Title

 

Authors

M. Del Re¹, F. Loupakis², A. Michelucci³, A. Di Paolo¹, A. Falcone², P. Simi³, G. Bocci¹, M. Cantore⁴, R. Bordonaro⁵, A. Di Leo⁶, C. Barbara⁷, F. Cappuzzo⁷, F. De Braud⁸, R. Danesi¹

1 Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa;
2 Div. of Oncology, Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa;
3 Cytogenetics and Molecular Genetics Unit, University Hospital, Pisa;
4 Div. of Oncology, AUSL1, Massa Carrara;
5 Div. of Oncology, Dept. of Surgical Sciences, University of Catania;
6 "Sandro Pitigliani" Medical Oncology Unit, Dept. of Oncology, Hospital of Prato, Istituto Toscano Tumori, Prato;
7 Div. of Oncology, USL 6, Livorno;
8 Clinical Pharmacology and New Drugs Development Div., European Institute of Oncology, Milan

 

Abstract

Background: 5-FU and prodrugs are associated with frequent gastrointestinal and hematologic toxicities which may be severe and, in sporadic cases, lethal. 5‐FU undergoes complex catabolic biotransformation, the deficiency of which may be a reason for treatment discontinuation (Boige V, et al., 2010) . The rate-limiting enzyme of drug detoxyfication is dihydropyrimidine dehydrogenase (DPD), which displays a substantial variability of activity in the overall population (Del Re M, et al., 2010). More than 30 single nucleotide polymorphisms (SNPs) have been identified thus far within DPD, the majority of these variants having no functional consequences on enzyme activity. Thuse far, the most common method for the evaluation of DPD activity is the measurement of uracil/dihydrouracil ratio in plasma (Kristensen MH, et al., 2010). However, a systematic analysis of the usefulness of pharmacogenetic screening in patients with toxicity is lacking. Aim: To identify genetic variants of DPD associated with enzyme deficiency to screen subjects before or after drug administration and to develop a clinical algorythm for prevention of potentially lethal fluoropyrimidine-related toxicity. Methods: This exploratory pharmacogenetic study enrolled 200 patients with breast, colorectal or head and neck cancers treated with standard fluoropyrimidine-based regimens and suffering from grade ≥2 gastrointestinal and hematological toxicity. Blood samples for DNA analysis were collected and used to screen patients for DPD SNPs by PCR and automatic sequencing of the entire coding region of the DPD gene. Results: Seven polymorphisms were strongly associated to 5-FU related toxicity including 496A>G, 1601G>A, 1627A>G, 1896T>C, IVS14+1G>A, 2194G>A, and 2846A>T. The frequency of genotypes is reported in table I. A total of 87% patients with toxicity were found to have at least one genetic variant associated with enzyme deficiency. Conclusion: The present study demonstrate that genetic screening of DPD variants is clinically feasible and may help the clinician in preventing severe fluoropyrimidine-associated toxicity or adjust the drug dose based on the DPD polymorphism detected.

Table I. DPD polymorphisms detected in patients with fluoropyrimidine-associated toxicity.

Variant	Heterozygous	Homozygous
496A>G	AG 20.2%	GG 0.8%
1602G>A	GA 8.5%	AA 0%
1627A>G	AG 28%	GG 3.35%
1896T>C	TC 2.5%	CC 0%
IVS14+1G>A	GA 3.4%	AA 0.8%
2194G>A	GA 15.25%	AA 3.4%
2846A>T	AT 0.84%	TT 0%

Boige V, et al. J Clin Oncol 2010;15:2556-64
Del Re M, et al., EPMA J 2010;1:495–502
Kristensen MH, et al. J Int Med Res 2010;4:1313-23