304 Platinum resistance as paradigm of preclinical and clinical conceptual differences

Abstract

Resistance to anticancer agents is the subject of intensive basic and applied research. Its definition is quantitative and expressed as n times the concentration of the agent in question, mostly in vitro. Schedule dependency, and concentration × time effects are seldom studied. No standards of normal sensitivity exist, since in most cases the resistance level is gauged against the parental line, seldom of human cancer origin. The medical oncologist perception of the resistance phenomenon is relative to both the quantitative aspects of antitumor response evaluation and qualitative respect to dynamics tumor progression. Clinical resistance definition is adhoc for every tumor type, and undergoes continuous evolution with new drugs and putative manipulations for its circumvention (modulation, dose, schedule). Resistance to platinum compounds has been studied through basic research and the main mechanisms have been elucidated. Only recently the relevance of the different mechanisms is being correlated to disease and natural history specific clinical settings. Non cross resistance between distinct platinum compound families has been perceived for over two decades, but its clinical potential was never implemented. Dose response and dose intensity delivery issues are also a long standing subject in Platinum efficacy assessment. The association of Cisplatin and Carboplatin, dose intensive schedules (weekly administration), the interaction with other agents, and the availability of Oxaliplatin, a non cross resistant DACH compound offer tools for the medical oncologist that will expand further the therapeutic role of Platinum compounds. Applied research preparing a solid rational for this horizon should be adapted to clinically relevant targets.