Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502390
Title: Combination treatments in in vitro and in vivo models between molecules reverting epigenetic gene silencing and DNA-interacting anticancer drugs
Author: Sabatino, Maria Antonietta
Awarding Body: The Open University
Current Institution: Open University
Date of Award: 2008
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Abstract:
Epigenetic transcriptional gene silencing plays a fundamental role in cancer development and has been considered as a target for cancer therapy in the last few years, mainly due to its reversibility by small molecules. Among the several methylated genes investigated, glutathione-S-transferase CGST) PI, a protein belonging to cellular detoxification systems, has been shown to be extensively promoter-methylated in prostate cancer. My study therefore describes a new therapeutic approach against prostate cancer, based on the combination of demethylating agents and brostallicin, a DNA minor groove binding drug, which is activated in the cell by binding to glutathione, a reaction catalyzed by GST. Among the demethylating molecules tested on the prostatic cancer cell line LNCaP in in vitro combinations with brostallicin, zebularine was able to increase brostallicin activity with little toxicity compared to the other tested demethylating drugs. These in vitro results prompted the in vivo testing of zebularine with brostallicin on LNCaP cells transplanted in mice. Prolonged treatment with zebularine was able to significantly improve brostallicin antitumour activity compared to both drugs administrated as single agents. When GSTPI expression was investigated in treated samples versus untreated controls, no protein re-expression was found and this was related to the unchanged levels of GSTPI promoter methylation. In contrast, the demethylating effect of zebularine was clearly evident in the promoter of GSTMI gene, which is also silenced by methylation in LNCaP cells. GSTMI codes for a class of GST. enzymes that has recently been found to be more active on brostallicin than GSTPI. This indicates that the activation of brostallicin cytotoxicity in LNCaP cells by zebularine likely depends on enzymatic activation by GSTMI rather than GSTPI and strengthens the feasibility of this combination as a treatment for prostate cancer in the clinic, and as model for the therapy of other solid tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.502390  DOI: Not available
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