The cladribine conundrum: deciphering the drug's mechanism of action.

Understanding fully the mechanism(s) of action of current and novel anticancer drugs is essential to optimize treatment regimens for oncology patients, to improve or extend drug efficacy and reduce patient side effects. Nucleoside analogues, either alone or in combination with additional therapeutic agents, are an essential part of first-line and salvage regimens directed against neoplastic diseases. However, many mechanistic studies on this class of drugs have been carried out in vitro or ex vivo at drug concentrations that are orders of magnitude higher than levels achieved in vivo. In this paper, we focus on the anti-leukemic drug and nucleoside analogue, cladribine (2-chloro-2'-deoxyadenosine), to illustrate the difficulty in interpreting the significance of in vitro results obtained using drug concentrations that would be markedly deleterious to patients. We review numerous research reports that have been conducted at pharmacologically achievable drug levels compared to those using toxic concentrations and contrast the respective results. We propose that cellular responses to supra-pharmacological drug concentrations occur via distinctly different mechanisms and signaling pathways compared to the much lower plasma concentrations achieved with clinically relevant doses, and thus may not provide appropriate insights into a drug's mechanism of action.