Pharmacological and initial therapeutic observations on 6-Diazo-5-Oxo-L-Norleucine (Don) in human neoplastic disease

Magill, Gordon B.; Myers, William G.; Reilly, H. Christine; Putnam, Richard C.; Magill, Judy; Sykes, Marguerite P.; Escher, George C.; Karnofsky, David A.; Burchenal, Joseph H.

doi:10.1002/1097-0142(195711/12)10:6<1138::aid-cncr2820100608>3.0.co;2-k

Cited by 89 publications

(72 citation statements)

References 5 publications

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“…Early clinical trials of DON showed that a dose of 0.1-0.3 mg/kg daily, given either orally or parenterally, produced stomatitis, diarrhea, nausea and vomiting (8). At a dose of 1.6 mg/kg repeated every four days, there is little stomatitis or myelosuppression but nausea and vomiting can be severe (8).…”

Section: Discussionmentioning

confidence: 58%

“…At a dose of 1.6 mg/kg repeated every four days, there is little stomatitis or myelosuppression but nausea and vomiting can be severe (8). In a Phase I study (13) in which DON was given intravenously at 100-500 mg/m 2 twice weekly, nausea and vomiting were dose-limiting and 39~ of the patients developed mucositis.…”

Section: Discussionmentioning

confidence: 99%

“…DON has antitumor activity in various murine tumor systems such as the L1210 and P388 leukemias, C26 and C38 colon tumors and CD8F1 mammary tumors, but is inactive against the intravenously implanted Lewis Lung, B16 melanoma and intracranially implanted ependymoblastomas (7). In early clinical trials it exhibited minor therapeutic activity against carcinomas of the breast, lung, uterus and gastrointestinal tract (8), choriocarcinoma (9,10), lymphomas and Hodgkin's disease (10). The related compound azotomycin is a pro-drug of DON composed of two molecules of DON and one molecule of glutamic acid (11).…”

Section: Introductionmentioning

confidence: 99%

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Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON)

et al. 1985

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The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m2 over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7-10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2 alpha = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m2 would be acceptable for Phase II studies of this drug administered on this schedule.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON)

et al. 1985

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“…The same dose continued for nine days in the second patient, N. M., again produced no untoward side effects, but when the dose was increased to 10 mg per day, an asymptomatic duodenal ulcer developed after five days. Although DON administered in higher doses as chemotherapy for cancer results in a significant incidence of leukopenia, thrombocytopenia, nausea and vomiting (9), no such toxic effects were observed during this study. The relatively high incidence of oral toxicity and peptic ulceration, even at relatively low doses, makes the use of DON imprudent in* managing patients who overproduce uric acid.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Uric Acid Synthesis in the Gouty Human by the Use of 6-Diazo-5-Oxo-L-Norleucine*

Grayzel¹,

Seegmiller²,

Love³

1960

J. Clin. Invest.

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“…Phase II trials demonstrated less toxicity at doses of 50 mg/m 2 , which were exhibited mainly as mild leukopenia. In larger doses (>50 mg/m 2 ), significant nausea and vomiting was noted with minimal efficacy [28,29]. In human clinical trials, most patients received oral doses in the range of 0.2–1.1 mg/kg/day.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Toxicity of the Analgesic Glutaminase Inhibitor 6-Diazo-5-Oxo-L-Norleucine in vitro and on Rat Dermal Skin Fibroblasts

Crosby

Ihnat

Miller

2015

MOJT

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6-diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist produced naturally by Streptomyces. It inhibits several glutamine-dependent enzyme pathways. Of particular note is its inhibitory effect on the mitochondrial enzyme, glutaminase (GLS), the primary producer of neuronal glutamate. Glutamate is an excitatory neurotransmitter released by primary sensory peripheral nerve terminals and spinal synaptic terminals during pain signaling. Previous work using the tail incision and inflammatory models of pain has demonstrated that a single application of the glutaminase inhibitor, DON, into a surgical incision or the paw of arthritic animals results in pain relief. Even though this compound shows promise as a therapeutic agent, limited data exist regarding its dermal toxicity. As a first approach, we evaluated the effect of several concentrations of DON, on the viability, mitochondrial oxidative capacity and proliferation of rat skin fibroblasts, and then examined the effect of DON after incubation with human liver microsomes on proliferation. Finally, we evaluated DON treated rat skin (tail and hind paw) for cellular necrosis, inflammation and mitotic bodies. No significant effects (p > 0.05) of DON were noted on apoptosis, necrosis, and mitochondrial activity in experiments with cultured rat skin fibroblasts. Flow cytometry revealed the absence of apoptosis in cells treated at the IC50 of 232.5 μM. Enhanced toxicity post-exposure to human microsomes was not observed when compared to DON alone. The H&E staining of the rat skin revealed no obvious pathology in the DON treatment group (10 mM). DON has no/minimal cellular toxicity in vitro on dermal fibroblasts at concentrations that effectively provide analgesia. The local application of concentrations greater than the in vitro IC50 for DON revealed no in vivo skin toxicity. These data provide results indicating zero-to-minimal cellular toxicity with DON and support the further investigation of DON as an analgesic.

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Pharmacological and initial therapeutic observations on 6-Diazo-5-Oxo-L-Norleucine (Don) in human neoplastic disease

Cited by 89 publications

References 5 publications

Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON)

Phase I study and clinical pharmacology of 6-diazo-5-oxo-L-norleucine (DON)

Suppression of Uric Acid Synthesis in the Gouty Human by the Use of 6-Diazo-5-Oxo-L-Norleucine*

Evaluating the Toxicity of the Analgesic Glutaminase Inhibitor 6-Diazo-5-Oxo-L-Norleucine in vitro and on Rat Dermal Skin Fibroblasts

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