Phase I study of Brequinar sodium (NSC 368390) in patients with solid malignancies

Schwartsmann, Gilberto; Dodion, Pierre; Vermorken, Jan B.; Huinink, W.W. ten Bokkel; Joggi, J; Winograd, B.; Gall, Helen; Simonetti, G.; Vijgh, W.J.F. van der; Hennik, M.B. van; Crespeigne, N.; Pinedo, H.M.

doi:10.1007/bf00686235

Cited by 40 publications

(15 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Brequinar is a potent and specific inhibitor of DHODH. Given encouraging pre-clinical activity, BRQ was previously evaluated in the phase-1 and -2 trials of patients with advanced solid tumor malignancies (Arteaga et al, 1989;Burris et al, 1998;Noe et al, 1990;Schwartsmann et al, 1990). BRQ was not effective at the doses and schedules evaluated in these trials.…”

Section: Dhodh In Human Diseasementioning

confidence: 99%

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Sykes

Kfoury

Mercier

et al. 2016

Cell

387

439

View full text Add to dashboard Cite

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

show abstract

Section: Dhodh In Human Diseasementioning

confidence: 99%

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Sykes

Kfoury

Mercier

et al. 2016

Cell

387

439

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

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

View full text Add to dashboard Cite

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

show abstract

“…The major side effect of Brequinar was myelosuppression, [7][8][9] indicating a specific effect on certain hematopoietic cells. Indeed we found pronounced inhibition of DHO-DH in mouse bone marrow cells.…”

Section: Discussionmentioning

confidence: 99%

“…Based on this principle DHO-DH activity in white blood cells (WBC) and plasma uridine levels were measured in patients entered in a Phase I study to determine its MTD at a 3-weekly schedule. [7,8] Inhibition of DHO-DH in WBC (>90% inhibition) and especially its recovery, and the depletion of plasma uridine (initial levels between 3.0 and 6.8 lM) were dose-dependent followed by a rebound. The uridine depletion at the highest dose was associated with a prolonged DHO-DH inhibition and with a decrease of WBC UTP and CTP levels down to 42 and 16% of pretreatment levels.…”

Section: Introductionmentioning

confidence: 99%

Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor

Peters

2018

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

DUP-785 (Brequinar sodium) is a potent inhibitor of the mitochondrial dihydroorotate dehydrogenase (DHO-DH), a rate-limiting enzyme in the pyrimidine de novo nucleotide synthesis. In phase I clinical studies at the maximum tolerated dose (MTD) Brequinar induced a long-term inhibition of DHO-DH in white blood cells (WBC) and a long-term depletion of plasma uridine. These two parameters were related to severe myelosuppression, so that in Phase II studies the dose of Brequinar was decreased considerably. We further characterized the mechanism of DHO-DH enzyme inhibition while in blood samples of patients entered into Phase II studies we evaluated DHO-DH inhibition in WBC and plasma uridine depletion. With Electron Spin Resonance it was demonstrated that DHO-DH produced oxygen radical formation, which was inhibited by Brequinar. In the Phase II study depending on the dose (600 to 2000 mg/m 2), uridine decreased to 20% (at the highest dose) or to 80-85% (at the middle dose) or did not change, which was associated with inhibition of DHO-DH (1% activity left vs 11 and 24% left). Inhibition of DHO-DH in the tumor of the latter patient was moderate as well (12% activity left). Brequinar was inactive in all tumor types evaluated possibly because of high uridine levels in the tumor. In conclusion, Brequinar was inactive against solid tumors, but DHO-DH inhibition was associated with myeloid toxicity, which may explain its potential for treatment of leukemia or inflammatory diseases.

show abstract

Phase I study of Brequinar sodium (NSC 368390) in patients with solid malignancies

Cited by 40 publications

References 4 publications

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia

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

Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor

Contact Info

Product

Resources

About