Kurzfassung

This multicentric, non-interventional, cross-sectional diagnostic study aims to establish an
innovative, cost-saving gene chip-array tool to predict adverse reaction of chemotherapy
applied to patients with breast cancer and colorectal carcinoma (CRC), respectively. The
study concentrates on examining the genotypes of the most important xenobiotic
metabolising enzymes; the diagnoses gained with the novel method will be validated with
Gold standard molecular methods.
Individual phenotypes of...This multicentric, non-interventional, cross-sectional diagnostic study aims to establish an
innovative, cost-saving gene chip-array tool to predict adverse reaction of chemotherapy
applied to patients with breast cancer and colorectal carcinoma (CRC), respectively. The
study concentrates on examining the genotypes of the most important xenobiotic
metabolising enzymes; the diagnoses gained with the novel method will be validated with
Gold standard molecular methods.
Individual phenotypes of xenobiotic metabolising enzymes can be related to ineffective drug
therapies and severe adverse drug reactions, eventually even causing deadly outcomes of
chemotherapies.
The primary objective of this prospective diagnostic study is to determine the allele
frequencies of the most numerous variations in the pivotal enzymes Dihydropyrimidin-
Dehydrogenase (DPD), Thymidylate synthase (TYMS) and Cytochrome P450 2D6
(CYP2D6). To attain this goal, two representative German cohorts will be examined.
Second objectives are
i) the conduct of a case control study (retrospective chart review) investigating the
association of relevant alleles of the investigated genes with adverse drug reactions -
characterised by WHO toxicity grades - in breast cancer and CRC patients receiving 5-
Fluorouracil (5-FU) based chemotherapy
ii) a prospective allele frequency study to shed light on the prevalence of less numerous
mutations in the xenobiotic metabolising enzymes with yet scarcely known clinical relevance.
One example should illustrate the vital importance of our study target: the investigated
enzyme DPD is the rate-limiting enzyme in the metabolism of the nucleic acids compounds
such as uracil. Thus, DPD degrades the antineoplastic drug 5-FU or related prodrugs. 5-FU
is frequently used in oncologic chemotherapy. The pharmacogenetic syndrome of DPD
deficiency is related to several variations in this gene leading to susceptibility to severe
toxicity symptoms during 5-FU-based chemotherapy. The diagnostic tool proposed can
effortlessly be implemented in molecular biology laboratories and will allow for a rapid and
affordable routine chip-based scan for predisposing mutations in all involved xenobiotic
metabolising enzymes. Detection of a relevant predisposing gene alteration will therefore
spare the respective patient a severely toxic or even lethal oncologic chemotherapy.

» weiterlesen» einklappen