FROM CONVENTIONAL TO NOVEL Pt-BASED ANTINEOPLASTIC AGENTS: MECHANISTIC ASPECTS AND BIOLOGICAL EFFECTS

In the last decades the research on inorganic drugs in medicine has registered remarkable progresses with particular emphasis to the field of anticancer drugs. Cisplatin, carboplatin and oxaliplatin are today widely used in the treatment of different type of malignance and often represent, even in combination with other drugs, a first choice therapy. Since the serendipitous discover of cisplatin and despite the efforts, still nowadays, these drug are the most important research products in this field, although resistance to the treatments and heavy side effects, are important limiting factors to their use in clinical protocols. Thus, there is urgent need of new and more effective Pt-based anticancer drugs able to circumvent these problems. The development of new metal-based anticancer molecules is not easy, mostly because it is difficult to predict their effects in vivo, starting from the analysis of the cellular effects in vitro. Furthermore it should taken into account the extreme complexity of biological systems; even limiting our consideration only to studies at the cellular level, already, there are an outstanding number of factors and variables to be consider. In this frame we have carried out studies on cell-free systems as well as cellular studies, characterising the reactivity and the cellular effects of cisplatin and a series of its analogues to shed light on analogies and differences between these drugs. Interestingly, it has been extensively characterised their interaction with model proteins. Despite today it is recognised that formation of Pt-protein adducts, is of central importance in relation to overall pharmacological and toxicological impact of cisplatin and its analogues, yet, the structural information concerning platination of protein, and the characterization of the resulting adducts, is limited. Thus the studies summarising in this thesis aimed to: i) gather information on mechanistic aspects correlated with the mode of action of Pt-based anticancer compounds that, to date, remains in part unclear; ii) compare, at different level, the behaviour of conventional platinum anticancer drugs with experimental complexes in order to find differences that may be significant in terms of pharmacological effect in vivo, iii) evaluate or re-evaluate comparatively the anticancer properties of selected cisplatin analogues. All these issues are addressed within this work, where the comparative characterization of protein binding for conventional platinum-based anticancer drugs is reported (chapter 3) as well as the reappraisal of old cisplatin analogues, overlooked so far as anticancer agents, studied in comparison with clinical used Pt compounds (chapter 4 and 5). Preliminary in vivo studies are also described (chapter 6).