Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (GW776C85) in primary and metastatic colorectal cancer

Heslin, Martin J.; Yan, Jieming; Weiss, Heidi L.; Shao, Lingning; Owens, J. Raymond; Lucas, Virginie; Diasio, Robert B.

doi:10.1007/s00280-003-0681-1

Cited by 10 publications

(7 citation statements)

References 11 publications

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“…Previous pharmacokinetic studies from our laboratory in a profoundly DPD-deficient patient demonstrated reduced 5-FU catabolism with prolonged elimination half-life compared with the "normal" population (26). Additional studies by our laboratory using eniluracil (a potent DPD inhibitor) showed similar results (27). Taken collectively, these data suggested that the reduced catabolism of 2-13 C-uracil in DPD-deficient individuals should result in a subsequent decline in 13 CO 2 levels in breath.…”

Section: Discussionsupporting

confidence: 63%

Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test

Mattison

Ezzeldin

Carpenter³

et al. 2004

Clinical Cancer Research

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121

110

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Purpose: Dihydropyrimidine dehydrogenase (DPD)-deficient cancer patients have been shown to develop severe toxicity after administration of 5-fluorouracil. Routine determination of DPD activity is limited by time-consuming and labor-intensive methods. The purpose of this study was to develop a simple and rapid 2-13 C-uracil breath test, which could be applied in most clinical settings to detect DPDdeficient cancer patients.Experimental Design: Fifty-eight individuals (50 "normal," 7 partially, and 1 profoundly DPD-deficient) ingested an aqueous solution of 2-13 C-uracil (6 mg/kg). 13 CO 2 levels were determined in exhaled breath at various time intervals up to 180 min using IR spectroscopy (UBiT-IR 300 ). DPD enzyme activity and DPYD genotype were determined by radioassay and denaturing high-performance liquid chromatography, respectively.Results: The mean (؎SE) C max , T max , ␦ over baseline values at 50 min (DOB 50 ) and cumulative percentage of 13 C dose recovered (PDR) for normal, partially, and profoundly DPD-deficient individuals were 186.4 ؎ 3.9, 117.1 ؎ 9.8, and 3.6 DOB; 52 ؎ 2, 100 ؎ 18.4, and 120 min; 174.1 ؎ 4.6, 89.6 ؎ 11.6, and 0.9 DOB 50 ; and 53.8 ؎ 1.0, 36.9 ؎ 2.4, and <1 PDR, respectively. The differences between the normal and DPD-deficient individuals were highly significant (all Ps <0.001).Conclusions: We demonstrated statistically significant differences in the 2-13 C-uracil breath test indices (C max , T max , DOB 50 , and PDR) among healthy and DPDdeficient individuals. These data suggest that a single time-point determination (50 min) could rapidly identify DPD-deficient individuals with a less costly and timeconsuming method that is applicable for most hospitals or physicians' offices.

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Section: Discussionsupporting

confidence: 63%

Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test

Mattison

Ezzeldin

Carpenter³

et al. 2004

Clinical Cancer Research

Self Cite

121

110

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“…Efficient inactivation of DPD by oral administration of eniluracil has been observed in primary and metastatic colorectal cancer. 341 However, eniluracil is currently withdrawn from further development because several studies showed that the combination of oral eniluracil and 5FU had lower activity compared to intravenous 5FU/LV treatment. 342…”

Section: A 5-fluorouracil (5-fu)mentioning

confidence: 99%

The dual role of thymidine phosphorylase in cancer development and chemotherapy

Bronckaers¹,

Gago²,

Balzarini³

et al. 2009

Medicinal Research Reviews

179

176

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Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.

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“…Because new DPD appears shortly after eniluracil has been eliminated, 15,16 it is important to administer an adequate dose of eniluracil that will also inactivate any DPD synthesized during the entire exposure to 5-FU. If variable amounts of DPD remain active, the regimen's highly predictable 5-FU pharmacokinetics and safety will be compromised.…”

Section: The Remedymentioning

confidence: 99%

A Possible Cause and Remedy for the Clinical Failure of 5-Fluorouracil Plus Eniluracil

Spector

Cao

2010

Clinical Colorectal Cancer

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Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (GW776C85) in primary and metastatic colorectal cancer

Cited by 10 publications

References 11 publications

Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test

Rapid Identification of Dihydropyrimidine Dehydrogenase Deficiency by Using a Novel 2-13C-Uracil Breath Test

The dual role of thymidine phosphorylase in cancer development and chemotherapy

A Possible Cause and Remedy for the Clinical Failure of 5-Fluorouracil Plus Eniluracil

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