Mucocutaneous side effects of brequinar sodium. A new inhibitor of pyrimidine de novo biosynthesis

Schwartsmann, Gilberto; Bork, E.; Vermorken, J. B.; Nieboer, C.; Dodion, Pierre; Huinink, W.W. ten Bokkel; Hansen, Niels; Armand, Jean‐Pierre; Winograd, B.; Gall, Helen; Pinedo, H.M.; Seldenrijk, A.

doi:10.1002/1097-0142(19890115)63:2<243::aid-cncr2820630207>3.0.co;2-7

Cited by 10 publications

(6 citation statements)

References 8 publications

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“…The second patient experienced a grade 4 rash after the second dose (cumulative dose, 2,400 mg). The rash associated with high-dose intermittent administration of brequinar has been described elsewhere [ 10]. Eight episodes of grade 3 toxicity occurred in five patients.…”

Section: Resultsmentioning

confidence: 93%

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck

Urba

Doroshow

Cripps

et al. 1992

Cancer Chemother. Pharmacol.

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A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m2. The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.

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Section: Resultsmentioning

confidence: 93%

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck

Urba

Doroshow

Cripps

et al. 1992

Cancer Chemother. Pharmacol.

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“…The inhibitors A77‐1726 and brequinar bind within this channel, athough there is some debate as to whether they bind to precisely the same site 13 . Although brequinar has other significant toxicities such as hematopoetic and skin 14,15 the relative absence of liver toxicity suggests that inhibition of DHO‐DH may not be the mechanism for liver toxicity discussed below, as this was not observed in brequinar‐treated patients. At the doses used clinically for RA, A77‐1726 does not affect the earliest stages of lymphocyte activation, such as transcription of IL‐2 or nuclear factor of T‐cell activation (NFAT) 16 …”

Section: Mode Of Actionmentioning

confidence: 99%

Leflunomide in the treatment of rheumatoid arthritis and other autoimmune disorders

Fox

Helfgott

2004

APLAR Journal of Rheumatology

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Leflunomide (Arava) is an isoxazole derivative approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA). Its mechanism of action is based on the inhibition of dihydroorotate dehydrogenase, an enzyme that controls the pathway for denovo synthesis of uridine ribose monophosphate (rUMP) in activated T-cells. Leflunomide is structurally unrelated to other known immunomodulatory drugs in clinical use. Data have demonstrated benefit in control of clinical symptoms and quality of life in RA and prevention of radiologic progression after 24 months of treatment. Further, studies suggest a role for the combination of methotrexate plus leflunomide in the treatment of some patients with refractory RA. Recent studies have also indicated efficacy in psoriatic arthritis, other autoimmune disorders and in prevention of allograft rejection. A recent important issue is reports of potentially serious liver toxicity and guidelines for monitoring toxicity.

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“…A study of Brequinar anti-tumour properties showed that Brequinar inhibited the growth of a broad spectrum of human solid tumours implanted in nude mice [12]. Brequinar sodium is currently in phase 2 clinical trials, however, several complications and toxicities of Brequinar sodium have been reported in Phase 1 clinical trials in patients with solid tumours mainly; myelosupression, thrombocytopenia, nausea, vomiting, skin rashes and mucositis [13]. These side effects are disappointing and this limits its potential use in AML [11].…”

Section: Introductionmentioning

confidence: 99%

Erythrinin C, From The Root of Pueraria Peduncularis, is a Potential Antagonist Against DHODH, A Therapeutic Target in Acute Myeloid Leukemia: An In Silico Study

Abolarinwa¹

2021

Preprint

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Acute myeloid leukaemia (AML) is the second most common form of leukaemia with an annual incidence of 3.6 per 100,000 adults in the United States. A 5-year survival rate of a person with AML is less than 50%. Myeloid leukemogenesis has been reported to arise by a differentiation arrest at early progenitor stage of hematopoietic maturation of the bone marrow; this has led researchers to identify the human dihydroorotate dehydrogenase (DHODH) to be a therapeutic target in the differentiation therapy for AML. Several inhibitors of DHODH have been developed; however only a few have reached clinical trials of which include Brequinar, a strong DHODH inhibitor. Brequinar has reached a phase 2 clinical trials, however, several complication and toxicities have been reported in phase 1 clinical trials in patients with solid tumours. This ranges from myelosupression, thrombocytopenia, nausea, vomiting, skin rashes, mucositis, and this limit its use in AML. In view of this, research is focused on identifying potent DHODH inhibitors with little or no toxic effect that can be used in the differentiation therapy of AML. Pueraria peduncularis belongs to the Leguminosae family and it is widely distributed in some parts of China, India, Pakistan, Nepal and Burma. A recent study has accessed and reported that flavonoids from root of Pueraria peduncularis have anti-tumour effects against cancer cell lines. The aim of this study was to analyse flavonoids from (plant source) root of Pueraria peduncularis for their DHODH inhibitory potential via computational docking studies. For this, four (4) flavonoids (phytochemicals), as well as the DHODH co-crystallized inhibitor, BAY 2402234 which serve as the standard in the present study, were retrieved from the literature and screened for their inhibitory effects on DHODH. Erythrinin C was the lead compound with a binding energy of -11.395kcal/mol. Computational docking and scoring analysis were performed using Lead Finder tool implemented in Flare software of Cresset Inc. (2019, Litlington, UK). The target was validated to ensure that the right target was used for this analysis.

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Mucocutaneous side effects of brequinar sodium. A new inhibitor of pyrimidine de novo biosynthesis

Cited by 10 publications

References 8 publications

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck

Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck

Leflunomide in the treatment of rheumatoid arthritis and other autoimmune disorders

Erythrinin C, From The Root of Pueraria Peduncularis, is a Potential Antagonist Against DHODH, A Therapeutic Target in Acute Myeloid Leukemia: An In Silico Study

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