Metabolism and action of amino acid analog anti-cancer agents

Ahluwalia, Gurpreet S.; Grem, Jean L.; Zhang, Hao; Cooney, David A.

doi:10.1016/0163-7258(90)90094-i

Cited by 220 publications

(181 citation statements)

References 177 publications

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“…The rest of our work is focused on the use of two irreversible glutamine analog CTP synthetase inhibitors, 6-diazo-5-oxo-L-norleucine (DON) and ␣-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin). These drugs have been used extensively in clinical trials against various cancers, and at least acivicin is known to penetrate the blood-brain barrier (6). We found that both drugs inhibited the proliferation of cultured trypanosomes at much lower concentrations than the levels measured in the blood of cancer patients.…”

mentioning

confidence: 75%

Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

Hofer

Steverding

Chabes

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

109

102

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The drugs in clinical use against African sleeping sickness are toxic, costly, or inefficient. We show that Trypanosoma brucei, which causes this disease, has very low levels of CTP, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. The CTP synthetase inhibitors 6-diazo-5-oxo-L-norleucine (DON) and ␣-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite CTP levels even further and inhibited trypanosome proliferation in vitro and in T. bruceiinfected mice. In mammalian cells, DON mainly inhibits de novo purine biosynthesis, a pathway lacking in trypanosomes. We could rescue DON-treated human and mouse fibroblasts by the addition of the purine base hypoxanthine to the growth medium. For treatment of sleeping sickness, we propose the use of CTP synthetase inhibitors alone or in combination with appropriate nucleosides or bases. U p to 500,000 people are estimated to suffer from African sleeping sickness (1, 2), a fatal disease caused by the protozoan parasites Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. These pathogens are transmitted by tsetse flies to their mammalian hosts, where they first establish an infection in the blood and lymph. In the second stage of the disease, the parasites invade the central nervous system. Most drugs used to treat sleeping sickness do not cross the bloodbrain barrier; as soon as the trypanosomes have entered the central nervous system, only eflornithine and arsenicals such as melarsoprol are effective. However, the arsenicals are highly toxic, whereas eflornithine is ineffective against T. b. rhodesiense (3) and is very expensive.Purine metabolism has been extensively studied in trypanosomes (4), and it is well established that they lack the ability to form purines de novo. They therefore absolutely depend on preformed purine bases or nucleosides for survival. Any purine source is fine, because they have all of the enzymes needed to interconvert IMP, AMP, and GMP. Much less attention has been paid to the synthesis of pyrimidines in trypanosomes (4); so far, no study of the pathways for CTP synthesis has been published.We have previously reported that cultured bloodstream T. brucei have a very small CTP pool in comparison with other NTP pools and the CTP pools of other cell types (5). In this paper, we demonstrate that the low CTP pools are a consequence of slow synthesis by the parasite CTP synthetase. We suggest that this enzyme is an excellent target for chemotherapy, because we found that the trypanosomes, unlike mammalian cells, cannot compensate for the inhibition of CTP synthetase by the salvage of cytidine. The rest of our work is focused on the use of two irreversible glutamine analog CTP synthetase inhibitors, 6-diazo-5-oxo-L-norleucine (DON) and ␣-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin). These drugs have been used extensively in clinical trials against various cancers, and at least acivicin is known to penetrate the blood-brain barrier (6). We found that both drug...

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mentioning

confidence: 75%

Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

Hofer

Steverding

Chabes

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

109

102

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“…Acivicin, 6-diazo-5-oxo-L-norleucine, and azaserine, three of the most widely studied analogs (Figure 1), all demonstrated variable degrees of gastrointestinal toxicity, myelosuppression, and neurotoxicity (72). Because these agents non-selectively target glutamine-consuming processes, recent interest has focused on developing methods directed at specific nodes of glutamine metabolism.…”

Section: Pharmacological Strategies To Inhibit Glutamine Metabolism Imentioning

confidence: 99%

Glutamine and cancer: cell biology, physiology, and clinical opportunities

Hensley¹,

Wasti²,

2013

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Glutamine is an abundant and versatile nutrient that participates in energy formation, redox homeostasis, macromolecular synthesis, and signaling in cancer cells. These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect, monitor, and treat cancer. Here we review the metabolic functions of glutamine as a super nutrient and the surprising roles of glutamine in supporting the biological hallmarks of malignancy. We also review recent efforts in imaging and therapeutics to exploit tumor cell glutamine dependence, discuss some of the challenges in this arena, and suggest a disease-focused paradigm to deploy these emerging approaches. IntroductionIt has been nearly a century since the discovery that tumors display metabolic activities that distinguish them from differentiated, non-proliferating tissues and presumably contribute to their supraphysiological survival and growth (1). Interest in cancer metabolism was boosted by discoveries that oncogenes and tumor suppressors could regulate nutrient metabolism, and that mutations in some metabolic enzymes participate in the development of malignancy (2, 3). The persistent appeal of cancer metabolism as a line of investigation lies both in its ability to uncover fundamental aspects of malignancy and in the translational potential of exploiting cancer metabolism to improve the way we diagnose, monitor, and treat cancer. Furthermore, an improved understanding of how altered metabolism contributes to cancer has a high potential for synergy with translational efforts. For example, the demonstration that asparagine is a conditionally essential nutrient in rapidly growing cancer cells paved the way for L-asparaginase therapy in leukemia. Additionally, the avidity of some tumors for glucose uptake led to the development of 18 fluoro-2-deoxyglucose imaging by PET; this in turn stimulated hundreds of studies on the biological underpinnings of tumor glucose metabolism.There continue to be large gaps in understanding which metabolic pathways are altered in cancer, whether these alterations benefit the tumor in a substantive way, and how this information could be used in clinical oncology. In this Review, we consider glutamine, a highly versatile nutrient whose metabolism has implications for tumor cell biology, metabolic imaging, and perhaps novel therapeutics.

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“…Thus deamidation is a control point for glutamine metabolism in tumor cells. In xenografts, glutaminase expression is temporally correlated with maximal growth rate, and suppression of glutaminase activity limits tumor growth [55][56][57].…”

Section: How Does Glutamine Metabolism Support Biosynthetic Activitiementioning

confidence: 99%

Brick by brick: metabolism and tumor cell growth

DeBerardinis¹,

Sayed²,

Ditsworth³

et al. 2008

Current Opinion in Genetics & Development

911

815

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SummaryTumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the 'Warburg effect'). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these pathways into focus. In this review, we discuss how tumor cells achieve high rates of nucleotide and fatty acid synthesis, how oncogenes and tumor suppressors influence these activities, and how glutamine metabolism enables macromolecular synthesis in proliferating cells.

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Metabolism and action of amino acid analog anti-cancer agents

Cited by 220 publications

References 177 publications

Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

Trypanosoma brucei CTP synthetase: A target for the treatment of African sleeping sickness

Glutamine and cancer: cell biology, physiology, and clinical opportunities

Brick by brick: metabolism and tumor cell growth

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