противоопухолевые ферменты

Нарушенный метаболизм метионина в злокачественных клетках — потенциальная мишень для противоопухолевой терапии

ОБЗОРЫ , , , , , ,

В.С. Покровский1, Д.Ж. Давыдов1, Н.В. Ануфриева2, Д.Д. Жданов3, Е.М. Трещалина1, Т.В. Демидкина2, Е.А. Морозова2

1 ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, лаборатория комбинированной терапии опухолей, Каширское ш., д. 24, Москва, Российская Федерация, 154478

2 ФГБУН «Институт молекулярной биологии им. В.А. Энгельгардта» РАН, ул. Вавилова, д. 32, Москва, Российская Федерация, 119991

3 ФГБУ «НИИ биомедицинской химии им. В.Н. Ореховича», Погодинская ул., д. 10, стр. 8, Москва, Российская Федерация, 119121

Для переписки: Вадим Сергеевич Покровский, д-р мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 154478; тел.: 8(499)324-14-09; e-mail: vadimpokrovsky@yandex.ru

Для цитирования: Покровский В.С., Давыдов Д.Ж., Ануфриева Н.В. и др. Нарушенный метаболизм метионина в злокачественных клетках — потенциальная мишень для противоопухолевой терапии. Клиническая онкогематология. 2017;10(3):324–32.

DOI: 10.21320/2500-2139-2017-10-3-324-332

РЕФЕРАТ

В обзоре представлены особенности клеточного метаболизма метионина, а также известные данные о механизмах развития метиониновой зависимости в злокачественных клетках. Рассмотрены возможности использования безметиониновой диеты для контроля опухолевого роста у больных с различными формами рака. Сгруппированы и обобщены новейшие сведения о метионин-γ-лиазе — ферменте, обеспечивающем элиминацию метионина из плазмы. Раскрыта его роль в качестве потенциального противоопухолевого фермента. Обобщены сведения о продуцентах метионин-γ-лиазы, активности данного фермента, полученного из различных источников, и сведения о моделях опухолей и клеточных культурах, проявляющих метиониновую зависимость.

Ключевые слова: метионин-γ-лиаза, метионин, метиониновая зависимость, злокачественные клетки, рак, противоопухолевые ферменты, противоопухолевая терапия.

Получено: 16 декабря 2016 г.

Принято в печать: 6 марта 2017 г.

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ЛИТЕРАТУРА

  1. Thomas D, Surdin-Kerjan Y. Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1997;61(4):503–32.
  2. Ravanel S, Gaki B, Job D, Douce R. The specific features of methionine biosynthesis and metabolism in plants. Proc Natl Acad Sci USA. 1998;95(13):7805–12. doi: 10.1073/pnas.95.13.7805.
  3. Sekowska A, Kung H, Danchin A, et al. Sulfur metabolism in Escherichia coli and related bacteria: facts and fiction. J Mol Microbiol Biotechnol. 2000;2(2):145–77.
  4. Guedes RL, Prosdocimi F, Fernandes GR, et al. Amino acids biosynthesis and nitrogen assimilation pathways: A great genomic deletion during eukaryotes. BMC Genom. 2011;12(Suppl 4):S2. doi: 10.1186/1471-2164-12-S4-S2.
  5. Satishchandran C, Taylor JC, Markham GD, et al. Novel Escherichia coli K-12 mutants impaired in S-adenosylmethionine synthesis. J Bacteriol. 1990;172(8):4489–96. doi: 10.1128/jb.172.8.4489-4496.1990.
  6. Zingg JM. Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis. Carcinogenesis. 1997;18(5):869–82. doi: 10.1093/carcin/18.5.869.
  7. Krasinskas A, Bartlett DL, Cieply K, et al. CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival. Mod Pathol. 2010;23(4):531–8. doi: 10.1038/modpathol.2009.186.
  8. Roje S. S-Adenosyl-L-methionine: Beyond the universal methyl group donor. Phytochemistry 2006;67(15):1686-1698. doi: 10.1016/j.phytochem.2006.04.019.
  9. Anderson ME. Glutatione: an overview of biosynthesis and modulation. Chem Biol Interact. 1998;111(112):1–14. doi: 10.1016/s0009-2797(97)00146-4.
  10. Thomas T, Tomas TJ. Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell Mol Life Sci. 2001;58(2):244–58. doi: 10.1007/PL00000852.
  11. Pirkov I, Norbeck J, Gustafsson L, et al. A complete inventory of all enzymes in the eukaryotic methionine salvage pathway. FEBS J. 2008;275(16):4111–20. doi: 10.1111/j.1742-4658.2008.06552.x.
  12. Quash G, Roch AM, Chantepie J, et al. Methional derived from 4-methylthio-2-oxobutanoate is a cellular mediator of apoptosis in BAF3 lymphoid cells. Biochem J. 1995;305(3):1017–25. doi: 10.1042/bj3051017.
  13. Bassila C, Ghemrawi R, Flayac J, et al. Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC. Biochim Biophys Acta. 2017;1863(1):103–12. doi: 10.1016/j.bbadis.2016.10.016.
  14. Морозова Е.А., Куликова В.В., Яшин Д.В. и др. Кинетические характеристики и цитотоксическая активность рекомбинантных препаратов метионин–гамма-лиазы Clostridium tetani, Clostridium sporogenes, Porphyromonas gingivalis и Citrobacter freundii. Acta Naturae. 2013;5:54–60.
    [Morozova EA, Kulikova VV, Yashin DV, et al. Kinetic parameters and cytotoxic activity of recombinant methionine γ-lyase from Clostridium tetani, Clostridium sporogenes, Porphyromonas gingivalis and Citrobacter freundii. Acta Naturae. 2013;5:54–60. (In Russ)]
  15. Cavuoto P, Fenech MF. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treat Rev. 2012;38(6):726–36. doi: 10.1016/j.ctrv.2012.01.004.
  16. Sugimura T, Birnbaum SM, Winitz M, et al. Quantitative nutritional studies with water-soluble, chemically defined diets. VIII. The forced feeding of diets each lacking in one essential amino acid. Arch Biochem Bioophys. 1959;81(2):448–55. doi: 10.1016/0003-9861(59)90225-5.
  17. Buch L, Streeter D, Halpern RM, et al. Inhibition of transfer ribonucleic acid methylase activity from several human tumors by nicotinamide and nicotinamide analogs. Biochemistry. 1972;11(3):393–7. doi: 10.1021/bi00753a015.
  18. Halpern BC, Clark BR, Hardy DN, et al. The effect of replacement of methionine by homocystine on survival of malignant and normal adult mammalian cells in culture. Proc Natl Acad Sci USA. 1974;71(4):1133–6. doi: 10.1073/pnas.71.4.1133.
  19. Judde JG, Ellis M, Frost P, et al. Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res. 1989;49(17):4859–65.
  20. Hoffman RM, Jacobsen J. Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci USA. 1980;77(12):7306–10. doi: 10.1073/pnas.77.12.7306.
  21. Guo H, Lishko VK, Herrera H, et al. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res. 1993;53(23):5676–9.
  22. Breillout F, Antoine E, Poupon MF. Methionine dependency of malignant tumors: a possible approach for therapy. J Natl Cancer Inst. 1990;82(20):1628–32. doi: 10.1093/jnci/82.20.1628.
  23. Lu S, Epner DE. Molecular mechanisms of cell cycle block by methionine restriction in human prostate cancer cells. Nutr Cancer. 2000;38(1):123–30. doi: 10.1207/S15327914NC381_17.
  24. Poirson-Bichat F, Goncalves RA, Miccoli L, et al. Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. Cancer Res. 2000;6(2):643–53.
  25. Guo H, Herrera H, Groce A, et al. Expression of the biochemical defect of methionine dependence in fresh patient tumors in primary histoculture. Cancer Res. 1993;53(11):2479–83.
  26. Kim DH, Muto M, Kuwahara Y, et al. Array-based comparative genomic hybridization of circulating esophageal tumor cells. Oncol Rep. 2006;16(5):1053–9. doi: 10.3892/or.16.5.1053.
  27. Poirson-Bichat F, Gonfalone G, Bras-Gone RA, et al. Growth of methionine dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Br J Cancer. 1997;75(11):1605–12. doi: 10.1038/bjc.1997.274.
  28. Jo YK, Park MH, Choi H, et al. Enhancement of the Antitumor Effect of Methotrexate on Colorectal Cancer Cells via Lactate Calcium Salt Targeting Methionine Metabolism / Nutr Cancer. 2017;69(4):663–73. doi: 10.1080/01635581.2017.1299879.
  29. Kreis W, Goodenow M. Methionine requirement and replacement by homocysteine in tissue cultures of selected rodent and human malignant and normal cells. Cancer Res. 1978;38(8):2259–62.
  30. Kennelly JC, Blair JA, Pheasant AE. Metabolism of 5-methyltetrahydrofolate by rats bearing the Walker 256 carcinosarcoma. Br J Cancer. 1982;46(3):440–3. doi: 10.1038/bjc.1982.222.
  31. Watkins D. Cobalamin metabolism in methionine-dependent human tumour and leukemia cell lines. Clin Investig Med. 1998;21(3):151–8.
  32. Bergstrom M, Ericson K, Hagenfeldt L, et al. PET study of methionine accumulation in glioma and normal brain tissue: competition with branched chain amino acids. J Comput Assist Tomogr. 1987;11(2):208–13. doi: 10.1097/00004728-198703000-00002.
  33. Stern PH, Hoffman RM. Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro. 1984;20(8):663–73. doi: 10.1007/bf02619617.
  34. Hoffman RM. Altered methionine metabolism and transmethylation in cancer. Anticancer Res. 1985;5(1):1–30.
  35. Давыдов Д.Ж., Морозова Е.А., Ануфриева Н.В. и др. Динамика содержания метионина в плазме крови мышей после введения метионин-гамма-лиазы. Российский биотерапевтический журнал. 2017;16(Suppl 1):28–9.
    [Davydov DZh, Morozova EA, Anufrieva NV, et al. The changes in plasma methionin concentrations in mice after methionine-gamma-lyase injection. Rossiiskii bioterapevticheskii zhurnal. 2017;16(Suppl 1):28–9. (In Russ)]
  36. Hoffman RM. Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis: a review and synthesis. Biochim Biophys Acta. 1983;738(1–2):49–87. doi: 10.1016/0304-419x(84)90019-2.
  37. de Oliveira SF, Ganzinelli M, Chila R, et al. Characterization of MTAP Gene Expression in Breast Cancer Patients and Cell Lines. PLoS One. 2016;11(1):e0145647. doi: 10.1371/journal.pone.0145647.
  38. Nobori T, Karras JG, Della Ragione F, et al. Absence of methilthioadenosine phosphorylase in human gliomas. Cancer Res. 1991;51(12):3193–7.
  39. Schmid M, Malicki D, Nobori T, et al. Homozygous deletions of methilthioadenosine phosphorylase (MTAP) are more frequent then p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancer (NSCLC). Oncogene. 1998;17(20):2669–75. doi: 10.1038/sj.onc.1202205.
  40. M’soka TJ, Nishioka J, Taga A, et al. Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay. Leukemia. 2000;14(5):935–40. doi: 10.1038/sj.leu.2401771.
  41. Garcia-Castellano JM, Villanueva A, Healey JH, et al. Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma. Clin Cancer Res. 2002;8(3):782–7.
  42. Behrmann I, Wallner S, Komyod W, et al. Characterization of methylthioadenosin phosphorylase (MTAP) expression in malignant melanoma. Am J Pathol. 2003;162(2):683–90. doi: 10.1016/S0002-9440(10)63695-4.
  43. Komatsu A, Nagasaki K, Fujimori M, et al. Identification of novel deletion polymorphisms in breast cancer. Int J Oncol. 2008;33(2):261–70.
  44. Nobori T, Miura K, Wu DJ, et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368(6473):753–6. doi: 10.1038/368753a0.
  45. Nobori T, Takabayashi K, Tran P, et al. Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. Proc Natl Acad Sci USA. 2000;93(12):6203–8. doi: 10.1073/pnas.93.12.6203.
  46. Brat DJ, James CD, Jedlicka AE, et al. Molecular genetic alterations in radiation-induced astrocytomas. Am J Pathol. 1999;154(5):1431–8. doi: 10.1016/S0002-9440(10)65397-7.
  47. Christopher SA, Diegelman P, Porter CW, et al. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16(cdkN2a/ARF), acts as a tumor suppressor in a breast cancer cell line. Cancer Res. 2002;62(22):6639–44.
  48. Jagasia AA, Block JA, Diaz MO, et al. Partial deletions of the CDKN2A and MTS2 putative tumor suppressor genes in a myxoid chondrosarcoma. Cancer Lett. 1996:105(1):77–90. doi: 10.1016/0304-3835(96)04273-5.
  49. Jagasia AA, Block JA, Qureshi A, et al. Chromosome 9 related aberration and deletions of the CDKN2 and MTS2 putative tumor suppressor genes in human chondrosarcomas. Cancer Lett. 1996;105(1):91–103. doi: 10.1016/0304-3835(96)04274-7.
  50. Powel EL, Leoni LM, Canto MI, et al. Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am J Surg Phatol. 2005;29(11):1497–504. doi: 10.1097/01.pas.0000170349.47680.e8.
  51. Kim J, Kim MA, Min SY, et al. Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma. Genes Chromos Cancer. 2011;50(6):421–33. doi: 10.1002/gcc.20867.
  52. Huang H-Y, Li S-H, Yu S-C, et al. Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors. Clin Cancer Res. 2009;15(22):6963–72. doi: 10.1158/1078-0432.CCR-09-1511.
  53. Suzuki T, Maruno M, Wada K, et al. Genetic analysis of human glioblastomas using a genomic microarray system. Brain Tumor Pathol. 2004;21(1):27–34. doi: 10.1007/bf02482174.
  54. Zhang H, Chen ZH, Savarese TM, et al. Codeletion of the genes for p16INK4 methihthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines. Cancer Genet Cytogenet. 1996;86(1):22–8. doi: 10.1016/0165-4608(95)00157-3.
  55. Perry A, Nobory T, Ru N, et al. Detection of p16 gene deletions in gliomas: comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR. J Neuropathol Exp Neurol. 1997;56(9):999–1008. doi: 10.1097/00005072-199709000-00005.
  56. Orentreich N, Matias JR, DeFelice A, Zimmerman JA. Low methionine ingestion by rats extends life span . J Nutr. 1993;123(2):269–74.
  57. Efferth DE, Miyachi H, Drexler HG, Gebhart E. Methionine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells. Blood Cells Mol Dis. 2002;28(1):47–56. doi: 10.1006/bcmd.2002.0483.
  58. Bertin R, Acquaviva C, Mirebeau D, et al. CDKN2A, CDKN2B and MTAP gene dosage permits precise characterization of mono- and bi-allelic 9p21 deletions in childhood acute lymphoblastic leukemia. Genes Chromos Cancer. 2003;37(1):44–57. doi: 10.1002/gcc.10188.
  59. Usvasalo A, Ninomiya S, Raty R, et al. Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single-nucleotide polymorphism microarray analyses. Genes Chromos Cancer. 2010;49(4):309–18. doi: 10.1002/gcc.20741.
  60. Kamath A, Tara H, Xiang B, et al. Double-minute MYC amplification and deletion of MTAP, CDKN2A, CDKN2B and ELAVL2 in an acute myeloid leukemia characterized by oligonucleotide-array comparative genomic hybridization. J Cancer Genet Cytogenet. 2008;183(2):117–20. doi: 10.1016/j.cancergencyto.2008.02.011.
  61. Marce S, Balague O, Colomo L, et al. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Clin Cancer Res. 2006;12(12):3754–61. doi: 10.1158/1078-0432.CCR-05-2780.
  62. Dreyling MH, Roulston D, Bohlander SK, et al. Codelition of CDKN2 and MTAP genes in a subset of non-Hodgkin’s lymphoma may be associated with histologic transformation from low-grade to diffuse large-cell lymphoma. Genes Chromos Cancer. 1998;22(1):72–8. doi: 10.1002/(sici)1098-2264(199805)22:1<72::aid-gcc10>3.3.co;2-g.
  63. Illei PB, Busch VW, Zakowski MF, Ladanyi M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Cancer Res. 2003;9(6):2108–13.
  64. Mora J, Alaminos M, de Torres C, et al. Comprehensive analysis of the 9p21 region in neuroblastoma suggests a role for genes mapping to 9p21–23 in the biology of favorable stage 4 tumours. Br J Cancer. 2004;91(6):1112–8. doi: 10.1038/sj.bjc.6602094.
  65. Hustinx SR, Hruban RH, Leoni LM, et al. Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy. Cancer Biol Ther. 2005;4(1):83–6. doi: 10.4161/cbt.4.1.1380.
  66. Hustinx SR, Leoni ML, Yeo CJ, et al. Concordant loss of MTAP and p16/CDRN2A expressions in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol. 2005;18(7):959–63. doi: 10.1038/modpathol.3800377.
  67. Chen ZH, Zhang H, Savarese TM. Gene deletion chemoselectivity: codeletion of the genes for p16 (INK4), methylthioadenosine phosphorylase, and the alpha- and beta-interferons in human pancreatic cell carcinoma lines and its implications for. Cancer Res. 1996;56(5):1083–90.
  68. Brownhill SC, Taylor C, Burchill SA. Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT. Br J Cancer. 2007;96(12):1914–23. doi: 10.1038/sj.bjc.6603819.
  69. Conway C, Beswick S, Elliott F. Deletion at chromosome arm 9p in relation to BRAF and NRAS mutation and prognostic significance for primary melanoma. Genes Chromos Cancer. 2010;49(5):425–38. doi: 10.1002/gcc.20753.
  70. Worsham MJ, Chem KM, Tiwari N, et al. Fine-mapping loss of gene architecture at the CDKN2B (p15INK4b), CDKN2A (p14ARF, p16INK4a) and MTAP genes in head and neck squamous cell carcinoma. Arch Otol Head Neck Surg. 2006;132(4):409–15. doi: 10.1001/archotol.132.4.409.
  71. Mirebeau D, Acquaviva C, Suciu S, et al. The prognostic significance of CDKN2A, CDKN2B and EORTC studies 58881 and 58951. Haematologica. 2006;91(7):881–5.
  72. Tang B, Li YN, Kruger WD. Defects in methylthioadenosine phosphorylase is associated with but not responsible for methionine-dependent tumor cell growth. Cancer Res. 2000;60(19):5.
  73. Basu I, Locker J, Cassera MB, et al. Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5ʹ-methilthioadenosine. J Biol Chem. 2010;286(6):4902–11. doi: 10.1074/jbc.M110.198374.
  74. Subhi AL, Diegelman P, Porter CW, et al. Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites. J Biol Chem. 2003;278(50):49868–73. doi: 10.1074/jbc.M308451200.
  75. Kenyon SH, Waterfield CJ, Timbrell JA, et al. Methionine synthase activity and sulphur amino acid levels in the rat liver tumor cells HTS and Phi-1. J. Biochem Pharmacol. 2002;63(3):381–91. doi: 10.1016/s0006-2952(01)00874-7.
  76. Ma E, Iwasaki M, Junko I, et al. Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer. 2009;24(9):122. doi: 10.1186/1471-2407-9-122.
  77. Stern PH, Wallace CD, Hoffman RM. Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell physiol. 1984;119(1):29–34. doi: 10.1002/jcp.1041190106.
  78. Lu M, Wang F, Qiu J. Methionine synthase A2756G polymorphism and breast cancer risk: a meta-analysis involving 18,953 subjects. Breast Cancer Res Treat. 2010;123(1):213–7. doi: 10.1007/s10549-010-0755-9.
  79. Linnebank M, Fliessbach K, Kolsch H, et al. The methionine synthase polymorphism c.2756Aright curved arrow G (D919G) is relevant for disease-free longevity. Int J Mol Med. 2005;16(4):759–61.
  80. Dhillon V, Thomas P, Fenech M. Effect of common polymorphisms in folate uptake and metabolism genes on frequency of micronucleated lymphocytes in a South Australian cohort. Mutat Res. 2009;665(1–2):1–6. doi: 10.1016/j.mrfmmm.2009.02.007.
  81. Beetstra S, Suthers G, Dhillon V, et al. Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer. Cancer Epidemiol Biomark Prev. 2008;17(10):2565–71. doi: 10.1158/1055-9965.EPI-08-0140.
  82. Drennan CL, Huang S, Drummond J, et al. How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase. Science. 1994;266(5191):1669–74. doi: 10.1126/science.7992050.
  83. Tisdale MJ. Methionine metabolism in Walker carcinosarcoma in vitro. Eur J Cancer. 1980;16(3):407–14. doi: 10.1016/0014-2964(80)90360-6.
  84. Liteplo RG, Hipwell SE, Rosenblatt DS, et al. Changes in cobalamin metabolism are associated with the altered methionine auxotrophy of highly growth autonomous human melanoma. J Cell Physiol. 1991;149(2):332–8. doi: 10.1002/jcp.1041490222.
  85. Fiskerstrand T, Christensen B, Tysnes OB, et al. Development and reversion of methionine dependence in a human glioma cell line: relation to homocysteine remethylation and cobalamin status. Cancer Res. 1994;54(18):4899–906.
  86. Watkins D. Cobalamin metabolism in methionine-dependent human tumour and leukemia cell lines. Clin Invest Med. 1998;21(3):151–8.
  87. Tang B, Mustafa A, Gupta S, et al. Methionine-deficient diet induces post-transcriptional down-regulation of cystathionine beta-synthase. Nutrition. 2009;26(11–12):170–5. doi: 10.1016/j.nut.2009.10.006.
  88. Breillout F, Hadida F, Echinard-Garin P, et al. Decreased rat rhabdomyosarcoma pulmonary metastases in response to low methionine diet. Anticancer Res. 1987;7(4b):861–7.
  89. Komninou D, Leutzinger Y, Reddy BS, et al. Methionine restriction inhibits colon carcinogenesis. Nutr Cancer. 2006;54(2):202–8. doi: 10.1207/s15327914nc5402_6.
  90. Graziosi L, Mencarelli A, Renga B, et al. Epigenetic modulation by methionine deficiency attenuates the potential for gastric cancer cell dissemination. J Gastrointest Surg. 2013;17(1):39–49. doi: 10.1007/s11605-012-1996-1.
  91. Theuer RC. Effect of essential amino acid restriction on the growth of female C57BL mice and their implanted BW10232 adenocarcinomas. J Nutr. 1971;101(2):223–32.
  92. Caro P, Gomez J, Sanchez I, et al. Forty percent methionine restriction decreases mitochondrial oxygen radical production and leak at complex I during forward electron flow and lowers oxidative damage to proteins and mitochondrial DNA in rat kidney and brain mitochondria. Rejuven Res. 2009;12(6):421–34. doi: 10.1089/rej.2009.0902.
  93. Ryu CS, Kwak HC, Lee KS, et al. Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells. Toxicol Appl Pharmacol. 2011;15;255(1):94–102. doi: 10.1016/j.taap.2011.06.004.
  94. Goseki N, Endo M. Thiol depletion and chemosensitization on nimustine hydrochloride by methionine-depleting total parenteral nutrition. Tohoku J Exp Med. 1990;161(3):227–39. doi: 10.1620/tjem.161.227.
  95. Hoshiya Y, Guo H, Kubota T, et al. Human tumors are methionine dependent in vivo. Anticancer Res. 1995;15(3):717–8.
  96. Epne DE, Morrow S, Wilcox M, Houghton JL. Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase l clinical trial of dietary methionine restriction. Nutr Cancer. 2002;42(2):158–66. doi: 10.1207/S15327914NC422_2.
  97. Goseki N, Yamazaki S, Shimojyu K, et al. Synergistic effect of methionine-depleting total parenteral nutrition with 5-fluorouracil on human gastric cancer: a randomized, prospective clinical trial. Jpn J Cancer Res. 1995;86(5):484–9. doi: 10.1111/j.1349-7006.1995.tb03082.x.
  98. Durando X, Farges MC, Buc E, et al. Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology. 2008;78(3–4):205–9. doi: 10.1159/000313700.
  99. Ornish D, Weidner G, Fair WR, et al. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005;174(3):1065–70. doi: 10.1097/01.ju.0000169487.49018.73.
  100. McCarty M, Barroso-Aranda J, Contreras F, et al. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses. 2009;72(2):125–8. doi: 10.1016/j.mehy.2008.07.044.
  101. Kack H, Sandmark J, Gibson K, et al. Crystal structure of diaminopelargonic acid synthase: evolutionary relationships between pyridoxal-5ʹ-phosphate-dependent enzymes. J Mol Biol. 1999;291:857–76. doi: 10.1006/jmbi.1999.2997.
  102. Fernandes HS, Silva Teixeira CS, Fernandes PA, et al. Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections. Expert Opin Ther Pat. 2017;27(3):283–97. doi: 10.1080/13543776.2017.1254194.
  103. Gay F, Aguera K, Senechal K, et al. Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6. Cancer Med. 2017. doi: 10.1002/cam4.1086.
  104. Покровский В.С., Трещалина Е.М. Ферментные препараты в онкогематологии: актуальные направления экспериментальных исследований и перспективы клинического применения. Клиническая онкогематология. 2014;7(1):28–38.
    [Pokrovskiy VS, Treshchalina YeM. Enzymes in oncohematology: relevant directions of experimental studies and prospects of clinical use. Klinicheskaya onkogematologiya. 2014;7(1):28–38. (In Russ)]
  105. Манухов И.В., Мамаева Д.В., Морозова Е.А. и др. L-метионин–гамма-лиаза Citrobacter freundii: клонирование гена и кинетические параметры фермента. Биохимия. 2006;71(4):454–63.
    [Manukhov IV, Mamaeva DV, Morozova EA, et al. L-methionine γ-lyase from Citrobacter freundii: cloning of the gene and kinetic parameters of the enzyme. Biokhimiya. 2006;71(4):454–63. (In Russ)]
  106. Cellarier E, Durando X, Vasson MP, et al. Methionine dependency and cancer treatment. Cancer Treat Rev. 2003;29(6):489–99. doi: 10.1016/s0305-7372(03)00118-x.
  107. Tan Y, Xu M, Hoffman RM. Broad selective efficacy of recombinant methioninase and polyethylene glycol-modified recombinant methioninase on cancer cells in vitro. Anticancer Res. 2010;30:1041–6.
  108. Kreis W, Hession C. Isolation and purification of L-methionine-alpha-deamino-gamma-mercaptomethane-lyase (L-methioninase) from Clostridium sporogenes. Cancer Res. 1973;33:1862–5.
  109. Hori H, Takabayashi K, Orvis L, et al. Gene cloning and characterization of Pseudomonas putida L-methionine-alpha-deamino-gamma-mercaptomethane-lyase. Cancer Res. 1996;56(9):2116–22.
  110. El-Sayed SA, Shouman HM, Nassrat HM. Pharmacokinetics, immunogenicity and anticancer efficiency of Aspergillus flavipes L-methioninase. Enzyme Microb Technol. 2012;51(4):200–10. doi: 10.1016/j.enzmictec.2012.06.004.
  111. Huang K-Y, Hu H-Y, Tang Y-L, et al. High-level expression, purification and large-scale production of L-methionine γ-Lyase from Ideomarina as a novel anti-leucemic drug. Mar Drugs. 2015;13(8):5492–507. doi: 10.3390/md13085492.
  112. Yano S, Li S, Han Q, et al. Selective methioninase-inducted trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget. 2014;5(18):8729–36. doi: 10.18632/oncotarget.2369.
  113. Nagahama T, Goseki N, Endo M. Doxorubicin and vincristine with methionine depletion contributed to survival in the Yoshida sarcoma bearing rats. Anticancer Res. 1998;18(1):25–31.
  114. Machrover D, Zittoun J, Broet Ph, et al. Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid. Biochem Pharmacol. 2001;61(7):867–76. doi: 10.1016/s0006-2952(01)00560-3.
  115. Smiraglia DJ. Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Hum Mol Genet. 2001;10(13):1413–9. doi: 10.1093/hmg/10.13.1413.
  116. Jeanblanc M, Mousli M, Hopfner R, et al. The retinoblastoma gene and its product are targeted by ICBP90: a key mechanism in the G1/S transition during the cell cycle. Oncogene. 2005;24(49):7337–45. doi: 10.1038/sj.onc.1208878.
  117. Hu J, Cheung NK. Methionine depletion with recombinant methioninase: In vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drug. Int J Cancer. 2009;124(7):1700–6. doi: 10.1002/ijc.24104.
  118. Kokkinakis DM, Schold H, Hori H, et al. Effect of long-term depletion of plasma methionine on the growth and survival of human brain tumor xenografts in athymic mice. Nutr Cancer. 1997;29(3):195–204. doi: 10.1080/01635589709514624.
  119. Tan Y, Xu M, Guo H, et al. Anticancer efficacy of methioninase in vivo. Anticancer Res. 1996;16(6С):3931–6.
  120. Tan Y, Sun X, Xu M, et al. Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res. 1999;5(8):2157–63.
  121. Yoshioka T, Wada T, Uchida N, et al. Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res. 1998;58(12):2583–7.
  122. Hoshiya Y, Kubota T, Matsuzaki SW, et al. Methionine starvation modulates the efficacy of cisplatin on human breast cancer in nude mice. Anticancer Res. 1996;16(6B):3515–7.
  123. Kokkinakis DM, Hoffman RM, Frenkel EP, et al. Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res. 2001;61(10):4017–23.
  124. Tan Y, Zavala JSr, Xu M, et al. Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients. Anticancer Res. 1996;16(6):3937–42.
  125. Morozova EA, Anufrieva NV, Davydov DZ, et al. Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes. Biomed Pharmacother. 2017;88:978–84. doi: 10.1016/j.biopha.2017.01.127.
  126. Покровский В.С., Лесная Н.А., Трещалина Е.М. и др. Перспективы разработки новых ферментных противоопухолевых препаратов. Вопросы онкологии. 2011;57(2):155–64.
    [Pokrovskii VS, Lesnaya NA, Treshchalina EM, et al. Perspectives in the development of new enzyme anticancer treatments. Voprosy onkologii. 2011;57(2):155–64. (In Russ)]
  127. Покровская М.В., Покровский В.С., Соколов Н.Н. Дифференциальная среда для выявления штаммов бактерий-продуцентов L-аспарагиназ. Прикладная биохимия и микробиология. 2011;47(2):183–6.
    [Pokrovskaya MV, Pokrovskii VS, Sokolov NN, et al. Differential medium for revealing bacterial producer strains of L-asparaginases.) Prikladnaya biokhimiya i mikrobiologiya. 2011;47(2):183–6. (In Russ)]
  128. Pokrovskii VS, Pokrovskaya MV, Aleksandrova SS, et al. Physicochemical properties and antiproliferative activity of recombinant Yersinia pseudotuberculosis L-asparaginase. Appl Biochem Microbiol. 2013;49(1):18–22. doi: 10.1134/s000368381301016x.
  129. Pokrovskaya MV, Pokrovskiy VS, Aleksandrova SS, et al. Recombinant intracellular Rhodospirillum rubrum L-asparaginase with low L-glutaminase activity and antiproliferative effect. Biochem (Moscow) Suppl. Series B: Biomed Chem. 2012;6(2):123–31. doi: 10.1134/s1990750812020096.
  130. Sidoruk KV, Bogush VG, Pokrovsky VS, et al. Creation of a producent, optimization of expression, and purification of recombinant Yersinia pseudotuberculosis L-asparaginase. Bull Exp Biol Med. 2011;152(2):219–23. doi: 10.1007/s10517-011-1493-7.
  131. Pokrovsky VS, Pokrovskaya MV, Aleksandrova SS, et al. Comparative immunogenicity and structural analysis of epitopes of different bacterial L-asparaginases. BMC Cancer. 2016;16(1):89. doi: 10.1186/s12885-016-2125-4.
  132. Sannikova EP, Bulushova NV, Cheperegin SE, et al. The modified heparin-binding L-asparaginase of Wolinella succinogenes. Mol Biotechnol. 2016;58(8–9):528–39. doi: 10.1007/s12033-016-9950-1.
  133. Pokrovskaya MV, Aleksandrova SS, Pokrovsky VS, et al. Identification of functional regions in the Rhodospirillum rubrum L-asparaginase by site-directed mutagenesis. Mol Biotechnol. 2015;57(3):251–64. doi: 10.1007/s12033-014-9819-0.
  134. Покровский В.С., Лукашева Е.В., Трещалина Е.М. и др. Экспериментальная оценка синергизма цисплатина с L-лизин-α-оксидазой. Вопросы онкологии. 2014;60(1):90–3.
    [Pokrovskii VS, Lukasheva EV, Treshchalina EM, et al. Experimental evaluation of synergism of cisplatin with L-lysine-α-oxidase.) Voprosy onkologii. 2014;60(1):90–3. (In Russ)]
  135. Покровский В.С., Трещалина Е.М., Трещалин И.Д. и др. Оценка противоопухолевой эффективности комбинации L-лизин-α-оксидазы и иринотекана в эксперименте. Онкология. 2012;2:58–61.
    [Pokrovskii VS, Treshchalina EM, Treshchalin ID, et al. Evaluation of the antitumor efficacy of a combination of L-lysine α-oxidase and irinotecan in the experiment. Onkologiya. 2012;2:58–61. (In Russ)]

Ферментные препараты в онкогематологии: актуальные направления экспериментальных исследований и перспективы клинического применения

ОБЗОРЫ , , , , , ,

В.С. Покровский, Е.М. Трещалина

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

РЕФЕРАТ

Последние годы в области разработки новых противоопухолевых препаратов на основе ферментов продемонстрированы существенные достижения. Помимо L-аспарагиназы, которая применяется в онкогематологии уже более 30 лет, два фермента — L-аргининдезиминаза и ранпирназа — прошли несколько этапов клинических исследований. Для целого ряда ферментов показана противоопухолевая активность на доклиническом этапе в экспериментах in vivo: L-метионин-гамма-лиаза, L-лизин-альфа-оксидаза, биназа. В настоящем обзоре представлены ферменты, продемонстрировавшие на различных этапах исследований противоопухолевую активность, и перспективы их использования в онкогематологии.

Ключевые слова: противоопухолевые ферменты, L-аспарагиназа, L-метионин-гамма-лиаза, L-лизин-альфа-оксидаза, L-аргининдезиминаза, L-фенилаланин-аммиак-лиаза, ранпирназа.

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ЛИТЕРАТУРА

  1. Kidd J.G. Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. J. Exp. Med. 1953; 98: 565–82.
  2. Broome J.D. Evidence that the L-asparaginase activity of guinea pig serum is responsible for its antilymphoma effects. Nature 1961; 191: 1114–5.
  3. Трещалина Е.М. Противоопухолевая активность веществ природного происхождения. М.: Практическая медицина, 2005. [Treshchalina Ye.M. Protivoopukholevaya aktivnost veshchestv prirodnogo proiskhozhdeniya (Anti-tumor activity of substances of natural origin). M.: Prakticheskaya meditsina, 2005.]
  4. Jaccard A., Petit B., Girault S. et al. L-asparaginase-based treatment of 15 western patients with extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol. 2009; 20(1): 110–6.
  5. Obama K., Tara M., Niina K. L-asparaginase induced complete remission in Epstein-Barr virus positive, multidrug resistant, cutaneous T-cell lymphoma. Int. J. Hematol. 1999; 69(4): 260–2.
  6. Yong W., Zheng W., Zhang Y. et al. L-аsparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int. J. Hematol. 2003; 78(2): 163–7.
  7. Ollenschlager G., Roth E., Linkesch W. et al. Asparaginase-induced derangements of glutamine metabolism: the pathogenetic basis for some drugrelated side-effects. Eur. J. Clin Invest. 1988; 18(5): 512–6.
  8. Villa P., Corada M., Bartosek I. L-asparaginase effects on inhibition of protein synthesis and lowering of the glutamine content in cultured rat hepatocytes. Toxicol. Lett. 1986; 32(3): 235–41.
  9. Warrell R.P.Jr., Chou T.C., Gordon C. et al. Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults. Cancer Res. 1980; 40(12): 4546–51.
  10. Reinert R.B., Oberle L.M., Wek A.S. et al. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparagine. J. Biol. Chem. 2006; 281: 31222–33.
  11. Woods J.S., Handschumacher R.E. Hepatic homeostasis of plasma L-asparagine. Am. J. Physiol. 1971; 221: 1785–90.
  12. Bendich A., Kafkewitz D., Abuchowski A., Davis F.F. Immunological effects of native and polyethylene glycol-modified asparaginases from Vibrio succinogenes and Escherichia coli in normal and tumour-bearing mice. Clin. Exp. Immunol. 1982; 48: 273–8.
  13. Distasio J.A., Salazar A.M., Nadji M., Durden D.L. Glutaminase-free asparaginase from vibrio succinogenes: an antilymphoma enzyme lacking hepatotoxicity. Int. J. Cancer. 1982; 30(3): 343–7.
  14. Capizzy R.L., Cheng Y.C. Therapy of neoplasia with asparaginase. In: Enzymes as drug. Ed. by J.S. Holcenberg, J. Roberts. NY: John Wiley and Sons, 1981: 1–24.
  15. Storti E., Quaglino D. Dysmetabolic and neurological complications in leukemic patients treated with L-asparaginase. In: Experimental and clinical effects of L-asparaginase. Ed. by E. Grundmann, H.F. Oettgen. Berlin, Heidelberg, NY: Springer Verlag, 1970: 344–9.
  16. Roberts J., Schmid F.A., Old L.J., Stockert E. A comparative study of the antitumor effectiveness of E. coli and Erwinia asparaginases. Cancer Biochem. Biophys. 1976; 1(4): 175–8.
  17. Steiner M., Attarbaschi A., Kastner U. et al. Distinct fluctuations of ammonia levels during asparaginase therapy for childhood acute leukemia. Pediatr. Blood Cancer 2007; 9(5): 640–2.
  18. Watanabe S., Miyake K., Ogawa C. et al. The ex vivo production of ammonia predicts L-asparaginase biological activity in children with acute lymphoblastic leukemia. Int. J. Hematol. 2009; 90(3): 347–52.
  19. Гладилина Ю.А., Соколов Н.Н., Красоткина Ю.В. Клонирование, экспрессия и выделение L-аспарагиназы Helicobacter pylori. Биомед. хим. 2008; 54(4): С. 482–6. [Gladilina Yu.A., Sokolov N.N., Krasotkina Yu.V. Cloning, expression, and isolation of Helicobacter pylori L-asparaginase. Biomed. khim. 2008; 54(4): S. 482–6. (In Russ.)].
  20. Cappelletty D., Chiarelli L.R., Pasquetto M.V. et al. Helicobacter pylori L-asparaginase: A promising new chemotherapeutic agent. Biochem. Biophys. Res. Commun. 2008; 377: 1222–6.
  21. Derst C., Henseling J., R hm K.H. Engineering the substrate specificity of Escherichia coli asparaginase II. Selective reduction of glutaminase activity by amino acid replacements at position 248. Protein Sci. 2000; 9: 2009–17.
  22. Avramis V.I., Panosyan E.H. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet. 2005; 44: 367–93.
  23. Avramis V.I., Tiwari P.N. Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int. J. Nanomed. 2006; 1(3): 241–54.
  24. Panosyan E.H., Grigoryan R.S., Avramis I.A. et al. Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961). Anticancer Res. 2004; 24(2C): 1121–5.
  25. Rotoli B.M., Uggeri J., Dall’Asta V. et al. Inhibition of glutamine synthetase triggers apoptosis in asparaginase-resistant cells. Cell Physiol. Biochem. 2005; 15(6): 281–92.
  26. Tardito S., Uggeri J., Bozzetto C. et al. The inhibition of glutamine synthetase sensitizes human sarcoma cells to L-asparaginase. Cancer Chemother. Pharmacol. 2007; 60(5): 751–8.
  27. Abuchowski A., Kazo G.M., Verhoest C.R. Jr. et al. Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycolasparaginase conjugates. Cancer Biochem. Biophys. 1984; 7(2): 175–86.
  28. Asselin B.L., Whitin J.C., Coppola D.J. et al. Comparative pharmacokinetic studies of three asparaginase preparations. J. Clin. Oncol. 1993; 11: 1780–6. 29. Khan A., Hill J.M. Atopic hypersensitivity to L-asparaginase: resistance to immunosupression. Int. Arch. Allergy Appl. Immunol. 1971; 40(3): 463–569.
  29. Alvarez O.A., Zimmerman G. Pegaspargase-induced pancreatitis. Med. Pediatr. Oncol. 2000; 34(3): 200–5.
  30. Кучумова А.В., Красоткина Ю.В., Хасигов П.З., Соколов Н.Н. Пегили- рование рекомбинантной аспарагиназы Erwinia carotovora полиэтиленгликолем 5000. Биомед. хим. 2007; 53(1): 107–11. [Kuchumova A.V., Krasotkina Yu.V., Khasigov P.Z., Sokolov N.N. Pegylation of recombinant Erwinia carotovora asparaginase with polyethilenglycol. 5000. Biomed. khim. 2007; 53(1): 107–11. (In Russ.)].
  31. Gaspar M.M., Perez-Soler R., Cruz M.E. Biological characterization of L-asparaginase liposomal formulations. Cancer Chemother. Pharmacol. 1996; 38(4): 373–7.
  32. Jean-Francois J., D’Urso E.M., Fortier G. Immobilization of L-asparaginase into a biocompatible poly(ethylene glycol)-albumin hydrogel: evaluation of performance in vivo. Biotechnol. Appl. Biochem. 1997; 26(Pt. 3): 203–12.
  33. Gaspar M.M., Blanco D., Cruz M.E., Alonso M.J. Formulation of L-asparaginase load poly(lactide-to-glycolide) nanoparticles: influence of polymer properties on enzyme loading, activity and in vitro release. J. Control. Release 1998; 52: 53–62.
  34. Qian G., Zhou J., Wang D., He B. The chemical modification of E. coli L-asparaginase by N, O-carboxymethyl chitosan. Artif. Cell. Blood Substit. Immobil. Biotechnol. 1996; 24: 567–77.
  35. Uren J.R., Hargis B.J., Beardsley P. Immunological and pharmacological characterization of poly-DL-alanyl-modified Erwinia carotovora L-asparaginase. Cancer Res. 1982; 42: 4068–71.
  36. Jorge J.C., Perez-Soler R., Morais J.G., Cruz M.E. Liposomal palmitoylL-asparaginase: characterization and biological activity. Cancer Chemother. Pharmacol. 1994; 34(3): 230–4.
  37. Zhang Y.Q., Zhou W.L., Shen W.D. et al. Synthesis, characterization and immunogenicity of silk fibroin-L-asparaginase bioconjugates. J. Biotechnol. 2005; 120(3): 315–26.
  38. Leal-Egana A., Scheibel T. Silk-based materials for biomedical applications. Biotechnol. Appl. Biochem. 2010; 55(3): 155–67.
  39. Spiess K., Lammel A., Scheibel T. Recombinant spider silk proteins for applications in biomaterials. Macromol. Biosci. 2010; 10(9): 998–1007.
  40. Kwon Y.M., Chung H.S., Moon C. et al. L-Asparaginase encapsulated intact erythrocytes for treatment of acute lymphoblastic leukemia. J. Control. Release 2009; 139(3): 182–9.
  41. Moola Z.B., Scawen M.D., Atkinson T., Nicholls D.J. Erwinia chrysanthemi L-asparaginase: epitope mapping and production of antigenically modified enzymes. Biochem. J. 1994; 302(Pt. 3): 921–7.
  42. Goldberg A.I., Cooney D.A., Glynn J.P. et al. The effects of immunization to L-asparaginase on antitumor and enzymatic activity. Cancer Res. 1973; 33: 256–61.
  43. Vrooman L.M., Supko J.G., Neuberg D.S. et al. Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer 2010; 54(2): 199–205.
  44. Zalewska-Szewczyk B., Gach A., Wyka K. et al. The cross-reactivity of anti-asparaginase antibodies against different L-asparaginase preparations. Clin. Exp. Med. 2009; 2: 113–6.
  45. Distasio J.A., Niederman R.A. Purification and characterization of Lasparaginase with anti-lymphoma activity from Vibrio succinogenes. J. Biol. Chem. 1976; 251(22): 6929–33.
  46. Абакумова О.Ю., Подобед О.В., Борисова А.А. и др. Противоопухолевая активность L-аспарагиназы из Yersinia pseudotuberculosis. Биомед. хим. 2008; 54(6): 712–9. [Abakumova O.Yu., Podobed O.V., Borisova A.A. et al. Anti-tumor activity of Yersinia pseudotuberculosis L-asparaginase. Biomed. khim. 2008; 54(6): 712–9. (In Russ.)].
  47. Carta De-Angeli L., Pocchiari F. et al. Effect of L-asparaginase from Aspergillus terreus on ascites sarcoma in the rat. Nature (London) 1970; 225: 549–50.
  48. Peterson L.E., Ciegler A. L-asparaginase production by Erwinia aroideae. Appl. Microbiol. 1969; 18: 64–7.
  49. Pritsa A.A., Papazisis K.T., Kortsaris A.H. et al. Antitumor activity of Lasparaginase from Thermus thermophilus. Anticancer Drugs 2001; 12: 137–42.
  50. Reddy V.V.S., Jayaram H.N., Sirsi M., Ramakrishnan T. Inhibitory activity of L-asparaginase from Mycobacterium tuberculosis on Yoshida ascites sarcoma in rats. Arch. Biochem. Biophys. 1969; 132: 262–7.
  51. Rowley B., Wriston J.C. Partial purification and antilymphoma activity of Serratia marcescens L-asparaginase. Biochem. Biophys. Res. Commun. 1967; 28: 160–5.
  52. Pokrovskaya M.V., Pokrovsky V.S., Aleksandrova S.S. et al. Recombinant intracellular Rhodospirillum riubrum L-asparaginase with low L-glutaminase activity and antiproliferative effect. Biochem. (Mosc.). Suppl. Series B: Biomed. Chem. 2012; 6: 121–31.
  53. Appel I.M., Hop W.C., Pieters R. Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases. Blood Coagul. Fibrinol. 2006; 17: 139–46.
  54. Duval M., Suciu S., Ferster A. et al. Comparison of Escherichia coliasparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children’s Leukemia Group phase 3 trial. Blood 2002; 99(8): 2734–9.
  55. Durden D.L., Salazar A.M., Distasio J.A. Kinetic analisys of hepatotoxicity associated with antineoplastic asparaginases. Cancer Res. 1983; 43: 1602–5.
  56. Eden O.B., Shaw M.P., Lilleyman J.S., Richards S. Non-randomised study comparing toxicity of Escherichia coli and Erwinia asparaginase in children with leukaemia. Med. Pediatr. Oncol. 1990; 18(6): 497–502.
  57. Howard J.B., Carpenter F.H. L-asparaginase from Erwinia carotovora. Substrate specificity and enzymatic properties. J. Biol. Chem. 1972; 247: 1020–30.
  58. Bach S.J., Lasnitzki I. Some aspects of the role of arginine and arginase in mouse carcinoma 63. Enzymologia 1947; 12(3): 198–205.
  59. Bach S.J., Maw G.A. Creatine synthesis by tumor-bearing rats. Biochem. Biophys. Acta 1953; 11(1): 69–78.
  60. Osunkoya B.O., Adler W.H., Smith R.T. Effect of arginine deficiency on synthesis of DNA and immunoglobulin receptor of Burkitt lymphoma cells. Nature 1970; 227: 398–9.
  61. Storr J.M., Burton A.F. The effects of arginine deficiency on lymphoma cells. Br. J. Cancer 1974; 30: 50–9.
  62. Cheng P.N., Lam T.L., Lam W.M. et al. Pegylated recombinant human arginase inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res. 2007; 67(1): 309–17.
  63. Savoca K.V., Davis F.F., van Es T. et al. Cancer therapy with chemically modified enzymes. II. The therapeutic effectiveness of arginase, and arginase modified by the covalent attachment of polyethylene glycol, on the taper liver tumor and the L5178Y murine leukemia. Cancer Biochem. Biophys. 1984; 7(3): 261–8.
  64. Hernandez C.P., Morrow K., Lopez-Barcons L.A. et al. Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood 2010; 115(25): 5214–21.
  65. Hsueh E.C., Knebel S.M., Lo W.H. et al. Deprivation of arginine by recombinant human arginase in prostate cancer cells. J. Hematol. Oncol. 2012; 5: 17. doi: 10.1186/1756-8722-5-17.
  66. Shibatani T., Kakimoto T., Chibata I. Crystallization and properties of L-arginine deiminase of Pseudomonas putida. J. Biol. Chem. 1975; 250(12): 4580–3.
  67. Takaku H., Takase M., Abe S. et al. In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. Int. J. Cancer. 1992; 51(2): 244–9.
  68. Park I.S., Kang S.W., Shin Y.J. et al. Arginine deiminase: a potential inhibitor of angiogenesis and tumour growth. Br. J. Cancer 2003; 89: 907–14.
  69. Ni Y., Li Z., Sun Z. et al. Expression of arginine deiminase from Pseudomonas plecoglossicida CGMCC2039 in Escherichia coli and its anti-tumor activity. Curr. Microbiol. 2009; 58(6): 593–8.
  70. Ensor C.M., Holtsberg F.W., Bomalaski J.S., Clark M.A. Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 2002; 62: 5443–50.
  71. Gong H., Zolzer F., von Recklinghausen G. et al. Arginine deiminase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis. Leukemia 2000; 14(5): 826–9.
  72. Noh E.J., Kang S.W., Shin Y.J. et al. Arginine deiminase enhances dexamethasone-induced cytotoxicity in human T-lymphoblastic leukemia CCRF-CEM cells. Int. J. Cancer 2004: 112: 502–8.
  73. Ascierto P.A., Scala S., Castello G. et al. Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J. Clin. Oncol. 2005; 23: 7660–8.
  74. Curley S.A., Bomalaski J.S., Ensor C.M. et al. Regression of hepatocellular cancer in a patient treated with arginine deiminase. Hepatogastroenterology 2003; 50(53): 1214–6.
  75. Glazer E.S., Piccirillo M., Albino V. et al. Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J. Clin. Oncol. 2010; 28(13): 2220–6.
  76. Izzo F., Marra P., Beneduce G. et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J. Clin. Oncol. 2004; 22: 1815–22.
  77. Glazer E.S., Piccirillo M., Albino V. et al. Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. J. Clin. Oncol. 2010; 28(13): 2220–6.
  78. Ott P.A., Carvajal R.D., Pandit-Taskar N. et al. Phase I/II study of pegylated arginine deiminase (ADI-PEG20) in patients with advanced melanoma. Invest. New Drugs 2013; 31(2): 425–34.
  79. Delage B., Luong P., Maharaj L. et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis. 2012; 3: e342.
  80. Wu L., Li L., Meng S. et al. Expression of argininosuccinate synthetase in patients with hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2013; 28(2): 365–8.
  81. Szlosarek P.W., Luong P., Phillips M.M. et al. Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase. J. Clin. Oncol. 2013; 31(7): e111–3.
  82. Feun L.G., Marini A., Walker G. et al. Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. Br. J. Cancer 2012; 106(9): 1481–5.
  83. Kelly M.P., Jungbluth A.A., Wu B.W. et al. Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br. J. Cancer 2012; 106(2): 324–32.
  84. Manca A., Sini M.C., Izzo F. et al. Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells. Oncol. Rep. 2011; 25(6): 1495–502.
  85. Bowles T.L., Kim R., Galante J. et al. Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int. J. Cancer 2008; 123: 1950–5.
  86. Kim H.J., Kim J.H., Yu Y.S. et al. Anti-tumor activity of arginine deiminase via arginine deprivation in retinoblastoma. Oncol. Rep. 2007; 18: 1373–7.
  87. Kim R.H., Coates J.M., Bowles T.L. et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res. 2009; 69: 700–8.
  88. Sigimura K., Ohno T., Kusuyama T., Azuma I. High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro. Melanoma Res. 1992; 2: 191–6.
  89. Szlosarek P.W., Klabatsa A., Pallaska A. et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin. Cancer Res. 2006; 12: 7126–31.
  90. Yoon C.Y., Shim Y.J., Kim E.H. et al. Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int. J. Cancer 2008; 120: 897–905.
  91. Tsai W.B., Aiba I., Lee S.Y. et al. Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol. Cancer Ther. 2009; 8(12): 3223–33.
  92. Ni Y., Liu Y., Schwaneberg U. et al. Rapid evolution of arginine deiminase for improved anti-tumor activity. Appl. Microbiol. Biotechnol. 2011; 90(1): 193–201.
  93. Holtsberg F.W., Ensor C.M., Steiner M.R. et al. Poly(ethylene glycol) (PEG) conjugated arginine deiminase: effects of PEG formulations on its pharmacological properties. J. Control. Release 2002; 80: 259–71.
  94. Kreis W., Hession C. Biological effects of enzymatic deprivation of Lmethionine in cell culture and an experimental tumor. Cancer Res. 1973; 33(8): 1866–9.
  95. Занин В.А., Лукина В.И., Березов Т.Т. Выделение и некоторые фи- зико-химические и каталитические свойства L-лизин-альфа-оксидазы из Pseudomonas putida. Вопр. мед. хим. 1989; 4: 84–9. [Zanin V.A., Lukina V.I., Berezov T.T. Isolation and some physicochemical and catalytical properties of Pseudomonas putida L-lysine alpha-oxidase. Vopr. med. khim. 1989; 4: 84–9. (In Russ.)].
  96. Манухов И.В., Мамаева Д.В., Морозова Е.А. и др. L-Метионин-гамма- лиаза Citrobacter freundii: клонирование гена и кинетические параметры фермента. Биохим. 2006; 74(4): 454–63. [Manukhov I.V., Mamayeva D.V., Morozova Ye.A. et al. Citrobacter freundii L-methionine gamma-lyase: gene cloning and clinical parameters of enzyme. Biokhim. 2006; 74(4): 454–63. (In Russ.)].
  97. Ito S., Nakamura T., Eguchi Y. Purification and characterization of methioninase from Pseudomonas putida. J. Biochem. 1976; 79(6): 1263–72.
  98. Lockwood B.C., Coombs G.H. Purification and characterization of methionine gamma-lyase from Trichomonas vaginalis. Biochem. J. 1991; 279: 675–82.
  99. Sato D., Yamagata W., Kamei K. et al. Expression, purification and crystallization of L-methionine gamma-lyase 2 from Entamoeba histolytica. Acta Crystallogr. 2006; 62(10): 1034–6.
  100. Tanaka H., Esaki N., Yamamoto T., Soda K. Purification and properties of methioninase from Pseudomonas ovalis. FEBS Lett. 1976; 66(2): 307–11.
  101. El-Sayed A.S. Purification and characterization of a new L-methioninase from solid cultures of Aspergillus flavipes. J. Microbiol. 2011; 49(1): 130–40.
  102. Пехов А.А., Жукова О.С., Занин В.А., Березов Т.Т. Цитостатический эффект L-метионин-g-лиазы на раковые клетки в культуре. Бюл. эксп. биол. мед. 1983; 5: 87–9. [Pekhov A.A., Zhukova O.S., Zanin V.A., Berezov T.T. Cytostatic effect of L-methionine g-lyase on cultured cancer cells. Byul. eksp. biol. med. 1983; 5: 87–9. (In Russ.)].
  103. Hu J., Cheung N.K. Methionine depletion with recombinant methioninase: in vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs. Int. J. Cancer 2009; 124(7): 1700–6.
  104. Kokkinakis D.M., Schold S.C.Jr., Hori H., Nobori T. Effect of long-term depletion of plasma methionine on the growth and survival of human brain tumor xenografts in athymic mice. Nutr. Cancer 1997; 29(3): 195–204.
  105. Tan Y., Sun X., Xu M. et al. Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin. Cancer Res. 1999; 5(8): 2157–63.
  106. Tan Y., Xu M., Guo H. et al. Anticancer efficacy of methioninase in vivo. Anticancer Res. 1996; 16(6C): 3931–6.
  107. Yoshioka T., Wada T., Uchida N. et al. Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res. 1998; 58(12): 2583–7.
  108. Hori H., Takabayashi K., Orvis L. et al Gene cloning and characterization of Pseudomonas putida L-methionine-alpha-deamino-gamma-mercaptomethane-lyase. Cancer Res. 1996; 56(9): 2116–22.
  109. El-Sayed A.S., Shouman S.A., Nassrat H.M. Pharmacokinetics, immunogenicity and anticancer efficiency of Aspergillus flavipes L-methioninase. Enzyme Microb. Technol. 2012; 51(4): 200–10.
  110. Tan Y., Zavala J.Sr., Xu M. et al. Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients. Anticancer Res. 1996; 16(6C): 3937–42.
  111. Sun X., Yang Z., Li S. et al. In vivo efficacy of recombinant methioninase is enhanced by the combination of polyethylene glycol conjugation and pyridoxal 5¢-phosphate supplementation. Cancer Res. 2003; 63(23): 8377–83.
  112. Xin L., Cao J., Cheng H. et al. Stealth cationic liposomes modified with anti-CAGE single-chain fragment variable deliver recombinant methioninase for gastric carcinoma therapy. J. Nanosci. Nanotechnol. 2013; 13(1): 178–83.
  113. Смирнова И.П., Хадуев С.Х. L-лизин-альфа-оксидазная активность некоторых видов Trichoderma. Микробиология 1984; 53: 163–5. [Smirnova I.P., Khaduyev S.Kh. L-lysine alpha-oxidase activity of some Trichoderma spp. Mikrobiologiya 1984; 53: 163–5. (In Russ.)].
  114. Kusakabe H., Kodama K., Kuninaka A. et al. A new antitumor enzyme, L-lysine alpha-oxidase from Trichoderma viride. Purification and enzymological properties. J. Biol. Chem. 1980; 255(3): 976–81.
  115. Жукова О.С., Хадуев С.Х., Добрынин Я.В. и др. Влияние L-лизин-a- оксидазы на кинетику клеточного цикла культивируемых клеток лимфомы Беркитта. Экспер. онкол. 1985; 7(6): 42–4. [Zhukova O.S., Khaduyev S.Kh., Dobrynin Ya.V. et al. Influence of L-lysine a-oxidase on kinetics of cell cycle of Burkitt’s lymphoma cultured cells. Eksper. onkol. 1985; 7(6): 42–4. (In Russ.)].
  116. Гогичаева Н.В., Лукашева Е.В., Гаврилова Е.М. и др. Получение конъюгатов L-лизин-a-оксидазы с антителами. Вопр. мед. хим. 2000; 46(4): 410–8. [Gogichayeva N.V., Lukasheva Ye.V., Gavrilova Ye.M. et al. Synthesis of conjugates of L-lysine a-oxidase with antibodies. Vopr. med. khim. 2000; 46(4): 410–8. (In Russ.)].
  117. Лукашева Е.В., Березов Т.Т. L-лизин-a-оксидаза: физико-химиче- ские и биологические свойства. Биохимия 2002; 67(10): 1394–402. [Lukasheva Ye.V., Berezov T.T. L-lysine a-oxidase: physicochemical and biological properties. Biokhimiya 2002; 67(10): 1394–402. (In Russ.)].
  118. Sarkissian C.N., Shao Z., Blain F. et al. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc. Natl. Acad. Sci. U S A 1999; 96(5): 2339–44.
  119. Calabrese J.C., Jordan D.B., Boodhoo A. et al. Crystal structure of phenylalanine ammonia-lyase: multiple helix dipoles implicated in catalysis. Biochemistry 2004; 43: 11403–16.
  120. Ritter H., Schulz G.E. Structural basis for the entrance into the phenylpropanoid metabolism catalyzed by phenylalanine ammonia-lyase. Plant Cell 2004; 16: 3426–36.
  121. Bourget L., Chang T.M. Artificial cell-microencapsulated phenylalanine ammonia-lyase. Applied Biochem. Biotechnol. 1984; 10: 57–9.
  122. Sarkissian C.N., Gamez A. Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? Mol. Gen. Metab. 2005; 86(Suppl. 1): S22–6.
  123. Abell C.W., Hodgins D.S., Stith W.J. An in vivo evaluation of the chemotherapeutic potency of phenylalanine ammonia-lyase. Cancer Res. 1973; 33(10): 2529–32.
  124. Stith W.J., Hodgins D.S., Abell C.W. Effects of phenylalanine ammonialyase and phenylalanine deprivation on murine leukemic lymphoblasts in vitro. Cancer Res. 1973; 33(5): 966–71.
  125. Ambrus C.M., Anthone S., Horvath C. et al. Extracorporeal enzyme reactors for depletion of phenylalanine in phenylketonuria. Ann. Intern. Med. 1987; 106: 531–7.
  126. Ledoux L. Action of ribonuclease on two solid tumours in vivo. Nature 1955; 176(4470): 36–7.
  127. Mitkevich V.A., Tchurikov N.A., Zelenikhin P.V. et al. Binase cleaves cellular noncoding RNAs and affects coding mRNAs. FEBS J. 2010; 277(1): 186–96.
  128. Darzynkiewicz Z., Carter S.P., Mikulski S.M. et al. Cytostatic and cytotoxic effects of Pannon (P-30 Protein), a novel anticancer agent. Cell Tissue Kinet. 1988; 21(3): 169–82.
  129. Ardelt W., Mikulski S.M., Shogen K. Amino acid sequence of an antitumor protein from Rana pipiens oocytes and early embryos. Homology to pancreatic ribonucleases. Biol. Chem. 1991; 266(1): 245–51.
  130. Wu Y., Mikulski S.M., Ardelt W. et al. A cytotoxic ribonuclease. Study of the mechanism of onconase cytotoxicity. J. Biol. Chem. 1993; 268(14): 10686–93.
  131. Juan G., Ardelt B., Li X. et al. G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation. Leukemia 1998; 12(8): 1241–8.
  132. Deptala A., Halicka H.D., Ardelt B. et al. Potentiation of tumor necrosis factor induced apoptosis by onconase. Int. J. Oncol. 1998; 13(1): 11–6.
  133. Lee I., Kalota A., Gewirtz A.M., Shogen K. Antitumor efficacy of the cytotoxic RNase, ranpirnase, on A549 human lung cancer xenografts of nude mice. Anticancer Res. 2007; 27(1A): 299–307.
  134. Lee I., Lee Y.H., Mikulski S.M., Shogen K. Effect of onconase +/- tamoxifen on ASPC-1 human pancreatic tumors in nude mice. Adv. Exp. Med. Biol. 2003; 530: 187–96.
  135. Воробьев И.И., Пономаренко Н.А., Дурова О.М. и др. Структурно- функциональное исследование рекомбинантных форм онконазы. Био- орган. хим. 2001; 27(4): 257–64. [Vorobyev I.I., Ponomarenko N.A., Durova O.M. et al. Structural-functional evaluation of Onconase recombinant forms. Bioorgan. khim. 2001; 27(4): 257–64. (In Russ.)].
  136. Notomista E., Cafaro V., Fusiello R. et al. Effective expression and purification of recombinant onconase, an antitumor protein. FEBS Lett. 1999; 463(3): 211–5.
  137. Ita M., Halicka H.D., Tanaka T. et al. Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines. Cancer Biol Ther. 2008; 7(7): 1104–8.
  138. Costanzi J., Sidransky D., Navon A. et al. Ribonucleases as a novel pro-apoptotic anticancer strategy: review of the preclinical and clinical data for ranpirnase. Cancer Invest. 2005; 23(7): 643–50.
  139. Mikulski S.M., Costanzi J.J., Vogelzang N.J. et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J. Clin. Oncol. 2002; 20(1): 274–81.
  140. Porta C., Paglino C., Mutti L. Ranpirnase and its potential for the treatment of unresectable malignant mesothelioma. Biologics 2008; 2(4): 601–9.
  141. Chang C.H., Sapra P., Vanama S.S. et al. Effective therapy of human lymphoma xenografts with a novel recombinant ribonuclease/anti-CD74 humanized IgG4 antibody immunotoxin. Blood 2005; 106(13): 4308–14.
  142. Calabrese J.C., Jordan D.B., Boodhoo A. et al. Crystal structure of phenylalanine ammonia-lyase: multiple helix dipoles implicated in catalysis. Biochemistry 2004; 43: 11403–16.
  143. Ardelt B., Ardelt W., Pozarowski P. et al. Cytostatic and cytotoxic properties of Amphinase: a novel cytotoxic ribonuclease from Rana pipiens oocytes. Cell Cycle 2007; 24: 3097–102.
  144. Ильинская О.Н., Зеленихин П.В., Колпаков А.И. и др. Избирательная цитотоксичность биназы в отношении фибробластов, экспрессирующих онкогены ras и AML/ETO. Учен. зап. Казан. ун-та. Серия «Естественные науки» 2008; 150(4): 268–73. [Ilinskaya O.N., Zelenikhin P.V., Kolpakov A.I. et al. Selective binase cytotoxicity against ras- and AML/ETO-oncogene-expressing fibroblasts. Uchen. zap. Kazan. un-ta. Seriya «Estestvennye nauki» 2008; 150(4): 268–73. (In Russ.)].
  145. Mitkevich V.A., Kretova O.V., Petrushanko I.Y. et al. Ribonuclease binase apoptotic signature in leukemic Kasumi-1 cells. Biochemie 2013; 95(6): 1344–9.
  146. Mitkevich V.A., Petrushanko I.Y., Spirin P.V. et al. Sensitivity of acute myeloid leukemia Kasumi-1 cells to binase toxic action depends on the expression of KIT and АML1-ETO oncogenes. Cell Cycle 2011; 10(23): 4090–7.