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- Mårs, UllaUppsala universitet,Institutionen för farmaceutisk biovetenskap (författare)
Melanogenesis as the basis for melanoma targeting
- BokEngelska1998
Förlag, utgivningsår, omfång ...
- Uppsala :Acta Universitatis Upsaliensis,1998
- 48 s.
- printrdacarrier
Nummerbeteckningar
- LIBRIS-ID:oai:DiVA.org:uu-893
- ISBN:9155442463
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-893URI
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- Språk:engelska
- Sammanfattning på:engelska
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Klassifikation
Serie
- Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,0282-7484 ;188
Anmärkningar
- The incidence of malignant melanoma has increased rapidly during the last decades, and the prognosis for disseminated melanoma is poor. The melanoma cells produce melanin, and therefore the melanogenesis may serve as a target for treatment of melanotic melanoma; thioureyelenes such as thiourea and 2-thiouracil, e.g., are known to be incorporated into melanin solely during its synthesis.By in vitro screening, using spectrophotometry, inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and HPLC, 22 substances, mainly thioureylenes, were studied in order to find candidates suitable for melanoma targeting, and to investigate the mechanisms of the incorporation into melanin.The results suggest that the incorporation occurs by binding to intermediates of the melanin synthetic pathway, i.e. dopaquinone and indolequinones. Substances that most effectively suppressed the early part of the synthetic pathway (dopachrome formation) were found also to be inhibitors of the essential enzyme tyrosinase. Mercaptobenzothiazole (MBT) showed the highest incorporation in the early part of the synthesis, whereas dithiouracil interacted with the later part of the synthesis. It was found that thiourea is incorporated into melanin by covalent binding to dopaquinone in 6-position via the sulfur ligand. Incorporation by binding to indolequinones could not be demonstrated.Both thiourea and MBT were accumulated and retained in melanotic melanoma transplanted to mice (shown by whole-body autoradiography) although MBT is a strong tyrosinase inhibitor. Incorporation of thiourea changed the properties of the melanin, such as the solubility and the colour, to a more pheomelanin-like pigment. The incorporation of thiourea may affect the protective role of melanin in the body. The binding to pheomelanin was found to be lower than the binding to eumelanin, though a high pheomelanin-related uptake of chloroquine was seen in the skin of yellow mice in vivo. The binding to thiourea-melanin was even lower. This indicates that the toxicological implications of the binding are applicable to persons with a high content of pheomelanin in the skin and hair.The thioureylenes may also be used as markers of the effects of radiation therapy of melanotic melanoma, since a changed uptake was seen in the tumours after irradiation.
Ämnesord och genrebeteckningar
- MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
- MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
- Pharmaceutical biosciences
- Farmaceutisk biovetenskap
- Biopharmacy
- Biofarmaci
- Toxicology
- toxikologi
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- Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)
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