Riassunto analitico
Ovarian cancer is a malignant neoplasm of epithelial origin of the gynaecological system normally treated with cytoreductive surgery and chemotherapy. Chemotherapeutic agents have a low cytotoxicity due to the reduced uptake through the plasma membrane caused by their pharmacokinetics or by chemoresistance mechanisms of treated cells. Electroporation (EP) is a physical method used to increase permeability of cell membrane facilitating the influx of drugs into the tumor cells to have a higher cytotoxicity and be able to reduce the concentrations used. The combination of chemotherapeutic drugs and electroporation is called electrochemotherapy (ECT). Electrochemotherapy is used in clinics to treat patients with various types of cancer (e.g., melanoma, head-neck tumors, breast, liver, intestinal tract, brain cancer). Only two chemotherapeutics are currently used in clinics: bleomycin and cisplatin. My thesis work has the aim to establish a reliable in vitro protocol to efficiently test drugs and potential drugs candidates to be used in combination with EP for ECT purposes on ovarian cancer cells. The activity performed are the following: 1. identification of the electrical conditions that result in electroporation with minimal cell death due to electrical treatment; 2. Identified electrical conditions are then used in combination with anticancer agents to evaluate the enhancement in cell growth inhibition relative to treatment with drugs alone. Three platinum drugs were studied (Cisplatin, Carboplatin and Oxaliplatin) in addition to two investigational drugs, LC1343 and LC1336. These latest investigational drugs work as dissociative inhibitors of the Thymidylate Synthase enzyme, a well-known cancer drug target. Furthermore, to evaluate if electrochemotherapy can overcome multidrug resistance, a cell line resistant to cisplatin was chosen. The results achieved demonstrated that Cisplatin and Carboplatin, as shown in preclinical studies on other tumours, are effective in combination with EP, and results of this study confirmed their ECT efficacy also on ovarian cancer cells, overcoming the resistant mechanisms. Instead, the combination of Oxaliplatin with EP did not increase its cytotoxicity: this result can be explained by the high ability of the drug itself to reach its intracellular target. LC1343 and LC1336, in combination with electric pulses increased their cytotoxicity respectively of 1.6 times and 1.3 times relative to treatment with drugs alone. The results of this study indicate that ECT could be successfully extended to include other types of tumors such as ovarian cancer and that ECT could take advantage from the combination with different chemotherapeutic drugs other than bleomycin.
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