An in vitro investigation of the anti-tumour efficacy of novel porphyrin-endoperoxide hybrids and naphthalimide-endoperoxide hybrids: identifying modality, maximising efficacy and tumour cell selectivity
Supervisor: Dr. James E. Murphy
Funding Body: Irish Research Council
Current cancer treatment typically involves chemotherapy and radiotherapy which are often limited by toxic side effects and multidrug resistance. The search for superior cancer treatment continues. Drug hybrids are an emerging class of chemotherapeutics where two active drugs are linked permanently with no cleavage of the bond. A significant advantage for the hybrid approach is the ability to overcome development of resistance to treatment by employing a dual mode of action. Excellent progress has been made in hybrid drug therapy in the past decade in treatment of a diverse range of diseases including anticancer, transdermal and neurodegenerative disorders. The current in vitro study evaluates a library of drug hybrids containing a selectively toxic endoperoxide linked to either a DNA targeting naphthalimide or a light activated porphyrin on both tumour and non-tumour cells.
The majority of novel compound analysis in vitro continues to be performed in an oxygen rich environment typical of atmospheric oxygen which is 20-21% (v/v) (159.6 mm Hg). This is far removed from the normoxic levels experienced by normal cells in vivo (3-5% (v/v) O2) or indeed from the hypoxic environment typical of a tumour mass (0-4% (v/v) O2). A novel aspect of the current research project involves regulation of oxygen environment to mimic in vivo conditions; cancer cell lines are analysed in typically hypoxic conditions (1% (v/v) O2) and non-tumour cells are analysed in typically normoxic conditions (4% (v/v) O2). A novel impedance based cell assay was used to measure cell toxicity in real time for dynamic biological evaluation of antitumour hybrids. To corroborate real time data, cell survival analysis was performed at selected time points following drug exposure. Data generated thus far has highlighted drug hybrids with anticancer activity in MCF-7 (breast cancer), HL60 (leukaemia) and PC-3 (prostate cancer) cell lines. Some drug hybrids were less potent in PNT1A (prostate non-tumour) cells when compared to PC-3 cells suggesting selective toxicity in cancer cells. The remainder of research project will focus on determining modality of best performing hybrids by analysing gene expression, oxidative stress and DNA damage.