PhD defence M. (Mirjam) de With

Below is a brief summary of the dissertation:

This thesis describes studies aimed at reducing the risk of side effects during treatment with chemotherapy from the 'fluoropyrimidines' group (namely capecitabine and 5- fluorouracil) and the cytostatic irinotecan.Both fluoropyrimidines and irinotecan are classic forms of chemotherapy that, despite the emergence of, for example, immunotherapy, are still the cornerstone for treating colon, oesophageal and pancreatic cancer.

The first chemotherapy intended to treat cancer was developed at the beginning of the 20th century.Not much later, in 1957, 5-fluorouracil (5-FU) was first used in the clinic. Capecitabine was approved for use as a chemotherapeutic agent in 1998. Capecitabine is taken orally and then converted into 5-FU in 3 steps, which is then 80% converted into an inactive degradation product (called a metabolite; by means of the enzyme dihydropyrimidine dehydrogenase; DPD) and a small percentage into active metabolites. These active metabolites cause cell death of cancer cells, as well as damage to healthy body cells, which can cause side effects. Irinotecan was also first approved in 1998 and is mainly used to treat colon and pancreatic cancer. Irinotecan is converted into the active metabolite SN-38 by the enzyme carboxylesterases. SN-38 is then broken down again by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) into inactive metabolites. SN-38 thus causes cell death of the cancer cells, as well as possible side effects.

Both fluoropyrimidines and irinotecan are known for their good anti-cancer activity, but also for the high risk of side effects such as hand-foot syndrome (with capecitabine), febrile neutropenia (with irinotecan) and severe diarrhoea (with both).These side effects can cause having to stop treatment early, they affect quality of life and can even be fatal for the patient.Overexposure to chemotherapy (in the blood and healthy tissues) can contribute to the development of side effects.It is therefore always a matter of finding the right balance between efficacy (sufficient exposure to the drug to achieve the anti-cancer effect) and toxicity (not exceeding limits of exposure that may cause side effects).There are numerous factors that can influence chemotherapy exposure, such as physical factors (e.g. body weight, gender and age), environmental factors (e.g. lifestyle and co-medication) or genetic factors. The latter falls within the scope of this thesis and will therefore be further explained below.

(Pharmaco)genetic research investigates the effect of variation in genes on the absorption, distribution, metabolism and excretion of medication.For example, variants in genes coding for metabolising enzymes (proteins that ensure the breakdown of medication) can cause the enzymes to break down a medication less well than would happen if those variants were not present.The result is then (usually) increased exposure to the drug, which can result in the occurrence of (severe) side effects.This makes genetic factors important in the balance between efficacy and toxicity.This thesis describes studies in which genetic factors (variants in genes) are used and tested to improve safety during treatment with fluoropyrimidines and irinotecanThis thesis describes studies in which genetic factors (variants in genes) are used and tested to improve safety during treatment with fluoropyrimidines and irinotecan.