Directly or indirectly, cancer will touch everyone's lives. There is no greater or more worthwhile challenge than the ongoing battle to develop and improve anti-cancer treatments, for everyone's sake.
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research report
University of Bradford
2003/4
School of Pharmacy
Head of Department: Professor B. Costall
Structure-activity studies on novel DNA affinic compounds incorporating oestrogen-receptor ligand, polyamine and antineoplastic moieties
Dr. S. Carrington, Prof. J. E. Brown, Ms. H. Mackay
Healthy breast tissue requires a constant supply of oestrogens for growth and maintenance. Consequently it has been shown that up to 65% of breast cancers in pre-menopausal women are also dependent on oestrogens to sustain growth. We aim to target oestrogen receptors in such tumour cells with drug conjugates to produce selective therapies.
We have begun investigating structure-activity relationships between compounds consisting of an oestrogenic ligand, a polyamine and a cytotoxic DNA-binding moiety. Such conjugates are designed to target, and exhibit selective cytotoxicity towards breast cancers. We have already shown that linking oestrone to doxorubicin can confer selective cytotoxicity towards cells expressing oestrogen receptors (ER). By including a polyamine we aim to increase cellular uptake via the polyamine transport mechanism and to demonstrate increased cytotoxicity by enhanced polyamine associated DNA-binding. Compounds are being synthesised by established methodologies and then assayed in three areas: (i) Preclinical evaluation by in vitro MTT assay utilising ER-positive and ER-negative cell lines. (ii) Mechanistic studies including thermodenaturation, spectrophotometric titrations, and topoisomerase assays to characterise DNA interactions. (iii) Analytical HPLC and microscopy studies to determine compound stability and fate in the cell. Together the data from these assays will inform the design of further compounds.
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