A Pharmacological Approach to Personalize the Use of Anti-Cancer Drugs

The individualization of anti-cancer therapy has been given much attention over the past decade. There has been a focus on differences between patients in tumor characteristics, but also the individualization of the given dose is extremely important. Many anti-cancer agents have a very narrow therapeutic window, which means that the range between drug concentrations at which severe toxicity is observed during treatment and the levels at which the drug has sub-therapeutic effects is small. As a result of these small therapeutic margins, the individual variability in toxicity during treatment and efficacy of treatment is large. The work described in this thesis provides a pharmacological approach contributing to the knowledge of factors influencing the metabolism and toxicity profiles of three anti-cancer agents known for their large inter-individual variation in pharmacokinetics and pharmacodynamics: the taxanes docetaxel and paclitaxel, and the anti-hormonal agent tamoxifen. Both environmental factors (i.e. smoking) as well as genetic factors (polymorphisms in genes coding for metabolizing enzymes and uptake/efflux transporters) were investigated in translational studies, including cell line experiments, mice experiments, and studies in patients with cancer. Finally, both an endogenous marker and exogenous marker were correlated with taxane and tamoxifen pharmacokinetics, respectively. Future studies should focus on further exploring factors that may influence systemic exposure of anti-cancer agents with a small therapeutic window. Ultimately, bringing these factors together in a predictive model that can be tested and validated in large cohorts of cancer patients should lead to more evidence-based dosing regimens for these drugs.

• View at Worldcat

Free Full Text ( Final Version , 12mb )