Midtveisevaluering - Tormod K. Bjånes
Hovedinnhold
ABSTRAKT
PhD project “Gemcitabine exposure and uptake in pancreatic ductal adenocarcinoma”
Supervisors: Ass. Prof Bettina Riedel (main supervisor), Prof. Jan Schjøtt and Prof. Emmet Mc Cormack
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, with an average 5-year survival of 5 %. This dismal prognosis is due to a large proportion of patients being inoperable at the time of diagnosis, and that chemotherapeutics provide limited benefits.
An important factor which limits the effects of chemotherapeutics in PDAC is the dense desmoplastic and hypovascular stroma that is prominent in this disease. These features may disfavor diffusion of the drugs into the extracellular fluid surrounding the tumour cells, which might result in insufficient cellular drug concentrations.
The current project focuses on the pharmacokinetics of the chemotherapeutic drug gemcitabine in PDAC, and on interventions that may increase drug delivery to the cancer cells. We have developed and validated liquid chromatography tandem mass spectrometric methods (LC-MS/MS) to quantify concentrations of gemcitabine and metabolites extra- and intracellularly and demonstrated preanalytical stability of the substances ex vivo and in vitro. Further, we have studied basic aspects of gemcitabine uptake, metabolism and effects in an in vitro model of PDAC cells, and performed pharmacokinetic assessments in a clinical phase 1 study exploring treatment with gemcitabine combined with ultrasound and microbubbles (sonoporation[1]), as an effort to increase local drug delivery and hence tumor control.
Preliminary data indicate that the uptake of gemcitabine in PDAC cells in vitro is related to extracellular drug concentrations, duration of exposure and on inherent variations in cellular metabolic pathways for activation and inactivation of the drug. Further, we have shown that sonoporation induces increased cellular drug uptake in vitro, but that the inactivating pathway of gemcitabine might hamper the benefits. Further studies will focus on pharmacodynamic effects of gemcitabine combined with sonoporation, pharmacokinetic augmentation (f.ex. inhibition of the inactivating pathway) and on uptake of other drugs in PDAC cells.