Pharmacologic Basis for High-dose Chemotherapy

High-dose chemotherapy utilized to condition patients prior to a transplant was based on the idea of eradicating the tumor and creating space, then engraftment would occur. This was accomplished by applying an empiric combination of total body irradiation (TBI) and cyclophosphamide. Cyclophosphamide (CY) was used mostly for its immunosuppressive properties. This chapter reviews the cytotoxic agents that are most commonly used in pretransplant conditioning and some of the emerging molecular, pharmacokinetic, pharmacodynamic, and pharmacogenetic data that are of importance for the development of even more effective high-dose therapy. It examines some data for clinical dose limiting toxicities and their pharmacologic basis. Bifunctional DNA-alkylating agents are still a cornerstone in highdose chemotherapy, but they are increasingly complemented with NAs, (monoclonal) antibodies, and other agents with alternative modes of action and different metabolism to improve both treatment efficacy and patient safety.