A phase I trial of a modified, dose intensive FAMTX regimen (High dose 5-fluorouracil + doxorubicin + high dose methotrexate + leucovorin) with oral uridine rescue

Schwartz, Gary K.; Christman, Kathy; Saltz, Leonard B.; Casper, Ephraim S.; Quan, Bao-Ku; Bertino, Joseph R.; Colofiore, Joseph; Kelsen, David P.

doi:10.1002/(sici)1097-0142(19961101)78:9<1988::aid-cncr21>3.0.co;2-t

Cited by 9 publications

(2 citation statements)

References 11 publications

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“…In previous clinical trials without uridine, 4 out of 6 patients could not tolerate a 600 mg/m 2 dose of 5-FU because of mucositis, diarrhea and a decrease in performance status. Another study of high dose 5-FU with doxorubicin, high dose methotrexate and leucovorin, oral uridine administration allowed for dose intensification of 5-FU and ensured rescue from 5-FU-induced hematologic toxicity without adverse impact on tumor response (47). As indicated in pre-clinical studies, properly delayed uridine rescue results in a faster clearance of 5-FU from RNA of bone marrow and enhancement of the rate of recovery of DNA synthesis (39).…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Uridine Phosphorylase in Tumors Contributes to an Improved Fluoropyrimidine Therapeutic Activity

Cao

Ziemba²,

McCabe

et al. 2011

Molecular Cancer Therapeutics

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Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and Capecitabine in our UPase knockout (UPase −/−) model. Treatment with 5-FU (85 mg/kg) or Capecitabine (1000 mg/kg) 5 days a week for 4 weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase −/− animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase −/− mice. UPase expressing colon 38 tumors implanted in UPase −/− mice revealed an improved therapeutic efficacy when treated with 5-FU and Capecitabine due to the higher maximum tolerated dose for fluoropyrimidines achievable in UPase −/− mice. 19F-MRS evaluation of Capecitabine metabolism in tumors revealed similar activation of the pro-drug in UPase −/− mice compared to WT. In WT mice, approximately 60% of Capecitabine was transformed over 3 hours into its active metabolites, while 80% was transformed in tumors implanted in UPase −/− mice. In UPase −/− mice, prolonged retention of 5′dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase −/− mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or Capecitabine-based chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of Uridine Phosphorylase in Tumors Contributes to an Improved Fluoropyrimidine Therapeutic Activity

Cao

Ziemba²,

McCabe

et al. 2011

Molecular Cancer Therapeutics

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“…Thus, exogenous uridine is more effective at competing with FUTP for incorporation into host RNA in normal tissues versus all solid tumors tested to date in murine systems. Although uridine has also been demonstrated to protect against 5-FU toxicity in humans, its low oral bioavailability, toxicity including fever and phlebitis, and the requirement for central venous access for parenteral administration limit its clinical utility [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency

Saif

Diasio

2016

Cancer Chemother Pharmacol

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coagulopathy and grade 3 neurological toxicity with a fatal outcome. DPYD status was evaluated as we have previously published. Results The first patient was found to have an abnormally low DPYD activity of 0.087-nmol/min/mg protein by radioisotopic assay (reference normal range 0.182-0.688 nmol/ min/mg protein). Because of pancytopenia, DPYD enzyme activity could not be assessed in patient 2; genotypic analysis of DPYD during autopsy revealed the presence of the heterozygous mutation, IVS14+1 G>A, DPYD*2A, now recognized as the most common cause of DPYD deficiency. Conclusion These two patients present the first two cases of DPYD deficiency that had either delay in severe toxicity or recovered from severe toxicity as they received oral Vistogard as a part of the conical trial. Toxicity was delayed in both patients by a mean of 3.5 weeks (range 3-4 weeks), indicating that Vistogard might be able to delay 5-FU toxicity despite higher doses than standard bolus dose of 5-FU used in gastrointestinal malignancies and the appearance of a potentially less toxic adverse effect of 5-FU at an unusual site (cutaneous) in one patient. The role of uridine triacetate with 5-FU in DPYD-deficient patients needs further investigation.

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Fluoropyrimidines as Antifolate Drugs

Peters¹,

Köhne²

1999

Antifolate Drugs in Cancer Therapy

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A phase I trial of a modified, dose intensive FAMTX regimen (High dose 5-fluorouracil + doxorubicin + high dose methotrexate + leucovorin) with oral uridine rescue

Abstract: In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles.

Cited by 9 publications

References 11 publications

Differential Expression of Uridine Phosphorylase in Tumors Contributes to an Improved Fluoropyrimidine Therapeutic Activity

Differential Expression of Uridine Phosphorylase in Tumors Contributes to an Improved Fluoropyrimidine Therapeutic Activity

Benefit of uridine triacetate (Vistogard) in rescuing severe 5-fluorouracil toxicity in patients with dihydropyrimidine dehydrogenase (DPYD) deficiency

Fluoropyrimidines as Antifolate Drugs

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