Riassunto analitico
Today, ovarian and colorectal cancers have the highest incidence and mortality in the world, after breast cancer: the disease is often diagnosed at an advanced stage and this leads to less effective therapy. Even if the chemotherapeutic drugs used (platinum derivatives, 5-FU) have an important cytotoxic effect, many cancers in advanced stages develop resistance to these drugs. For this reason, research is looking for new therapeutic strategies, in particular these drugs are being studied in combination with other methods that promote their entry into the cell. Electroporation (EP) is a physical method that uses high-frequency electrical pulses to create pores into which the drug can permeate. The combination of electroporation and chemotherapy drugs is called electrochemotherapy (ECT). The aim of my thesis work was to evaluate the effect of electrochemotherapy on the growth of both ovarian (A2780 and A2780/CP) and colorectal (HCT116) cancer cell lines using platinum derivatives (Cisplatin, Carboplatin and Oxaliplatin), as DNA alkylating agents, and human thymidylate synthase (hTS) inhibitors (5-FU, E7, E3). hTS is involved in the folate pathways, specifically in the de novo pyrimidine biosynthesis. This enzyme is an important target for anticancer agents, such as 5-FU and the novel dissociative inhibitors (E7, E3) synthesized in the Drug Discovery and Biotechnology lab of professor Maria Paola Costi. To this end, the activities carried out are as follows: 1) dose-effect curves for individual drugs on the three cell lines (A2780, A2780/CP and HCT116) without electroporation to determine the relative IC20 and IC50 concentrations; 2) ECT experiments with drugs at the IC20 and IC50 concentrations previously identified; 3) synergism quotient analysis to determine whether electroporation gives an advantage in terms of cytotoxicity. Results showed that platinum derivatives, with the exception of Oxaliplatin, have greater efficacy when combined with electroporation. 5-FU and the new dissociative TS inhibitors (E3 and E7) also take advantage of ECT because EP increases drug uptake into the cell. In conclusion, ECT appears to be a viable strategy to obviate the problem of resistance in ovarian and colorectal cancers, to deliver compounds inside cells overcoming uptake limits, especially for the low lipophilic compounds whose cytotoxic efficacy is hampered by the obstacle of biological membranes.
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