and presentation pathway. This led to the identification of a mutated form of human CDC27, which gave rise to an HLA-DR4-restricted melanoma antigen. A mutated form of triosephosphate isomerase, isolated by a biochemical method, was also identified as an HLA-DR1-restricted antigen. Thus, this approach may be generally applicable to the identification of antigens recognized by CD4(+) T cells, which could aid the development of strategies for the treatment of patients with cancer, autoimmune diseases, or infectious diseases. (+info)
Functional localization of a melanoma tumor suppressor gene to a small (< or = 2 Mb) region on 11q23.
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We have previously demonstrated the existence of a melanoma tumor suppressor gene(s) on the long arm of chromosome 11 through suppression of tumorigenicity assays. Although loss of heterozygosity studies also support this finding, only a large critical region (44 cM) has been identified to date on 11q22-25. To further localize a tumor suppressor gene(s) within this region, we have now generated and characterized nine melanoma microcell hybrids, each retaining an introduced fragment of 11q. Of the nine hybrids, four were suppressed for tumor formation in nude mice, while five formed tumors at the same rate as the parental melanoma cell line (UACC 903). Molecular analysis of the hybrids with 118 microsatellite markers narrowed the location of a putative suppressor gene to a small (< or =2 Mb) candidate region on 11q23 between the markers D11S1786 and D11S2077 and within the larger region frequently deleted in melanoma tumors and cell lines. While multiple tumor suppressor genes are likely to reside on 11q22-25, the presence of this region in all four suppressed hybrids supports the simplest model that a single locus is responsible for the suppressed phenotype observed in UACC 903. (+info)
Adenoviral vectors capable of replication improve the efficacy of HSVtk/GCV suicide gene therapy of cancer.
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A major obstacle to the success of gene therapy strategies that directly target cancer cells is the poor vector distribution within solid tumors. To address this problem, we developed an E1b 55 kDa attenuated, replication-competent adenovirus (Ad.TKRC) which expresses the herpes simplex-1 thymidine kinase (HSVtk) gene to sensitize tumors to ganciclovir (GCV). Efficacy of this combined strategy was tested in nude mice with subcutaneous human A375 melanoma and ME180 cervical carcinomas. Intratumoral injection of a replication-defective adenoviral vector expressing HSVtk (Ad.TK) followed by GCV treatment resulted in doubling of the survival time of mice bearing A375 tumors and 20% long-term survival of mice with ME180 tumors. Treatment of tumors with Ad.TKRC without GCV resulted in a similar antitumor effect, confirming that the replicating vector has an oncolytic effect. When GCV was initiated 3 days after Ad.TKRC injection, survival of mice with each tumor type was greatly prolonged, with 60% of animals with ME180 tumors surviving for over 160 days. These results confirm that both the oncolysis caused by a replicating virus and suicide/prodrug gene therapy with HSVtk/GCV have potent antitumor effects. When combined, these two approaches are complementary resulting in a significantly improved treatment outcome. (+info)
MIA (melanoma inhibitory activity): a potential serum marker for rheumatoid arthritis.
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OBJECTIVE: MIA (melanoma inhibitory activity) is correlated with metastasis in patients with malignant melanoma. As MIA is not only produced by melanoma cells, but also by differentiated chondrocytes, we examined whether serum levels of MIA are correlated with inflammation and/or joint destruction in rheumatic diseases. METHODS: MIA serum concentrations of patients with different rheumatic diseases were examined and compared with healthy individuals and malignant melanoma patients. In addition, MIA concentrations were correlated to inflammatory parameters and joint destruction. RESULTS: Increased MIA serum concentrations were found only in patients with rheumatic diseases associated with joint destruction, such as rheumatoid arthritis (RA), osteoarthritis, HLA B27-associated oligoarthritis, and psoriatic arthritis. Of these rheumatic diseases, a significant increase in MIA serum concentrations was seen only in patients with RA, associated with rheumatoid factor (RF) positivity and joint destruction. CONCLUSIONS: In addition to RF, MIA might therefore be useful in the differential diagnosis of RA vs non-destructive rheumatic diseases, and the presence of elevated levels of MIA in serum very likely reflects joint destruction in RA. (+info)
Moles and melanomas--who's at risk, who knows, and who cares? A strategy to inform those at high risk.
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BACKGROUND: Malignant melanoma is uncommon but potentially fatal. Knowledge and attitudes play an important part in the early detection of this skin cancer. AIM: To assess knowledge, risk perception, and intended behaviour related to melanoma compared with actual risk status. To suggest measures to improve the primary and secondary prevention of melanoma in general practice for a high-risk group. METHOD: A prospective questionnaire survey was carried out on consecutive adults attending in 16 randomly selected group practices. Applying MacKie's personal risk factor chart for melanoma, the study assessed self-reported risk, knowledge of skin cancer--especially malignant melanoma--and self-reported preventive activity. RESULTS: A total of 3105 (69%) attenders completed the questionnaire. The responders showed greater concern for minor rather than major clinical signs in pre-existing moles. Young people and the professional classes were the least knowledgeable about skin cancer and exhibited the most risky behaviour in terms of sun exposure, failure to check their skin, and to seek medical advice about new or changing moles. The majority of an 8.7% high-risk group showed lack of awareness of their increased risk, and women in this group reported the highest desire for a suntan and the use of sunbeds. In addition to showing less concern than their low risk counterparts about moles growing in size, they were also reluctant to seek medical advice about new moles. CONCLUSION: Consideration should be given to targeting primary prevention and selective screening in general practice towards a high-risk group for malignant melanoma. Young people and the professional social class should receive particular attention. (+info)
Major histocompatibility complex class I restricted cytotoxic T cells specific for natural melanoma peptides recognize unidentified shared melanoma antigen(s).
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CTLs were generated in vitro from two healthy donors and one melanoma patient by stimulation of CD8+ T cells with autologous dendritic cells pulsed with natural melanoma peptides (NMPs), obtained by acid treatment of HLA-matched melanoma cells. CTLs showed MHC class I-restricted melanoma-specific cytolytic activity. Importantly, CTLs from the patient, induced with NMPs obtained from an allogeneic HLA-A-matched melanoma, killed the autologous tumor. COS-7 cells cotransfected with the cDNA of 13 melanoma antigens and the HLA-A1-restricting allele did not induce cytokines release from NMP-specific CTLs, suggesting that they recognize unidentified shared melanoma antigens and that they may be valuable for identification of new tumor antigens. These results strongly support the use of autologous and/or allogeneic NMP-pulsed dendritic cells as cancer vaccines in patients whose neoplasms do not express or have lost expression of known tumor antigens. (+info)