Activating adaptive cellular mechanisms of resistance following sublethal cytotoxic chemotherapy: Implications for diagnostic microdosing

As Phase 0 studies have proven to be reasonably predictive of therapeutic dose pharmacokinetics, the application of microdosing has expanded into metabolism, drug-drug interactions and now diagnostics. One potentially serious issue with this application of microdosing that has not been previously discussed is the possibility of activating cellular mechanisms of drug resistance. Here, we provide an overview of Phase 0 microdosing and drug resistance, with an emphasis on cisplatin resistance, followed by a discussion of the potential for inducing acquired resistance to platinum-based or other types of chemotherapy in cancer patients participating in Phase 0 diagnostic microdosing studies. A number of alternative approaches to diagnostic microdosing, such as the human tumor cloning assay and the use of peripheral blood mononuclear cells as a surrogate for measuring DNA adducts, are discussed that would avoid exposing cancer patients to low doses of first-line chemotherapy and the possible risk of triggering cellular mechanisms of acquired resistance. Until it has been established that diagnostic microdosing in cancer patients poses no risk of acquired drug resistance, such studies should be approached with caution.