Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
Replicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower... Show moreReplicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower replicative capacity of human fibroblasts from donors of higher chronological age, but these inverse relations have not been reported unequivocally. The relation between chronological age and fibroblast growth characteristics was assessed in nonagenarian subjects of the Leiden 85+ Study. A high remaining replicative capacity impressively showed that even in the very elderly a crucial number of cells with high mitotic capacity are left to give rise to fibroblast strains with the capacity for more than 100 population doublings. During the course of fibroblast growth in vitro, beta-galactosidase activity has been shown to be a reliable biomarker for replicative senescence. In myoblast cultures the relation between mixed cultures and clonal cultures was studied, showing marked heterogeneity between clonal cultures that all had a significantly lower replicative capacity when compared to mixed cultures, indicating heterogeneity of cells within one tissue compartment in their in vivo history. In a formal review on the replicative capacity of fibroblasts from patients suffering from accelerated ageing syndromes, age related diseases and donor age it was found that except for premature ageing syndromes, the replicative capacity of fibroblasts in vitro does not mirror key characteristics of human life histories. Show less
