Meccanismi d'azione di farmaci antitumorali in uso e in sperimentazione: attività a livello di topoisomerasi e telomerasi

The mechanism of action of antitumor drugs, both used in clinical practice and investigated for preclinical development, has been studied. The first part of this thesis focused on the interactions between anticancer drugs currently used for treatment of solid malignancies. The study was aimed at optimizing drug combination and administration protocols, by analyzing the rational basis for their interaction both in vivo and in vitro. In particular, the effect of the interaction between alkylating agents, antimetabolites and antitopoisomerasic drugs on DNA topoisomerase expression was studied, based on the observation that topological enzymes are essential enzymes involved in most of DNA repair/replication processes. Indeed, the current study has been able to show that both antimetabolites and alkylating agents affect topoisomerases expression, and that higher cytotoxic effects are obtained when the topoisomerase poison is administered (at high doses) before the alkylating or antimetabolite drugs (at doses lower than their IC50). In the second part, new synthetic quinone methide derivates have been studied. These display alkylating properties upon selective and controlled bioactivation. The aim of this thesis was to define the tested compound mechanism of action and intracellular molecular targets, for potential development of telomerase-targeted anticancer drugs. Some of these innovative compounds have demonstrated to selectively recognize and alkylate telomeric sequences in their folded G-quadruplex conformation. Compounds presenting the naphtho diimidic nucleus and conformationally free reactive aromatic arms were the best stabilizers and binders of the G-quadruplex folded sequence. Moreover, preliminary studies highlighted an antiviral activity toward HSV-1, not directly dependent on the compound covalent reactivity.