A Prospective Randomized Trial Comparing Intravenous 5- Fluorouracil and Oral Doxifluridine As Postoperative Adjuvant Treatment for Advanced Rectal Cancer

Min, Jin Sik; Kim, Nam Kyu; Park, Jea Kun; Yun, Sungmin; Noh, Jae Kyung

doi:10.1007/s10434-000-0674-9

Cited by 13 publications

(3 citation statements)

References 12 publications

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“…6 ). This premature activation of the prodrug may therefore lead into gastrointestinal toxicity – again, a side effect commonly associated with oral doxifluridine 41,42 .…”

Section: Resultsmentioning

confidence: 99%

Systematic mapping of drug metabolism by the human gut microbiome

Chankhamjon

Javdan

Lopez

et al. 2019

Preprint

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25The human gut microbiome harbors hundreds of bacterial species with 26 diverse biochemical capabilities, making it one of nature's highest density, 27 highest diversity bioreactors. Several drugs have been previously shown to be 28 directly metabolized by the gut microbiome, but the extent of this phenomenon 29 has not been systematically explored. Here, we develop a systematic screen for 30 mapping the ability of the complex human gut microbiome to biochemically 31 transform small molecules (MDM-Screen), and apply it to a library of 575 clinically 32 used oral drugs. We show that 13% of the analyzed drugs, spanning 28 33 pharmacological classes, are metabolized by a single microbiome sample. In a 34 proof-of-principle example, we show that microbiome-derived metabolism occurs 35 in vivo, identify the genes responsible for it, and provide a possible link between 36 its consequences and clinically observed features of drug bioavailability and 37 toxicity. Our findings reveal a previously underappreciated role for the gut 38 microbiome in drug metabolism, and provide a comprehensive framework for 39 characterizing this important class of drug-microbiome interactions. 40 41 42 43 44 45 46 47iii) a defined mouse colonization assay for assessing the effect of the microbiome on the 94 pharmacokinetics of selected drugs. Using MDM-Screen with 575 clinically used, orally 95 administered, small molecule drugs, we discovered that 13% of them can be subject to 96 MDM. As a proof-of-principle example, we selected one of these transformations -97 MDM deglycosylation of fluoropyrimidines -for further functional investigations. We 98 identify microbiome-derived species and enzymes responsible for this transformation, 99show that it occurs in vivo in a microbiome-dependent manner, and provide evidence 100 that its consequences may explain outcomes already observed in the clinic. Our screen 101 described here, and the findings obtained from it represent the first systematic map of 102 microbiome-derived metabolism of clinically used drugs, and provide a framework for 103incorporating an "MDM" module in future drug development pipelines.

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“…6 ). This premature activation of the prodrug may therefore lead into gastrointestinal toxicity – again, a side effect commonly associated with oral doxifluridine 41,42 .…”

Section: Resultsmentioning

confidence: 99%

Systematic mapping of drug metabolism by the human gut microbiome

Chankhamjon

Javdan

Lopez

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…of the prodrug may therefore lead to gastrointestinal toxicityagain, a side effect commonly associated with oral doxifluridine (Kim et al, 2001;Min et al, 2000). Additional studies are necessary to directly correlate the level of MDM deglycosylation of different FPs in humans to their clinically observed pharmacokinetics and/or toxicity.…”

Section: Llmentioning

confidence: 99%

Personalized Mapping of Drug Metabolism by the Human Gut Microbiome

Javdan

Lopez

Chankhamjon

et al. 2020

Cell

298

247

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“…Only grade I-II diarrhoea were reported, 36% in the doxifluridine arm and 14% in the intravenous 5FU arm. Min et al [77] studied the efficacy of oral doxifluridine compared to bolus intravenous 5FU in the postoperative combination treatment of 166 stage II-III rectal cancer patients. Comparable therapeutic effects were found in both arms, but grade III-IV diarrhoea was significantly more frequent in the doxifluridine arm (17% vs. 0%) and leucopenia in the intravenous arm (0% vs. 7%).…”

Section: Clinical Resultsmentioning

confidence: 99%

Developments in treatment of primary irresectable rectal cancer

Reerink¹,

Mulder²,

Szabo³

et al. 2004

Colorectal Disease

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The treatment options for primary irresectable rectal cancers are discussed. Assessment of tumour stage is the first step for an appropriate choice of treatment. Following a diagnosis of rectal cancer, a vast array of diagnostic procedures is available to determine its stage, and thereby its best treatment options. From the many (new) diagnostic options the merits and drawbacks are discussed. If a diagnosis of irresectability is made, further treatment options should include radiotherapy in most cases, some aspects of timing and application, i.e. intra-operative treatment are discussed. Chemotherapy options are manifold, the results are discussed and some new options are explored.

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A Prospective Randomized Trial Comparing Intravenous 5- Fluorouracil and Oral Doxifluridine As Postoperative Adjuvant Treatment for Advanced Rectal Cancer

Abstract: Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy. The oral regimen also can be safely given with appropriate toxicity and tolerability.

Cited by 13 publications

References 12 publications

Systematic mapping of drug metabolism by the human gut microbiome

Systematic mapping of drug metabolism by the human gut microbiome

Personalized Mapping of Drug Metabolism by the Human Gut Microbiome

Developments in treatment of primary irresectable rectal cancer

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