Evidence that the L-Asparaginase Activity of Guinea Pig Serum is responsible for its Antilymphoma Effects

Broome, J. D.

doi:10.1038/1911114a0

Cited by 411 publications

(163 citation statements)

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“…Guinea pigs are relatively unique among mammals in having serum aspariginase activity 157 , which was found to be responsible for the anti--lymphoma effect in mice 55,158 . Asparaginase was found to be a particularly effective agent in ALL and associated high--grade lymphomas, inducing remission as a single agent in greater than 50% of children with the disease 159 .…”

Section: Box 2 Development Of L--asparaginase To Treat Allmentioning

confidence: 99%

Targeting cancer metabolism: a therapeutic window opens

Heiden

2011

Nat Rev Drug Discov

1,265

1,076

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PrefaceGenetic driver events in cancer activate signaling pathways that alter cell metabolism. Clinical evidence has linked metabolism with cancer outcomes.Together, this has raised interest in targeting metabolic enzymes for cancer therapy, but also concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies target the specific metabolic needs of cancer cells and remain effective agents used in the clinic today. Research to understand how changes in cell metabolism promote tumor growth has accelerated in recent years. This has refocused efforts on targeting metabolic dependencies of cancer cells, an approach with the potential to have a major impact on patient care.

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Section: Box 2 Development Of L--asparaginase To Treat Allmentioning

confidence: 99%

Targeting cancer metabolism: a therapeutic window opens

Heiden

2011

Nat Rev Drug Discov

1,265

1,076

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“…The search for other asparaginase sources, like eucaryotic microorganisms, can lead to an enzyme with less adverse effects. The importance of microorganisms as L-asparaginase sources has been focused since the time it was obtained from Escherichia coli and its antineoplastic activity demonstrated in guinea pig serum (Broome 1961, Mashburn & Wriston 1964, Roberts et al 1966, Schawartz et al 1966. The E. coli and Erwinia enzymes were isolated, purified, and experimentally used as an anti-leukaemic agent in human patients (Clavell et al 1986, Story et al 1993.…”

mentioning

confidence: 99%

Production of L-asparaginase by filamentous fungi

Sarquis

Oliveira

Santos

et al. 2004

Mem. Inst. Oswaldo Cruz

141

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L-asparaginase production was investigated in the filamentous fungi Aspergillus tamarii and Aspergillus terreus.The fungi were cultivated in medium containing different nitrogen sources. A. terreus showed the highest L-asparaginase (activity) production level (58 U/L) when cultivated in a 2% proline medium. Both fungi presented the lowest level of L-asparaginase production in the presence of glutamine and urea as nitrogen sources. These results suggest that L-asparaginase production by of filamentous fungi is under nitrogen regulation.Key words: filamentous fungi -production of L-asparaginase -Aspergillus tamarii -Aspergillus terreus Asparaginase (L-asparagine amido hydrolase, E.C. 3.5.1.1) is an anti-neoplastic agent, used in the lymphoblastic leukaemia chemotherapy. Neoplastic cells cannot synthetase L-asparagine due the absence of L-asparagine synthetase (Keating et al. 1993). For this reason the commonest therapeutic practice is to inject intravenously free enzyme in order to decrease the blood concentration of Lasparagine affecting selectively the neoplastic cells (Mitchell et al. 1994). However, L-asparaginase from bacterial origin can cause hypersensitivity in the long-term used, leading to allergic reactions and anaphylaxis (Reynolds & Taylor 1993). The search for other asparaginase sources, like eucaryotic microorganisms, can lead to an enzyme with less adverse effects. The importance of microorganisms as L-asparaginase sources has been focused since the time it was obtained from Escherichia coli and its antineoplastic activity demonstrated in guinea pig serum (Broome 1961, Mashburn & Wriston 1964, Roberts et al. 1966, Schawartz et al. 1966. The E. coli and Erwinia enzymes were isolated, purified, and experimentally used as an anti-leukaemic agent in human patients (Clavell et al. 1986, Story et al. 1993. It demonstrated high potential against children's acute lymphoblastic leukaemia (Hill et al. 1967, Oettgen et al. 1967. Several research groups have studied asparaginase production and purification in attempt to minimize impurities that produce allergenic reations , Boss 1997, Gallagher et al. 1999.It has been observed that eukaryote microorganisms like yeast and filamentous fungi have a potential for asparaginase production (Wade et al. 1971, Wiame et al.1985, Pinheiro et al. 2001 asparaginase (De-Angeli et al. 1970, Arima et al. 1972, Curran et al. 1985.L-asparaginase belongs to an amidase group that produces aspartic acid and ammonia by asparagine hydrolysis (Wriston & Yellin 1973, Capizzi et al. 1984. Here we present a simple and rapid assay method for the detection of asparaginase from different strains of Aspergillum, Penicillium, and Fusarium genera of fungi using the Gulati et al. (1997) method. After an initial screening, strains presenting high asparaginase activity were cultivated in submerged fermentation in order to determine the production of this enzyme in the presence of different nitrogen sources. Moreover the question whether asparaginase from filamentous fungi is nitrogen regulated a...

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“…The precise mechanism of its action is still unknown although hydrolysis proceeds in two steps via a betaacyl enzyme as intermediate ( Figure 1) [14]. The mechanism of action of L-asparaginase has been elucidated by Broome in [15] (Figure 2). Where, following the administration of L-asparaginase, the nonessential amino acid asparagine is hydrolyzed into aspartic acid and ammonia, prevents protein synthesis of neoplasms.…”

Section: Antineoplastic Actionmentioning

confidence: 99%

Microbial Amidases and their Industrial Applications: A Review

El-Ghonemy¹

2015

J Med Microb Diagn

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Among the pediatric cancer in developed countries, acute leukemia ¬constitutes the major part with affecting 30-45 per 1,000,000 children each year. The effect of treatment varies with differences in patients clinical, immunologic and genetic characteristics. Therefore, the search for efficient drugs to solve this problem is being continued worldwide. Although several kinds of treatments are available, enzyme therapy is equally effective. Enzymes have been used as drugs; likewise L-asparaginase and L-glutaminase had received much attention in recent years due to their anticarcinogenic potential. These enzymes constitute one of the most biotechnologically and biomedically important group of therapeutic enzymes accounting for about 40% of the total worldwide enzyme sales. Various sources are found to be good producers of the enzymes: bacteria, fungi along with some of the plant and animal species. Food and Drug Administration and World Health Organization have approved L-asparaginase for the effective treatment of acute lymphoblastic leukemia and lymphsarcoma. L-asparaginase and L-glutaminase break down L-asparagine or L-glutamine into L-aspartic acid or L-glutamic acid, respectively, and ammonia. L-asparagine depletion results in nutritional deprivation, inhibition of protein synthesis, and subsequent apoptotic cell death in lymphoblasts. On the other hand, the ability of L-asparaginase to selectively hydrolyzes L-asparagine into L-aspartateis a potential way to reduce the amount of free L-asparagine in the starting materials of food production, thus reducing the imminent risk of generating a potential carcinogenic and neurotoxic acrylamide that formed from L-asparagine and reducing sugars in carbohydrate-containing foods (such as snacks and biscuits) when they are heated above 120oC. Therefore, the present review is an attempt to compile information on the sources, antino plastic action and industrial application of microbial amidases enzymes.

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Evidence that the L-Asparaginase Activity of Guinea Pig Serum is responsible for its Antilymphoma Effects

Cited by 411 publications

References 5 publications

Targeting cancer metabolism: a therapeutic window opens

Targeting cancer metabolism: a therapeutic window opens

Production of L-asparaginase by filamentous fungi

Microbial Amidases and their Industrial Applications: A Review

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