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Dihydropyrimidine dehydrogenase pharmacogenetics in patients with colorectal cancer
1Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, UK.
Abstract:
Individuals with a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) may experience severe life-threatening toxicity when treated with 5-fluorouracil (5-FU). As routine measurement of enzyme activity is not practical in many clinical centres, we have investigated the use of DNA mutation analysis to identify cancer patients with low enzyme levels. We have identified two new mutations at codons 534 and 543 in the DPD cDNA of a patient with low enzyme activity and screened the DNA from 75 colorectal cancer patients for these mutations and the previously reported splice site mutation (Vreken et al, 1996; Wei et al, 1996). In all cases, DPD enzyme activity was also measured. The splice site mutation was detected in a patient (1 out of 72) with low enzyme activity whereas mutations at codons 534 (2 out of 75) and 543 (11 out of 23) were not associated with low enzyme activity. These studies highlight the need to combine DPD genotype and phenotype analysis to identify mutations that result in reduced enzyme activity.
Insights
Dihydropyrimidine dehydrogenase (DPD) deficiency can cause severe toxicity with 5-fluorouracil (5-FU) chemotherapy. DNA mutation analysis combined with enzyme activity testing is crucial for identifying patients at risk.
Area of Science:
- Pharmacogenetics
- Clinical Chemistry
- Molecular Biology
Background:
- Dihydropyrimidine dehydrogenase (DPD) deficiency is a genetic condition.
- DPD deficiency leads to severe toxicity in patients treated with 5-fluorouracil (5-FU).
- Routine DPD enzyme activity measurement is not always feasible in clinical settings.
Purpose of the Study:
- To investigate DNA mutation analysis for identifying cancer patients with low DPD enzyme levels.
- To correlate specific DPD gene mutations with DPD enzyme activity.
- To improve the identification of patients at risk of 5-FU toxicity.
Main Methods:
- DNA mutation analysis of DPD cDNA.
- Identification of novel mutations at codons 534 and 543.
- Screening of 75 colorectal cancer patients for DPD mutations.
- Measurement of DPD enzyme activity in all patients.
Main Results:
- A previously reported splice site mutation was found in one patient with low DPD activity.
- Novel mutations at codons 534 and 543 were identified but not consistently associated with low DPD activity.
- The study identified a need for combined genotype and phenotype analysis.
Conclusions:
- DPD genotype analysis alone is insufficient to identify all patients with reduced enzyme activity.
- Combining DPD genetic testing with enzyme activity measurements is essential for accurate risk assessment.
- This approach can help prevent severe 5-FU toxicity in cancer patients.