Abstract
Fluoropyrimidine-based chemotherapeutic drugs are the backbone of several treatment regimens for solid tumors due to their therapeutic efficacy. The active compound, 5-fluorouracil (5-FU), causes cumulative damage to the genetic material of cancer cells but is also associated with a narrow therapeutic window, leading to a high risk of severe adverse events. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, mitigates these toxicities by converting 85% of 5-FU into a non-toxic compound. DPD deficiency can lead to severe consequences due to high systemic exposure of 5-FU. Therefore, it is crucial to screen for pathogenic DPYD variants, that lead to a reduced DPD activity. The current genotyping strategy relies on series of extraction steps from whole blood, extended hands-on-time, lengthy analytical procedures and skilled personnel. This results in increased complexity and a turnaround time of two to four weeks, causing a significant treatment delay. To simplify and expedite DPYD genotyping, this project will employ a technology involving strand displacement, hybridization chain reaction and photoelectrochemical biosensing. This innovative strategy aims for reliable DPYD variant detection in whole blood samples and reduces analytical time-to-results, leading to a turnaround time of less than an hour. Accordingly, implementation of this strategy will minimize treatment delays, thereby improving patient outcomes, and lay the foundation for a point-of-care device.
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