[Increase of dose intensity by pharmacomodulation. General concepts and therapeutic applications]

There are two distinct levels where dose intensity can be increased by pharmacomodulation. The first level implies the inhibition of clearly identified resistance mechanisms. Among them, MDR type resistance is the most studied currently. MDR resistance is mediated by GP170, a cell membrane protein, which can be inhibited by several pharmacological agents like verapamil, ciclosporine and S 9788 which are currently being clinically investigated. The inhibition of DNA repair mechanisms is another approach and a representative example is the inhibition of O6-alkylguanine DNA alkyltransferase by O6-methylguanine or O6-benzylguanine. Modulation of detoxification pathways has also been considered, with for instance, the use of buthionine sulfoximide (BSO) to deplete intracellular glutathione levels. The second level for pharmacomodulation concerns pharmacological interferences with metabolic pathways controlling the activity of anticancer agents and particularly the antimetabolites like ara-C and 5-FU. The use of hydroxyurea or PALA in the case of 5-FU are good illustrations of pharmacomodulation via specific metabolic routes. Finally, the 5-FU-folinic acid combination could characterise a third level of pharmacomodulation where cytotoxic activity is optimised at the site of interaction between activated drug (5FdUMP) and target (thymidilate synthase).