Chelators Controlling Metal Metabolism and Toxicity Pathways: Applications in Cancer Prevention,Diagnosis and Treatment

Chelating drugs and chelator metal complexes are used for the prevention, diagnosis and treatment of cancer. Cancer cells and normal cells require essential metal ions such as iron, copper and zinc for growth and proliferation. Chelators can target the metabolic pathways of cancer cells through the control of proteins involved in the regulation of these metals and also of other molecules involved in cell cycle control, angiogenesis and metastatic suppression. Other targets include the inhibition of specific proteins such as ribonucleotide reductase involved in DNA synthesis, the inhibition of free radical damage on DNA caused by iron and copper catalytic centers, the inhibition of microbial growth in immuno compromised cancer patients and the decorporation of radioactive and other toxic metals causing cancer. Chelating drugs and metal ions can affect the metabolism, efficacy and toxicity of anti-cancer drugs such as doxorubicin, mitozantrone, bleiomycin and hydroxyurea (HU). Although many experimental chelators have been shown to be effective as anti-cancer agents, only a few, e.g., dexrazoxane, deferoxamine (DFO) and triapine, have reached the stage of clinical testing or application. In many experimental models, deferiprone (L1) has been shown to be effective in cancer prevention and treatment, and in the inhibition of doxorubicin-induced cardiotoxicity. New anti-cancer drugs could be developed using chelators and chelator complexes with platinum and other metals, and also new protocols of combinations of chelators with known anti-cancer drugs.     

Lack of Fas (APO-1/CD95) gene structural alterations or transcript variant ratio changes in breast cancer

Fas (APO-1/CD95) is a transmembrane receptor protein involved in cell death signaling. Fas receptor and ligand are both expressed in breast cancer cells, however these cells are resistant to apoptosis. Fas gene mutations were detected in hematological and solid tumors, while overexpression of a soluble Fas isoform in serum was related to cancer stage and prognosis. In this work, direct sequencing of exons 6 and 9 of the Fas gene from 90 patients did not reveal any structural alterations. Moreover, no decrease was found in the ratio of the corresponding mRNA species of transmembrane versus soluble Fas isoforms in 31 breast cancer samples compared to 14 controls. Therefore, inhibition of Fas-mediated apoptosis may not be due to structural alterations in the critical exons 6 and 9 of the Fas gene or a shift of expression towards the soluble Fas isoform, but to other mechanisms operating in breast cancer cells.     

Dietary compliance and life style of children with coeliac disease

Background: Coeliac disease (CD) is common and requires a permanent strict gluten‐free diet (GFD). However, data concerning how the situation is experienced by children are limited. The present study aimed to investigate the compliance with a GFD and the impact of CD and GFD on the lifestyle of patients and their families, together with proposed recommendations for improvement of quality of life. Methods: Children with biopsy confirmed CD were recruited consecutively from the outpatient gastroenterology clinic. Participants were evaluated by a special questionnaire for compliance with the GFD, patients’ knowledge about CD, and the well‐being and lifestyle of children and their families. Comparisons between discrete variables were performed by a chi‐square test. Results: Seventy‐three children of median age 9.4 (interquartile range = 5–14.5) years were evaluated. Compliance to diet was reported by 58%. Reasons for noncompliance were: poor palatability (32%), dining outside home (17%), poor availability of products (11%), and asymptomatic disease diagnosed by screening (11%). The acceptance of the GFD was reported as good in 65%, whereas avoidance of travelling and restaurants was stated by 17% and 46% of families, respectively. Most families experienced difficulties detecting gluten from the food label. Proposed factors for improvement of quality of life were: better labelling of gluten‐containing ingredients (76%) and more gluten‐free (GF) foods in supermarkets (58%) and restaurants (42%). Conclusions: Children with CD have low compliance with the GFD. Better education about the disease, the availability of GF products, and appropriate food labelling could improve compliance and quality of life.     

Use of color texture in determining the nature of melanocytic skin lesions--a qualitative and quantitative approach

Melanocytic nevi are recognized as precursors of melanoma. Aiding in early recognition of melanoma, we estimated color texture parameters, fractal dimension and lacunarity of melanoma and other melanocytic nevi. Digital images of the lesions were processed. Graphic three-dimensional pseudoelevation images of the lesions and surrounding skin were produced to identify irregularities in color texture within the lesions. Estimation of lacunarity and fractal dimension followed in order to produce a numerical estimate of the coarseness of color texture. Clinicians readily perceive the resulting "geographical" images. Irregularity in the anaglyph, which might veil malignancy, is effortlessly identified through these images, and therefore an early excision of a suspect lesion is indicated.     

Melatonin and immunomodulation: connections and potential clinical applications

Melatonin is the main hormone secreted by the pineal gland in the human brain. It has a strong impact on the sleep-wake cycle and is considered a general modulator of the human circadian rhythm. Apart from these well-established properties, melatonin possesses immunomodulatory, antioxidative and antiinflammatory properties. The potential ability of this hormone to act synergistically with several cytokines by enhancing their antitumoral activity and dramatically decreasing their adverse effects has placed melatonin among the new and promising agents in cancer immunotherapy. The use of the neurohormone alone or in combination with cytokines and traditional chemotherapeutic drugs is currently under vigorous investigation. Experimental and clinical trials have already depicted some of the immunomodulatory and antitumor effects of melatonin, delineating the need for further research in this field.     

Assessment of megakaryopoiesis in children with acute lymphoblastic leukemia

The effect of the underlying disease and chemotherapy on megakaryopoiesis has not been extensively studied in children with acute lymphoblastic leukemia (ALL) during and at the end of therapy. Using a serum-free assay, we assessed the megakaryocyte (Mk) colony formation in vitro from bone marrow mononuclear cells of 25 children with ALL during chemotherapy and shortly after the cessation of it. Twelve children with solid tumors without bone marrow involvement and cord blood from 10 full-term normal vaginal deliveries were used as controls. A significant reduction in the number of Mk colonies was observed at diagnosis of ALL, and Mk colony formation remained lower than controls throughout the different phases of leukemia treatment. Our study suggests that defects in megakaryopoiesis of children with ALL in long-term remission may persist during chemotherapy and at least shortly after the end of it.