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Pathway Description
Cladribine Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-07-14
Last Updated: 2023-11-27
Cladribine is an antineoplastic agent with immunosuppressive effects (antimetabolite). It is used in the treatment of active hairy cell leukemia and relapsing forms of Multiple sclerosis (MS). This drug is mostly used with patients who did not respond to alternative MS drugs. It is also used as an alternative drug for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma. This molecule is a synthetic purine nucleoside, it is structurally close to deoxyadenosine. The only difference is that cladribine has a chlorine atom at position 2 of the purine ring, this makes the drug resistant to the enzymatic degradation by adenosine deaminase. Due to this resistance, this molecule has the ability to prolong its cytotoxicity. The complete mechanism of action of cladribine is still unclear, it is thought that it is phosphorylated to nucleotidecladribine triphosphate and this metabolite is incorporated into the DNA of T and B cells. This results in DNA strand breakage and inhibition of the DNA synthesis and/or repair. This drug has cytotoxic effects on resting as well as proliferating lymphocytes, which differentiates it from all the other antimetabolite drugs. The drug causes the lymphocytes to stay and accumulate in the G1/S phase. This suggests that the cell cytotoxicity is caused during critical events to enter the S phase. An overdose of this drug would result in irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia. This drug is administered as an intravenous solution or as an oral tablet.
References
Cladribine 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
Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis--focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. doi: 10.2147/dddt.s6627.
Pubmed: 20689698
Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Oct 21;116(16):2884-96. doi: 10.1182/blood-2010-02-246140. Epub 2010 Jul 15.
Pubmed: 20634380
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Pubmed: 19715446
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Pubmed: 19576186
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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
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
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
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
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
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