Phase II trial with Brequinar (DUP-785, NSC 368390) in patients with metastatic colorectal cancer: A study of the Early Clinical Trials Group of the EORTC

Dodion, Pierre; Wagener, T.; Stoter, G.; Drozd, Anna; Lev, Louise M.; Skovsgaard, Torben; Rénard, Josette; Cavalli, F

doi:10.1093/oxfordjournals.annonc.a057680

Cited by 31 publications

(27 citation statements)

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“…Several inhibitors of DHODH have been described previously [28], with brequinar sodium and leflunomide/teriflunomide being the most well-known agents tested in humans. The anticancer activity of brequinar was tested in the 1990s in solid tumor patients [29][30][31], but brequinar was not given to patients with myeloid malignancies. Moreover, despite preclinical evidence supporting the need for continuous target engagement [32,33], the clinical trials of brequinar in solid tumors used intermittent dosing schedules similar to those of classical chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

et al. 2019

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Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234-a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.

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Section: Discussionmentioning

confidence: 99%

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

et al. 2019

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“…With the success in preclinical results, brequinar was tested on patients. However, the drug demonstrated unsatisfactory responses in a number of different cancers, including breast (133), melanoma (134), colon (135), lung (136) and gastrointestinal (137). Therapeutic responses were not detected even at higher doses of the compound.…”

Section: Dhodh Inhibitors With Relevance To Cancermentioning

confidence: 99%

Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina

2016

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“…The Ki varies between 10 and 100 nM depending on the source of the enzyme. Brequinar is a 4-quinoline carboxylic acid with significant antitumour activity in experimental tumours (Dexter et al, 1985;Braakhuis et al, 1990) which was therefore selected for clinical Phase I and II investigations (Arteaga et al, 1989;Bork et al, 1989;Dodion et al, 1990;Noe et al, 1990;Schwartsmann et al, 1990). The maximum tolerated dose (MTD) proved to be 1,800 mg m2.…”

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confidence: 99%

In vitro and in vivo studies on the combination of Brequinar sodium (DUP-785; NSC 368390) with 5-fluorouracil; effects of uridine

Peters

Kraal²,

Pinedo³

1992

Br J Cancer

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Summary Brequinar sodium (DUP-785; Brequinar) is a potent inhibitor of the pyrimidine de novo enzyme dihydroorotate dehydrogenase (DHO-DH), leading to a depletion of pyrimidine nucleotides, which could be reversed by uridine. In in vitro studies we investigated the effect of different physiological concentrations of uridine on the growth-inhibition by Brequinar, the effect of the nucleoside transport inhibitor, dipyridamole, and the combination of Brequinar and 5-fluorouracil (5FU). Uridine at 1 gLM slightly reversed the growth inhibition by Brequinar, while the effect of 5-500 gM was greater. However, at Brequinar concentrations > 30 gM, uridine could not reverse the growth-inhibitory effects. Addition of dipyridamole could only partially prevent the reversing effects of uridine. The combination of Brequinar and 5FU was more than additive in the absence of uridine in the culture medium, but not in the presence of uridine. The combination of Brequinar and 5FU was tested in vivo in two murine colon tumour models, Colon 26 and Colon 38. Scheduling of both compounds appeared to be very important. In Colon 38 no potentiating effect of Brequinar could be observed. In contrast in Colon 26 a more than additive effect could be observed. Since uridine concentrations are considerably different in these tumours (higher in Colon 38), it was concluded from both the in vitro and in vivo experiments that uridine is an important determinant in combinations of Brequinar and 5FU.Brequinar Sodium (Brequinar; DUP-785; NSC 368390) is a potent inhibitor of dihydroorotic acid dehydrogenase (DHO-DH), the fourth enzyme in the de novo pyrimidine nucleotide synthesis (Figure 1) which is located on the outer site of the inner membrane of the mitochondrion (Chen et al., 1986;Peters et al., 1987a (Peters et al., 1987a;1990b;Schwartsmann et al., 1988). Drug exposure resulted in accumulation of cells in the S phase (Schwartsmann et al., 1988). Growth-inhibitory effects of Brequinar could be prevented and reversed by addition of uridine or cytidine (Peters et al., 1987a;Schwartsmann et al., 1988), but not by thymidine or deoxycytidine. Depletion of pyrimidine deoxyribonucleotides was proportional to that of the ribonucleotides (Schwartsmann et al., 1988), while both could be reversed by uridine.Inhibition of the pyrimidine de novo pathway can enhance the anti-tumour activity of 5FU; both acivicin and Nphosphonacetyl-L-aspartate (PALA) have been investigated in preclinical in vitro and in vivo studies Grem et al., 1988; Spiegelman et al., 1980 lowered (Grem et al., 1988;Martin et al., 1985;Casper et al., 1983

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Phase II trial with Brequinar (DUP-785, NSC 368390) in patients with metastatic colorectal cancer: A study of the Early Clinical Trials Group of the EORTC

Cited by 31 publications

References 1 publication

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies

Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina

In vitro and in vivo studies on the combination of Brequinar sodium (DUP-785; NSC 368390) with 5-fluorouracil; effects of uridine

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