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Pathway Description
Nelarabine Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-08-10
Last Updated: 2023-11-27
Nelarabine is an antineoplastic agent from the nucleoside analog drug class. This drug is indicated in the treatment of T-cell lymphoblastic leukemia, particularly T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), in both adult and pediatric patients whose disease has not responded to or has relapsed following at least two chemotherapy regimens. At the structure level of this molecule, it is a prodrug of the cytotoxic deoxyguanosine analog 9-ß-D-arabinofuranosylguanine (ara-G). Before entering the cells, it is metabolized by adenosine deaminase (ADA) to ara-G. The molecule then enters the cell to be phosphorylated three times, resulting in the formation of ara-G triphosphate (ara-GTP). Ara-GTP is the molecule with the cytotoxic activity. Since T lymphoblasts have a higher expression of deoxycytidine kinase, ara-G accumulates in higher quantities in T cells over B cells, thus showing higher toxicity to T lymphoblasts. Since ara-GTP accumulates in leukemic blasts, it will incorporate the DNA to exert its S phase-specific cytotoxic effects. This activity leads to the apoptosis of the cell. As a nucleoside analog, ara-GTP competes with endogenous deoxyGTP (dGTP) for incorporation into DNA. The mechanism of action that leads to apoptosis is not well understood. It is thought that the inclusion of ara-GTP into the DNA strand can impair proper DNA repair processes, leading to inhibition of DNA elongation, apoptosis, and cellular destruction. It is anticipated that overdosage of this drug result in severe neurotoxicity, myelosuppression, and potential death. Nelarabine is administered as an intravenous injection.
References
Nelarabine Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. doi: 10.1016/j.clinthera.2007.09.002.
Pubmed: 18035189
DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. doi: 10.1016/j.hoc.2009.07.008.
Pubmed: 19825456
Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47. doi: 10.2165/00003495-200868040-00004.
Pubmed: 18318562
Roecker AM, Allison JC, Kisor DF: Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8. doi: 10.2217/14796694.2.4.441.
Pubmed: 16922610
Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. doi: 10.2174/157488706778250104.
Pubmed: 18473971
Zwaan CM, Kowalczyk J, Schmitt C, Bielorai B, Russo MW, Woessner M, Ranganathan S, Leverger G: Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol. 2017 Oct;179(2):284-293. doi: 10.1111/bjh.14874. Epub 2017 Aug 2.
Pubmed: 28771663
Pavloff N, Rivard D, Masson S, Shen SH, Mes-Masson AM: Sequence analysis of the large and small subunits of human ribonucleotide reductase. DNA Seq. 1992;2(4):227-34.
Pubmed: 1627826
Zhou B, Yen Y: Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses. Cytogenet Cell Genet. 2001;95(1-2):52-9. doi: 10.1159/000057017.
Pubmed: 11978970
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A: A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet. 2009 Aug;85(2):290-5. doi: 10.1016/j.ajhg.2009.07.009. Epub 2009 Aug 6.
Pubmed: 19664747
Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chretien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rotig A: Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007 Jun;39(6):776-80. doi: 10.1038/ng2040. Epub 2007 May 7.
Pubmed: 17486094
Bornstein B, Area E, Flanigan KM, Ganesh J, Jayakar P, Swoboda KJ, Coku J, Naini A, Shanske S, Tanji K, Hirano M, DiMauro S: Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscul Disord. 2008 Jun;18(6):453-9. doi: 10.1016/j.nmd.2008.04.006. Epub 2008 May 27.
Pubmed: 18504129
Griffiths M, Beaumont N, Yao SY, Sundaram M, Boumah CE, Davies A, Kwong FY, Coe I, Cass CE, Young JD, Baldwin SA: Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med. 1997 Jan;3(1):89-93.
Pubmed: 8986748
Lum PY, Ngo LY, Bakken AH, Unadkat JD: Human intestinal es nucleoside transporter: molecular characterization and nucleoside inhibitory profiles. Cancer Chemother Pharmacol. 2000;45(4):273-8. doi: 10.1007/s002800050040.
Pubmed: 10755314
Sankar N, Machado J, Abdulla P, Hilliker AJ, Coe IR: Comparative genomic analysis of equilibrative nucleoside transporters suggests conserved protein structure despite limited sequence identity. Nucleic Acids Res. 2002 Oct 15;30(20):4339-50. doi: 10.1093/nar/gkf564.
Pubmed: 12384580
Wang J, Su SF, Dresser MJ, Schaner ME, Washington CB, Giacomini KM: Na(+)-dependent purine nucleoside transporter from human kidney: cloning and functional characterization. Am J Physiol. 1997 Dec;273(6):F1058-65. doi: 10.1152/ajprenal.1997.273.6.F1058.
Pubmed: 9435697
Ritzel MW, Yao SY, Ng AM, Mackey JR, Cass CE, Young JD: Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol. 1998 Oct-Dec;15(4):203-11.
Pubmed: 10087507
Valerio D, Duyvesteyn MG, Dekker BM, Weeda G, Berkvens TM, van der Voorn L, van Ormondt H, van der Eb AJ: Adenosine deaminase: characterization and expression of a gene with a remarkable promoter. EMBO J. 1985 Feb;4(2):437-43.
Pubmed: 3839456
Rostampour F, Biglari M, Vaisi-Raygani A, Salimi S, Tavilani H: Adenosine deaminase activity in fertile and infertile men. Andrologia. 2012 May;44 Suppl 1:586-9. doi: 10.1111/j.1439-0272.2011.01231.x. Epub 2011 Sep 15.
Pubmed: 21919946
Daddona PE, Shewach DS, Kelley WN, Argos P, Markham AF, Orkin SH: Human adenosine deaminase. cDNA and complete primary amino acid sequence. J Biol Chem. 1984 Oct 10;259(19):12101-6.
Pubmed: 6090454
Ronchi D, Garone C, Bordoni A, Gutierrez Rios P, Calvo SE, Ripolone M, Ranieri M, Rizzuti M, Villa L, Magri F, Corti S, Bresolin N, Mootha VK, Moggio M, DiMauro S, Comi GP, Sciacco M: Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. Brain. 2012 Nov;135(Pt 11):3404-15. doi: 10.1093/brain/aws258. Epub 2012 Oct 4.
Pubmed: 23043144
Johansson M, Karlsson A: Cloning and expression of human deoxyguanosine kinase cDNA. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7258-62. doi: 10.1073/pnas.93.14.7258.
Pubmed: 8692979
Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. doi: 10.1038/nature03466.
Pubmed: 15815621
Williams JB, Lanahan AA: A mammalian delayed-early response gene encodes HNP36, a novel, conserved nucleolar protein. Biochem Biophys Res Commun. 1995 Aug 4;213(1):325-33. doi: 10.1006/bbrc.1995.2133.
Pubmed: 7639753
Griffiths M, Yao SY, Abidi F, Phillips SE, Cass CE, Young JD, Baldwin SA: Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J. 1997 Dec 15;328 ( Pt 3):739-43. doi: 10.1042/bj3280739.
Pubmed: 9396714
Crawford CR, Patel DH, Naeve C, Belt JA: Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line. J Biol Chem. 1998 Feb 27;273(9):5288-93. doi: 10.1074/jbc.273.9.5288.
Pubmed: 9478986
Barnes DE, Johnston LH, Kodama K, Tomkinson AE, Lasko DD, Lindahl T: Human DNA ligase I cDNA: cloning and functional expression in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6679-83. doi: 10.1073/pnas.87.17.6679.
Pubmed: 2204063
Grimwood J, Gordon LA, Olsen A, Terry A, Schmutz J, Lamerdin J, Hellsten U, Goodstein D, Couronne O, Tran-Gyamfi M, Aerts A, Altherr M, Ashworth L, Bajorek E, Black S, Branscomb E, Caenepeel S, Carrano A, Caoile C, Chan YM, Christensen M, Cleland CA, Copeland A, Dalin E, Dehal P, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Garcia C, Georgescu AM, Glavina T, Gomez M, Gonzales E, Groza M, Hammon N, Hawkins T, Haydu L, Ho I, Huang W, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Larionov V, Leem SH, Lopez F, Lou Y, Lowry S, Malfatti S, Martinez D, McCready P, Medina C, Morgan J, Nelson K, Nolan M, Ovcharenko I, Pitluck S, Pollard M, Popkie AP, Predki P, Quan G, Ramirez L, Rash S, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, She X, Smith D, Slezak T, Solovyev V, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wagner M, Wheeler J, Wu K, Xie G, Yang J, Dubchak I, Furey TS, DeJong P, Dickson M, Gordon D, Eichler EE, Pennacchio LA, Richardson P, Stubbs L, Rokhsar DS, Myers RM, Rubin EM, Lucas SM: The DNA sequence and biology of human chromosome 19. Nature. 2004 Apr 1;428(6982):529-35. doi: 10.1038/nature02399.
Pubmed: 15057824
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