A phase II study of 6-diazo-5-oxo-L-norleucine (DON, NSC-7365) in advanced large bowel carcinoma

Rubin, Joseph; S, Sorensen; Aj, Schutt; Ga, van Hazel; Mj, O'Connell; Cg, Moertel

doi:10.1097/00000421-198306000-00012

Cited by 18 publications

(10 citation statements)

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“…In this study, DON was administered at low daily intramuscular doses of only 5 to 20 mg and inhibited glutamine utilization as measured by radiotracer. These doses were more than an order of magnitude lower than those used in subsequent cancer trials in the 1980s (45,50,51), supporting the notion that high intermittent dosing was not an optimal schedule to achieve blockade of glutamine metabolism with DON.…”

Section: Clinical Studiesmentioning

confidence: 72%

“…The subsequent phase II studies of DON at intermittent high doses carried out between the 1980s and 2000s generally had disappointing outcomes (Table 1) (48–51). Four of these studies used DON as a single agent in advanced or refractory adult solid tumors.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…Taken together, these observations suggest that low daily or divided dose exposures produced low plasma concentrations and a characteristic local GI toxicity, while high intermittent doses lead to more typical chemotherapy-induced nausea and vomiting. Of note, at the time many of the clinical studies on DON were done, 5HT 3 receptor antagonists were not routinely in clinical practice as antiemetics, although several of the phase II studies and a pediatric phase I study pretreated patients with prochlorperazine or chlorpromazine and observed decreased severity of nausea and vomiting (48,51), (43). Other non-dose limiting toxicities of DON observed in the high intermittent dosing studies include reversible myelosuppression and transient hypocalcemia (43,44,47).…”

Section: Clinical Studiesmentioning

confidence: 99%

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We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

Lemberg

Vornov

Rais

et al. 2018

Molecular Cancer Therapeutics

167

162

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The broadly active glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) has been studied for 60 years as a potential anticancer therapeutic. Clinical studies of DON in the 1950s using low daily doses suggested antitumor activity, but later phase I and II trials of DON given intermittently at high doses were hampered by dose-limiting nausea and vomiting. Further clinical development of DON was abandoned. Recently, the recognition that multiple tumor types are glutamine-dependent has renewed interest in metabolic inhibitors such as DON. Here, we describe the prior experience with DON in humans. Evaluation of past studies suggests that the major impediments to successful clinical use included unacceptable gastrointestinal (GI) toxicities, inappropriate dosing schedules for a metabolic inhibitor, and lack of targeted patient selection. To circumvent GI toxicity, prodrug strategies for DON have been developed to enhance delivery of active compound to tumor tissues, including the CNS. When these prodrugs are administered in a low daily dosing regimen, appropriate for metabolic inhibition, they are robustly effective without significant toxicity. Patients whose tumors have genetic, metabolic, or imaging biomarker evidence of glutamine dependence should be prioritized as candidates for future clinical evaluations of novel DON prodrugs, given either as monotherapy or in rationally directed pharmacologic combinations. .

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Section: Clinical Studiesmentioning

confidence: 72%

Section: Clinical Studiesmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

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We're Not “DON” Yet: Optimal Dosing and Prodrug Delivery of6-Diazo-5-oxo-L-norleucine

Lemberg

Vornov

Rais

et al. 2018

Molecular Cancer Therapeutics

167

162

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“…In fact, CTPS has been an attractive anti-cancer target for decades. However, treatment with CTPS inhibitors such as acivicin and 6-Diazo-5-oxo-L-norleucine (DON) often provokes some unacceptable side effects, such as neurotoxicity, nausea and vomiting, which has hindered their further applications (Lynch et al., 1982; Rubin et al., 1983; Earhart et al., 1990; Falkson et al., 1990; Maroun et al., 1990). A recent study also reported that inactivation of CTPS caused imbalance of dNTP pools and increased mutagenesis in Saccharomyces cerevisiae (Schmidt et al., 2017).…”

Section: Discussionmentioning

confidence: 99%

mTOR-S6K1 pathway mediates cytoophidium assembly

Sun

Liu

2019

Journal of Genetics and Genomics

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CTP synthase (CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila , bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin (mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1 (mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing mTOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells. Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.

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“…In fact, CTPS has been an attractive anti-cancer target for decades. However, the unwanted side effects like neurotoxicity, nausea and vomiting after CTPS inhibitors treatment hindered their further development 16,17 . Previous studies showed that the size and abundance of cytoophidia are positively related to the activity and expression of proto-oncogenes, including Myc, Casitas B-lineage lymphoma (Cbl), and activated cdc42-associated kinase (Ack) in Drosophila 12,18,19 .…”

mentioning

confidence: 99%