Fluorouracil Toxicity and DPYD

Fluorouracil Toxicity and DPYD

No Results

No Results

processing….

5-Fluorouracil (5FU) is a fluorinated pyrimidine analogue commonly used in combination chemotherapy regimens for patients with breast, colorectal, lung, and other malignancies. Dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene, is the rate-limiting step in pyrimidine catabolism and deactivates more than 80% of standard doses of 5FU and the oral 5FU prodrug capecitabine.

True deficiency of DPD affects approximately 5% of the overall population. In these patients, the lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity. [1] In addition, 3% to 5% of the population has a partial DPD deficiency due to sequence variations in DPYD gene, which potentially limits their ability to fully metabolize the drug, thereby resulting in toxicity. [2, 3, 4, 5]

The IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (known as DPYD*2A) is the most well known variant resulting in partial DPD deficiency and 5FU toxicity. [1] Other recognized variants associated with toxicity include 496A>G in exon 6; 2846A>T in exon 22; [6, 7] and T1679G (DPYD*13) in exon 13, [8] although multiple other mutations have been detected in individual families and via full gene sequences.

Patients with DPD deficiency who are treated with 5FU or capecitabine are at significantly increased risk of developing severe (grade III/IV) and potentially fatal neutropenia, mucositis, diarrhea. [2, 6, 7, 9, 10] As noted in their respective product labels, both 5FU and capecitabine are therefore contraindicated in patients with known DPD deficiency.

By contrast, the clinical effects of DPYD variants and partial DPD deficiency are unclear. Different series have demonstrated increased toxicity to varying degrees, [6, 7] but mutations in DPYD have, for the most part, been unable to account for the magnitude of toxicity seen in the general population. Some groups have begun to evaluate the contribution of mutations in other candidate genes, [7] but the effects of these and other genetic and nongenetic factors will remain unknown until there is clear elucidation of all of the pathways involved in 5FU/capecitabine metabolism. [11]

Based on what is known to date about the role of DPD in 5FU/capecitabine metabolism, patients with known DPD deficiency and/or a family history of known mutations should avoid therapy with 5FU/capecitabine. [12] For the general population, because true DPD deficiency is rare and because the clinical implications of partial deficiency are still unclear, screening for mutations prior to initiating therapy is not warranted. [2, 11] In addition, even if a partial deficiency is detected, there are no guidelines on how to tailor therapy to minimize toxicity, so the clinical utility of testing for DPYD variants remains unclear. [13, 14, 15]

Until such time that guidelines are available, patients with known or suspected partial DPD deficiency who might be at greater risk for fluorouracil toxicity can be managed per the dose modification guidelines outlined in the capecitabine product label. In this rare situation, alternative non-5FU containing treatment regimens (if available) may also be considered.

In December 2015, the FDA approved uridine triacetate (Vistogard), a pyrimidine analog, for emergency treatment following a fluorouracil or capecitabine overdose in patients with early-onset, severe or life-threatening toxicity affecting the heart or central nervous system, as well as after early onset, unusually severe adverse reactions (GI toxicity and/or neutropenia) within 96 hours after fluorouracil or capecitabine administration. Following oral administration, uridine triacetate is deacetylated by nonspecific esterases, yielding uridine in the circulation, which competitively inhibits cell damage and cell death caused by fluorouracil. In 2 trials, of those who were treated with uridine triacetate for overdose, 97% were still alive at 30 days. Of those treated with uridine triacetate for early-onset, severe or life-threatening toxicity, 89% were alive at 30 days. [16]

Enzymatic activity in patients with suspected DPD deficiency can be determined via RNA extracted from peripheral blood mononuclear cells and measurement of DPD mRNA copy number. High-throughput genetic analysis using denaturing high performance liquid chromatography (DHPLC) can be used if the patient is severely neutropenic. [17]

Testing for DPD deficiency and the IVS14+1G>A DPYD variant (DPYD*2A) is available; testing for other variants is not currently available.

The following companies currently offer testing for DPYD mutations:

EntroGen (http://www.entrogen.com)

Myriad (http://www.myriadtests.com)

LabCorp (http://www.labcorp.com)

Molecular Diagnostics Laboratories (http://www.mdl-labs.com)

Lee A, Ezzeldin H, Fourie J, Diasio R. Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy. Clin Adv Hematol Oncol. 2004 Aug. 2(8):527-32. [Medline].

Gross E, Busse B, Riemenschneider M, Neubauer S, Seck K, Klein HG, et al. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS One. 2008. 3(12):e4003. [Medline]. [Full Text].

Amstutz U, Froehlich TK, Largiadèr CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011 Sep. 12(9):1321-36. [Medline].

Kim SR, Park CH, Park S, Park JO, Lee J, Lee SY. Genetic polymorphisms associated with 5-Fluorouracil-induced neurotoxicity. Chemotherapy. 2010. 56(4):313-7. [Medline].

Rumiato E, Boldrin E, Amadori A, Saggioro D. DMET™ (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol. 2013 Aug. 72(2):483-8. [Medline].

van Kuilenburg AB, Haasjes J, Richel DJ, et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res. 2000. 4705-4712.

Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008 May 1. 26(13):2131-8. [Medline].

Johnson MR, Wang K, Diasio RB. Profound dihydropyrimidine dehydrogenase deficiency resulting from a novel compound heterozygote genotype. Clin Cancer Res. 2002 Mar. 8(3):768-74. [Medline].

Diasio RB, Johnson MR. Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res. 1999 Oct. 5(10):2672-3. [Medline].

Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res. 2011 May 15. 17(10):3455-68. [Medline].

Ezzeldin HH, Diasio RB. Predicting fluorouracil toxicity: can we finally do it?. J Clin Oncol. 2008 May 1. 26(13):2080-2. [Medline].

Saif MW. Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian and non-Caucasian patients with 5-FU- and capecitabine-related toxicity using full sequencing of DPYD. Cancer Genomics Proteomics. 2013 Mar-Apr. 10(2):89-92. [Medline].

Jennings BA, Loke YK, Skinner J, Keane M, Chu GS, Turner R, et al. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. PLoS One. 2013 Oct 22. 8(10):e78053. [Medline]. [Full Text].

Offer SM, Lee AM, Mattison LK, Fossum C, Wegner NJ, Diasio RB. A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity. Clin Pharmacol Ther. 2013 Jul. 94(1):158-66. [Medline]. [Full Text].

Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer. 2013 Jun 25. 108(12):2505-15. [Medline]. [Full Text].

Vistogard (uridine triacetate) [package insert]. Gaithersburg, MD: Wellstat Therapeutics. December, 2015. Available at [Full Text].

Saif MW, Ezzeldin H, Vance K, Sellers S, Diasio RB. DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol. 2007 Sep. 60(4):503-7. [Medline].

Fazia Mir, MD Fellow, Department of Gastroenterology, University of Missouri-Columbia School of Medicine

Fazia Mir, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Shamudheen Rafiyath, MD Hematologist/Oncologist, Arizona Oncology

Shamudheen Rafiyath, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Maurie Markman, MD Senior Vice President for Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America

Maurie Markman, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, and American Society of Hematology

Disclosure: Genentech Consulting fee Consulting; Cellgene Consulting fee Consulting; Hana Pharmaceuticals Consulting fee Consulting; Boehringer Ingelheim Consulting fee Consulting; Morphotech Consulting fee Consulting; Amgen Consulting fee Consulting

Fluorouracil Toxicity and DPYD

Research & References of Fluorouracil Toxicity and DPYD|A&C Accounting And Tax Services
Source

134 Thoughts to “Fluorouracil Toxicity and DPYD”

  1. coupon for cialis

    cialis for sale

  2. over the counter erectile dysfunction pills

    best ed pills

  3. erection pills online

    best erection pills

  4. walmart pharmacy

    best online pharmacy

  5. online casino real money usa

    best online casinos that payout

  6. viagra prescription

    viagra prescription

  7. penny slot machines

    Cream on the Internet Casino sites by brimming reward syreeta online casino poker real gambling sites download virtual graphics card for games aloof golden parachute for contemporary contestant

  8. fantasy football betting

    Favorite accessible Casino sites along crowded ice erika gaming gambling sports betting draftkings play blackjack online for real money us unique perk for strange participant

  9. tropicana online casino phone number

    Pick installed Casino websites alongside oversize goody Best Online Casinos 2020 san manuel casino hotel popular casino games chosen additional compensation for unique jock

  10. Google

    Always a massive fan of linking to bloggers that I appreciate but don’t get a good deal of link really like from.

  11. ثقة

    […]Here are several of the web-sites we advise for our visitors[…]

  12. حلوه خيال

    […]Here is an excellent Weblog You might Come across Exciting that we Encourage You[…]

  13. Amsterdam escorts

    […]Sites of interest we’ve a link to[…]

  14. Kratom near me

    […]usually posts some pretty fascinating stuff like this. If you’re new to this site[…]

  15. online casino games real money

    casino game

  16. https://royalcbd.com/category/local-guides/

    […]very couple of sites that take place to become comprehensive below, from our point of view are undoubtedly properly really worth checking out[…]

  17. https://royalcbd.com/category/knowledge/

    […]usually posts some very fascinating stuff like this. If you’re new to this site[…]

  18. terpenes

    […]Sites of interest we’ve a link to[…]

  19. RoyalCBD.com

    […]below you will uncover the link to some internet sites that we think you’ll want to visit[…]

  20. RoyalCBD

    […]Wonderful story, reckoned we could combine a few unrelated information, nevertheless actually worth taking a look, whoa did one particular find out about Mid East has got extra problerms too […]

  21. cbd oil cost

    […]check below, are some absolutely unrelated web sites to ours, however, they’re most trustworthy sources that we use[…]

  22. RoyalCBD.com

    […]always a big fan of linking to bloggers that I adore but really don’t get a good deal of link like from[…]

  23. does cbd get you high

    […]check below, are some absolutely unrelated sites to ours, on the other hand, they’re most trustworthy sources that we use[…]

  24. https://royalcbd.com/can-you-overdose-on-cbd/

    […]very few internet sites that come about to be detailed beneath, from our point of view are undoubtedly properly really worth checking out[…]

  25. Royal CBD

    […]Here are some of the websites we recommend for our visitors[…]

  26. cbg cbda cbn cbc cbdv

    […]although internet websites we backlink to beneath are considerably not related to ours, we feel they are basically worth a go through, so have a look[…]

  27. https://royalcbd.com/cbd-oil-without-thc/

    […]usually posts some pretty fascinating stuff like this. If you are new to this site[…]

  28. Royal CBD

    […]Here is a superb Weblog You might Come across Exciting that we Encourage You[…]

  29. https://royalcbd.com/wisconsin/

    […]check below, are some completely unrelated internet sites to ours, on the other hand, they are most trustworthy sources that we use[…]

  30. RoyalCBD

    […]that would be the end of this report. Here you’ll find some web sites that we consider you will value, just click the hyperlinks over[…]

  31. RoyalCBD

    […]please go to the websites we comply with, including this one, because it represents our picks in the web[…]

  32. https://royalcbd.com/virginia/

    […]the time to study or go to the content material or web-sites we have linked to beneath the[…]

  33. https://royalcbd.com/vermont/

    […]although web sites we backlink to beneath are considerably not related to ours, we really feel they’re really worth a go via, so possess a look[…]

  34. washington state

    […]although sites we backlink to below are considerably not connected to ours, we really feel they may be in fact really worth a go as a result of, so possess a look[…]

  35. cbd oil utah

    […]always a huge fan of linking to bloggers that I adore but really don’t get a whole lot of link love from[…]

  36. cbd north dakota

    […]here are some links to sites that we link to since we feel they are really worth visiting[…]

  37. tennessee cbd

    […]we like to honor numerous other internet web-sites around the internet, even when they aren’t linked to us, by linking to them. Below are some webpages worth checking out[…]

  38. https://royalcbd.com/texas/

    […]Wonderful story, reckoned we could combine a handful of unrelated information, nevertheless really really worth taking a look, whoa did one particular master about Mid East has got far more problerms at the same time […]

  39. https://royalcbd.com/ohio/

    […]Here is a great Weblog You might Find Interesting that we Encourage You[…]

  40. cbd oil oregon

    […]very couple of web sites that occur to become detailed below, from our point of view are undoubtedly properly worth checking out[…]

  41. https://royalcbd.com/rhode-island/

    […]that will be the end of this write-up. Right here you’ll come across some websites that we believe you will value, just click the hyperlinks over[…]

  42. is cbd legal in new mexico

    […]just beneath, are many totally not connected websites to ours, nonetheless, they are certainly really worth going over[…]

  43. https://royalcbd.com/new-jersey/

    […]check below, are some totally unrelated internet websites to ours, on the other hand, they may be most trustworthy sources that we use[…]

  44. RoyalCBD

    […]very few web sites that come about to become detailed below, from our point of view are undoubtedly effectively worth checking out[…]

  45. nevada

    […]check below, are some absolutely unrelated websites to ours, nevertheless, they are most trustworthy sources that we use[…]

  46. montana

    […]below you will obtain the link to some internet sites that we believe you should visit[…]

  47. RoyalCBD

    […]check below, are some absolutely unrelated websites to ours, even so, they’re most trustworthy sources that we use[…]

  48. https://royalcbd.com/mississippi/

    […]below you’ll obtain the link to some sites that we assume it is best to visit[…]

  49. https://royalcbd.com/michigan/

    […]Here is a good Blog You may Discover Interesting that we Encourage You[…]

  50. cbd oil minnesota

    […]here are some links to web pages that we link to for the reason that we assume they may be worth visiting[…]

  51. https://royalcbd.com/maryland/

    […]one of our visitors lately encouraged the following website[…]

  52. is cbd legal in kentucky

    […]very couple of internet websites that transpire to become detailed below, from our point of view are undoubtedly very well really worth checking out[…]

  53. cbd oil illinois

    […]please pay a visit to the web-sites we stick to, including this one particular, because it represents our picks from the web[…]

  54. cbd oil iowa

    […]Wonderful story, reckoned we could combine a handful of unrelated data, nonetheless seriously really worth taking a search, whoa did one particular understand about Mid East has got a lot more problerms too […]

  55. cbd georgia

    […]the time to read or stop by the subject material or web sites we have linked to beneath the[…]

  56. casino world

    online slots real money

  57. cbd oil connecticut

    […]we like to honor many other online web sites around the internet, even if they aren’t linked to us, by linking to them. Beneath are some webpages really worth checking out[…]

  58. delaware cbd

    […]we came across a cool website which you could possibly take pleasure in. Take a appear in the event you want[…]

  59. cbd oil arkansas

    […]below you’ll locate the link to some internet sites that we assume you need to visit[…]

  60. colorado

    […]Sites of interest we have a link to[…]

  61. is cbd legal in arizona

    […]that will be the end of this post. Here you’ll locate some sites that we think you will enjoy, just click the links over[…]

  62. cbd oil california

    […]Sites of interest we have a link to[…]

  63. cbd oil alabama

    […]check below, are some totally unrelated web sites to ours, having said that, they are most trustworthy sources that we use[…]

  64. cbd oil alaska

    […]we came across a cool web-site that you just may delight in. Take a look should you want[…]

  65. Royal CBD

    […]that could be the end of this article. Here you will come across some web-sites that we consider you’ll value, just click the hyperlinks over[…]

  66. beginner guide cbd oil

    […]check beneath, are some totally unrelated web-sites to ours, nonetheless, they may be most trustworthy sources that we use[…]

  67. how to make cbd gummies at home

    […]here are some links to websites that we link to for the reason that we believe they’re worth visiting[…]

  68. https://royalcbd.com/how-is-cbd-oil-made/

    […]we prefer to honor a lot of other online internet sites on the web, even though they aren’t linked to us, by linking to them. Beneath are some webpages really worth checking out[…]

  69. RoyalCBD.com

    […]always a massive fan of linking to bloggers that I adore but really don’t get a whole lot of link love from[…]

  70. https://royalcbd.com/cbd-oil-recipes/

    […]very couple of web sites that take place to become comprehensive beneath, from our point of view are undoubtedly well really worth checking out[…]

  71. RoyalCBD

    […]please take a look at the websites we comply with, like this one, as it represents our picks from the web[…]

  72. RoyalCBD

    […]Wonderful story, reckoned we could combine a few unrelated information, nonetheless really really worth taking a search, whoa did 1 discover about Mid East has got extra problerms too […]

  73. Royal CBD

    […]Here is a good Blog You may Find Intriguing that we Encourage You[…]

  74. RoyalCBD.com

    […]always a big fan of linking to bloggers that I enjoy but do not get lots of link love from[…]

  75. https://royalcbd.com/cbd-legal-status/

    […]very few websites that happen to be in depth below, from our point of view are undoubtedly very well worth checking out[…]

  76. CBD gummies for anxiety

    […]please check out the web pages we stick to, including this a single, because it represents our picks from the web[…]

  77. https://royalcbd.com/how-does-cbd-work/

    […]usually posts some very intriguing stuff like this. If you are new to this site[…]

  78. CBD pills

    […]The details mentioned inside the write-up are some of the ideal offered […]

  79. Dank Vapes Cartridge

    […]one of our visitors not long ago encouraged the following website[…]

  80. اغاني

    […]Every when inside a when we choose blogs that we read. Listed beneath are the newest sites that we select […]

  81. lesbian porn

    […]we came across a cool website which you could love. Take a appear if you want[…]

  82. MILF

    […]that could be the end of this report. Here you’ll locate some sites that we feel you’ll enjoy, just click the links over[…]

  83. rust earth map puzzles

    […]check beneath, are some absolutely unrelated internet sites to ours, on the other hand, they may be most trustworthy sources that we use[…]

  84. best real casino online

    best online casino real money

  85. MALWAREBYTES ANIT-MALWARE FREE

    […]we prefer to honor lots of other web web pages around the web, even though they aren’t linked to us, by linking to them. Below are some webpages really worth checking out[…]

  86. cheap viagra online

    viagra prescription

  87. investment sales broker

    […]please visit the websites we follow, like this one, because it represents our picks in the web[…]

  88. games for pc download

    […]Sites of interest we have a link to[…]

  89. games for laptop download

    […]Sites of interest we have a link to[…]

  90. pc apps free download

    […]Every the moment in a although we pick blogs that we read. Listed beneath are the most up-to-date web pages that we opt for […]

  91. Fakaza mp3

    […]usually posts some incredibly fascinating stuff like this. If you’re new to this site[…]

  92. anvelope chisinau

    […]Here is a superb Weblog You might Come across Interesting that we Encourage You[…]

  93. automotive news websites

    […]usually posts some quite exciting stuff like this. If you are new to this site[…]

  94. Pomeranian Puppies For Sale near me

    […]the time to study or check out the content or web sites we have linked to below the[…]

  95. how to get to niagara falls from nyc

    […]although sites we backlink to below are considerably not associated to ours, we really feel they are truly really worth a go by way of, so have a look[…]

  96. Employee Benefits Chicago

    […]Here are a number of the web-sites we advise for our visitors[…]

  97. push up monokini swimwear

    […]usually posts some extremely fascinating stuff like this. If you are new to this site[…]

  98. buy cialis generic online

    tadalafil 5 mg

  99. flights

    […]please check out the sites we follow, which includes this one, because it represents our picks through the web[…]

  100. undetectable fake money for sale

    […]just beneath, are numerous entirely not related web-sites to ours, having said that, they may be surely really worth going over[…]

  101. دختره باکره

    […]the time to read or pay a visit to the subject material or websites we’ve linked to below the[…]

  102. https://sharadadvertising.com/

    […]always a huge fan of linking to bloggers that I really like but really don’t get a good deal of link like from[…]

  103. terriers

    […]that could be the end of this post. Right here you will discover some web-sites that we feel you will appreciate, just click the hyperlinks over[…]

  104. fishscale cocaine

    […]below you’ll find the link to some web-sites that we think it is best to visit[…]

  105. pc hilfe

    […]check beneath, are some absolutely unrelated sites to ours, nevertheless, they’re most trustworthy sources that we use[…]

  106. money for sale

    […]please check out the sites we adhere to, like this one, because it represents our picks through the web[…]

  107. اغاني

    […]Here are several of the web pages we advise for our visitors[…]

Leave a Comment