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DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS.
Pak J Med Sci 2007; 23(6):832-839PJ

Abstract

OBJECTIVES:

5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome.

METHODOLOGY:

Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-(13)C uracil breath test (UraBT).

RESULTS:

Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2', 3', 5'-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients of 112.8; PDR of 49.4%) and borderline normal values revealed 1 to be DPD-deficient (DOB(50) of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among (DOB(50) DPD-deficient patients (28%).

CONCLUSIONS:

DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique.

Authors+Show Affiliations

Yale University School of Medicine, New Haven, CT Athens Medical School, Sotiria General Hospital, Athens, Greece.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18846242

Citation

Saif, M Wasif, et al. "DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) in GI MALIGNANCIES: EXPERIENCE of 4-YEARS." Pakistan Journal of Medical Sciences, vol. 23, no. 6, 2007, pp. 832-839.
Saif MW, Syrigos K, Mehra R, et al. DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS. Pak J Med Sci. 2007;23(6):832-839.
Saif, M. W., Syrigos, K., Mehra, R., Mattison, L. K., & Diasio, R. B. (2007). DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS. Pakistan Journal of Medical Sciences, 23(6), pp. 832-839.
Saif MW, et al. DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) in GI MALIGNANCIES: EXPERIENCE of 4-YEARS. Pak J Med Sci. 2007;23(6):832-839. PubMed PMID: 18846242.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS. AU - Saif,M Wasif, AU - Syrigos,Kostas, AU - Mehra,Ranee, AU - Mattison,Lori K, AU - Diasio,Robert B, PY - 2008/10/11/pubmed PY - 2008/10/11/medline PY - 2008/10/11/entrez SP - 832 EP - 839 JF - Pakistan journal of medical sciences JO - Pak J Med Sci VL - 23 IS - 6 N2 - OBJECTIVES: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. METHODOLOGY: Twenty-three patients were tested for DPD deficiency after excessive toxicities from 5-FU and/or capecitabine. DPD activity was evaluated by Peripheral Blood Mononuclear Cell (PBMC) radioassay, genotyping of DPYD gene by Denaturing High Performance Liquid Chromatography (DHPLC), or 2-(13)C uracil breath test (UraBT). RESULTS: Of 23 patients with excessive toxicities from 5-FU and/or capecitabine, 7 (30%) were DPD deficient with a median age of 66 years, M:F ratio = 1.3:1 and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). DPD activity ranged from 0.064 - 0.18nmol/min/mg. Three patients were treated with bolus 5-FU/LV, two with capecitabine, and two with high dose bolus 5-FU with 2', 3', 5'-tri-O-acetyluridine. Toxicities included mucositis (71%), diarrhea (43%), skin rash (43%), memory loss/altered mental status (43%), cytopenias (43%), nausea (29%), hypotension (14%), respiratory distress (14%) and acute renal failure (14%) Re-challenge with capecitabine in one patient after the Mayo regimen caused grade 3 hand-foot syndrome. Genotypic analysis of the DPYD gene in one patient with severe leucopenia demonstrated a heterozygous mutation (IVS14+1 G>A, DPYD). The UraBT in two patients of 112.8; PDR of 49.4%) and borderline normal values revealed 1 to be DPD-deficient (DOB(50) of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths among (DOB(50) DPD-deficient patients (28%). CONCLUSIONS: DPD deficiency was observed in several ethnicities. Akin to 5-FU, capecitabine can also lead to severe toxicities in DPD-deficient patients. Screening patients for DPD deficiency prior to administration of 5-FU or capecitabine using UraBT could potentially lower risk of toxicity. Future studies should validate this technique. SN - 1682-024X UR - https://www.unboundmedicine.com/medline/citation/18846242/DIHYDROPYRIMIDINE_DEHYDROGENASE_DEFICIENCY__DPD__IN_GI_MALIGNANCIES:_EXPERIENCE_OF_4_YEARS_ DB - PRIME DP - Unbound Medicine ER -