Asparaginase information and research studies

L-asparaginase is a hydrolase enzyme that catalyzes the conversion of L-asparagine. The discovery of the tumor-inhibitory properties of asparaginase began in the early 1950s with the observation that guinea pig serum-treated lymphoma-bearing mice underwent rapid and often complete regression.

L-asparaginase is one of the most important agent used in multidrug chemotherapy regimens in the treatment of cancers which derive from lymphoid system (acute lymhoblastic leukemias and non-hodgkin lymphoma). L-asparaginase leads to enzymatic cleavage of L-asparagine (amino acid essential for lymphoblasts' growth) to ammonia and L-aspartic acid, what results in depletion of L-asparagine in a serum and cerebrospinal fluid, and finally leads to destruction of lymphoblasts, which lack ability of endogenic L-asparagine production. In the course of L-asparaginase therapy severe side effects could be observed such as: coagulation disturbances, acute pancreatitis, anaphylactic shock and other types of allergic reaction, as well as liver and CNS failure.

Evaluation of Antineoplastic Activity of Extracellular Asparaginase Produced by Isolated Bacillus circulans.
Appl Biochem Biotechnol. 2009, Hymavathi M, Subba Rao C, Kennady PK, Nasaruddin K. Bioengineering and Environmental Centre, Indian Institute of Chemical Technology, Hyderabad, India
L-: Asparaginase is an important component in the treatment of acute lymphoblastic leukemia in children. Its antineoplastic activity toward malignant cells is due to their characteristic nature in slow synthesis of L-: asparagine (Asn), which causes starvation for this amino acid, while normal cells are protected from Asn starvation due to their ability to produce this amino acid. The relative selectivity with regard to the metabolism of malignant cells forces to look for novel asparaginase with little glutaminase-producing systems compared to existing enzyme. In this investigation, the role of the extracellular asparaginase enzyme produced by an isolated bacterial strain was studied. Biochemical characterization denoted that this isolated bacterial strain belongs to the Bacillus circulans species. The strain was tested for L-: asparaginase production, and it was observed that, under an optimized environment, this isolate produces a maximum of 85 IU ml(-1) within 24-h incubation. This enzyme showed less (60%) glutaminase activity compared to commercial Erwinia sp. L-: asparaginase. The partially purified enzyme showed an approximate molecular weight of 140 kDa. This enzyme potency in terms of antineoplastic activity was analyzed against the cancer cells, CCRF-CEM. Flow cytometry experiments indicated an increase of sub-G1 cell population when the cells were treated with L-: asparaginase.

Use of L-asparaginase in acute lymphoblastic leukemia: recommendations of the Polish Adult Leukemia Group.
Pol Arch Med Wewn. 2008; Piatkowska-Jakubas B, Adamczyk-Cioch M, Piszcz J, Hołowiecki J; Polish Adult Leukemia Group. Department of Hematology, Jagiellonian University, Medical College, Kraków, Poland.
L-asparaginase is a hydrolase that catalyzes the conversion of L-asparagine--an endogenous amino acid necessary for the function of some neoplastic cells, such as lymphoblasts. In most human cells deficiency of L-asparagine can be compensated by alternative synthesis pathway through which L-asparagine is produced from aspartic acid and glutamine by asparagine synthethase. Depletion of L-asparagine from plasma by L-asparaginase results in inhibition of RNA and DNA synthesis with the subsequent blastic cell apoptosis. Owing to the unique anti-cancer mechanism of action, L-asparaginase has been introduced to the multi drug chemotherapy in children and adults with acute lymphoblastic leukemia, which has contributed to significant improvement of therapy outcomes and to achieve complete remission in about 90% of patients. Notwithstanding its high therapeutic efficacy, L-asparaginase can increase the risk of thrombosis. Inhibition of protein synthesis causes most complications observed during treatment with a native and pegylated form of L-asparaginase, including impaired functions of liver, kidneys or central nervous system. Thrombotic events occur as a result of inhibited synthesis of anticoagulant proteins (mainly antithrombin). Coagulopathy has been observed in 1.1-4% of patients treated with the pegylated L-asparaginase and in 2.1-15% of those receiving its native form. In this paper approaches to optimize the therapy with L-asparaginase have been discussed.

Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia.
Int J Nanomedicine. 2006, Department of Pediatrics, Division of Hematology/Oncology, Keck School of Medicine, Childrens Hospital Los Angeles, Los Angeles, CA, USA.
About 4000 cases of acute lymphoblastic leukemia (ALL) are diagnosed very year in the US and many more through out the world. The majority of these cases are in children and young adults, making ALL the most common form of malignancy in these age groups. The treatment protocols of ALL are complex and use 6-12 drugs. Consequently, the improvement in the protocol design has improved significantly the success rate for long-term event-free survival in the past 20-30 years, which is now approximately 75% for patients afflicted with the higher risk ALL features and just above this percentage for patients with standard or good features. Despite this success, approximately 15% of patients die from ALL, making leukemic relapse the most common cause of treatment failure in pediatric oncology. Asparaginases have been the cornerstone of ALL therapies since the late 1970s. Native or pegylated L-asparaginase (ASNase or PEG-ASNase) are highly specific for the deamination of L-asparagine (Asn) to aspartic acid and ammonia. Depletion of Asn leads to a nutritional deprivation and inhibition of protein biosynthesis, resulting in apoptosis in T-lymphoblastic leukemias, which require Asn from external sources. The reactions of the host exposed to repeated asparaginase treatments as well as the up-regulation of the mammalian enzymes to overcome the ASN-depletion toxic condition are of significant importance and may make us relearn the lessons on this important antileukemic drug.

Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors.
J Transl Med. 2010.
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC. In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizimab, vincristine, and asparaginase. Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC preclinical studies. The rapamycin dosing comparison study indicates that the duration of rapamycin treatment is more important than dose intensity. We also found that angiogenesis inhibitors and asparaginase reduce tumor growth in a TSC2 tumor mouse model and although these drugs are not as effective as rapamycin, these drug classes may have some therapeutic potential in the treatment of TSC related tumors.