PL EN


Preferences help
enabled [disable] Abstract
Number of results
2007 | 7 | 4 | 246-253
Article title

Mechanizmy działania cytostatyków stosowanych w neurologii

Content
Title variants
EN
Mechanism of action of cytostatic drugs used in neurology
Languages of publication
EN PL
Abstracts
EN
The aim of this review is the presentation of molecular mechanisms of action of cytostatic drugs used in the therapy of neurological disorders, mostly of multiple sclerosis (MS). From many years cytostatics like mitoxantrone, cyclophosphamide, cladribine and methotrexate were used in the MS clinical trials. So far only mitoxantrone has been approved by FDA for the treatment of progressive MS. The other cytostatics are still studied in clinical trials, the main problem with their approval for human therapy are their numerous side effects. So far those drugs are mostly used in oncology and haematology where the usage of this type of drugs is better justified. Now there are many studies leading to better understanding of mechanisms of action of cytostatics at the cellular and subcellular level. Mitoxantrone induces apoptosis and reduce the population of inflammatory egzocells capable to initiate demyelination in the central nervous system (CNS). At the molecular level mitoxantrone damages genome of inflammatory cells by inhibition of activity of topoisomerase II (TOP II) or direct interaction with DNA structure. Cyclophosphamide is a cytostatic acting mainly on dividing cells, in which it alkylates DNA and interferes with replication and cell apoptosis. Methotrexate inhibits activity of dehydrofolate reductase what leads to disturbance of replication and blocks phase S of the cell cycle in leukocytes. Cladribine is an antagonist of transcription. The detailed analysis of these mechanisms may lead to diminishing of the level of their side effects and to increase of their therapeutic potential, also in neurological therapy.
PL
Celem niniejszej pracy jest przedstawienie molekularnych mechanizmów działania cytostatyków stosowanych w próbach terapii niektórych chorób neurologicznych, głównie stwardnienia rozsianego (SM). Od wielu lat w terapii tego schorzenia próbuje się wykorzystywać takie cytostatyki, jak mitoksantron, cyklofosfamid, metotreksat i kladrybina. W chwili obecnej jedynym lekiem z tej grupy zatwierdzonym przez FDA do leczenia postępującego SM jest mitoksantron. Pozostałe cytostatyki wciąż poddawane są badaniom, a główny problem we wprowadzeniu ich do terapii neurologicznej stanowią liczne efekty uboczne. Leki te wykorzystywane są głównie w onkologii i hematologii, gdzie stosowanie tego typu leków jest bardziej uzasadnione. W chwili obecnej prowadzone są liczne badania zmierzające do lepszego poznania mechanizmów działania cytostatyków na poziomach komórkowym i subkomórkowym. Przyjmuje się, że mitoksantron indukuje apoptozę, co zmniejsza pulę komórek zapalnych zdolnych do wywoływania demielinizacji w obrębie ośrodkowego układu nerwowego (OUN). Na poziomie molekularnym mechanizm jego działania polega na uszkodzeniu genomu tych komórek poprzez hamowanie aktywności topoizomerazy II (TOPII) lub bezpośrednie wbudowywanie się w strukturę ich DNA. Cyklofosfamid jest cytostatykiem działającym w głównej mierze na komórki dzielące się, w których alkiluje on DNA, co indukuje zaburzenia replikacji oraz apoptozę tych komórek. Działanie lecznicze metotreksatu wynika ze zdolności do hamowania aktywności reduktazy dehydrofolianowej. W ten sposób zaburzony zostaje metabolizm zasad azotowych prowadzący do zaburzeń replikacji i bloku fazy S cyklu komórkowego leukocytów. Kladrybina działa jako antagonista procesu transkrypcji. Dokładne poznanie mechanizmów działania prezentowanych leków może doprowadzić do zmniejszenia nasilenia ich efektów ubocznych oraz do zwiększenia ich potencjału leczniczego, również w terapii neurologicznej.
Discipline
Year
Volume
7
Issue
4
Pages
246-253
Physical description
References
  • 1. Minotti G., Menna P., Salvatorelli E. i wsp.: Anthracy-clines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev. 2004; 56: 185-229.
  • 2. Goodin D.S., Arnason B.G., Coyle PK. i wsp.; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology: The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003; 61: 1332-1338.
  • 3. Boland M.P, Fitzgerald K.A., O’Neill L.A.: Topoiso-merase II is required for mitoxantrone to signal nuclear factor kB activation in HL60 cells. J. Biol. Chem. 2000: 275:25231-25238.
  • 4. Halicka H.D., Smolewski P., Darzynkiewicz Z. i wsp.: Arsenic trioxide arrests cells early in mitosis leading to apoptosis. Cell Cycle 2002; 1: 201-209.
  • 5. Chikamori M., Fukushima K.: A new hexose transporter from Cryptococcus neoformans: molecular cloning and structural and functional characterization. Fungal Genet. Biol. 2005; 42: 646-655.
  • 6. Parker B.S., Cullinane C., Phillips D.R.: Formation of DNA adducts by formaldehyde-activated mitoxantrone. Nucleic Acids Res. 1999; 27: 2918-2923.
  • 7. Parker B.S., Buley T, Evison B.J. i wsp.: A molecular understanding of mitoxantrone-DNA adduct formation: effect of cytosine methylation and flanking sequences. J. Biol. Chem. 2004; 279: 18814-18823.
  • 8. Parker B.S., Cutts S.M., Cullinane C., Phillips D.R.: Formaldehyde activation of mitoxantrone yields CpG and CpA specific DNA adducts. Nucleic Acids Res. 2000; 28: 982-990.
  • 9. Parker B.S., Cutts S.M., Phillips D.R.: Cytosine methylation enhances mitoxantrone-DNA adduct formation at CpG dinucleotides. J. Biol. Chem. 2001; 276: 15953-15960.
  • 10. Barker C.R., Hamlett J., Pennington S.R i wsp.: The topoi-somerase II-Hsp90 complex: a new chemotherapeutic target? Int. J. Cancer 2006; 118: 2685-2693.
  • 11. Campbell K.J., O’Shea J.M., Perkins N.D.: Differential regulation of NF-kB activation and function by topoiso-merase II inhibitors. BMC Cancer 2006; 6: 101.
  • 12. Bhalla K., Ibrado A.M., Tourkina E. i wsp.: High-dose mitoxantrone induces programmed cell death or apoptosis in human myeloid leukemia cells. Blood 1993; 82: 3133-3140.
  • 13. Bullock G., Ray S., Reed J. i wsp.: Evidence against a direct role for the induction of c-jun expression in the mediation of drug-induced apoptosis in human acute leukemia cells. Clin. Cancer Res. 1995; 1: 559-564.
  • 14. Gorczyca W, Gong J., Ardelt B. i wsp.: The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents. Cancer Res. 1993; 53: 3186-3192.
  • 15. Plo I., Hernandez H., Kohlhagen G. i wsp.: Overexpression of the atypical protein kinase C reduces topoiso-merase II catalytic activity, cleavable complexes formation, and drug-induced cytotoxicity in monocytic U937 leukemia cells. J. Biol. Chem. 2002; 277: 31407-31415.
  • 16. Bellosillo B., Villamor N., López-Guillermo A. i wsp.: Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. Blood 2002; 100: 1810-1816.
  • 17. Anderson J.M., Heindl L.M., Bauman P.A. i wsp.: Cytok-eratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents. Clin. Cancer Res. 1996; 2: 97-105.
  • 18. Hazlehurst L.A., Valkov N., Wisner L. i wsp.: Reduction in drug-induced DNA double-strand breaks associated with β1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 2001; 98: 1897-1903.
  • 19. Hui M.K., Wu W.K., Shin VY. i wsp.: Polysaccharides from the root of Angelica sinensis protect bone marrow and gastrointestinal tissues against the cytotoxicity of cyclophosphamide in mice. Int. J. Med. Sci. 2006; 3: 1-6.
  • 20. Wang E., Simard M., Ouellet N. i wsp.: Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice. Infect. Immun. 2002; 70: 4226-4238.
  • 21. Zuluaga A.F., Salazar B.E., Rodriguez C.A. i wsp.: Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases. BMC Infect. Dis. 2006; 6: 55.
  • 22. Hickman-Davis J.M., Lindsey J.R., Matalon S.: Cyclophosphamide decreases nitrotyrosine formation and inhibits nitric oxide production by alveolar macrophages in mycoplasmosis. Infect. Immun. 2001; 69: 6401-6410.
  • 23. Ginsberg A.H., Monte W.T., Johnson K.P: Effect of cyclophosphamide in vitro and on vaccinia virus replication in tissue culture. J. Virol. 1977; 21: 277-283.
  • 24. Torchinsky A., Lishanski L., Wolstein O. i wsp.: NF-kB DNA-binding activity in embryos responding to a teratogen, cyclophosphamide. BMC Dev. Biol. 2002; 2: 2.
  • 25. Cai Y., WuM.H., Ludeman S.M. iwsp.: Role of O6-alkylguanine-DNA alkyltransferase in protecting against cyclophosphamide-induced toxicity and mutagenicity. Cancer Res. 1999; 59: 3059-3063.
  • 26. Joqueviel C., Gilard V, Martino R. i wsp.: Urinary stability of carboxycyclophosphamide and carboxyifosfamide, two major metabolites of the anticancer drugs cyclophosphamide and ifosfamide. Cancer Chemother. Pharmacol. 1997; 40: 391-399.
  • 27. Pass G.J., Carrie D., Boylan M. i wsp.: Role of hepatic cytochrome p450s in the pharmacokinetics and toxicity of cyclophosphamide: studies with the hepatic cytochrome p450 reductase null mouse. Cancer Res. 2005; 65: 4211-4217.
  • 28. Ren S., Yang J.S., Kalhorn T.F., Slattery J.T.: Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver micro-somes. Cancer Res. 1997; 57: 4229-4235.
  • 29. Chang T.K., Weber G.F., Crespi C.L., Waxman D.J.: Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver micro-somes. Cancer Res. 1993; 53: 5629-5637.
  • 30. Balow J.E., Hurley D.L., Fauci A.S.: Cyclophosphamide suppression of established cell-mediated immunity. Quantitative vs. qualitative changes in lymphocyte populations. J. Clin. Invest. 1975; 56: 65-70.
  • 31. Zhu L.P, Cupps T.R., Whalen G., Fauci A.S.: Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells. J. Clin. Invest. 1987; 79: 1082-1090.
  • 32. Ralph J.A., McEvoy A.N., Kane D. i wsp.: Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses. J. Immunol. 2005; 175: 555-565.
  • 33. Majumdar S., Aggarwal B.B.: Methotrexate suppresses NF-kB activation through inhibition of IkBix phosphorylation and degradation. J. Immunol. 2001; 167: 2911-2920.
  • 34. Cronstein B.N., Eberle M.A., Gruber H.E., Levin R.I.: Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc. Natl Acad. Sci. USA 1991; 88: 2441-2445.
  • 35. Rudwaleit M., Yin Z., Siegert S. i wsp.: Response to methotrexate in early rheumatoid arthritis is associated with a decrease of T cell derived tumour necrosis factor α, increase of interleukin 10, and predicted by the initial concentration of interleukin 4. Ann. Rheum. Dis. 2000; 59: 311-314.
  • 36. Hildner K., Finotto S., Becker C. i wsp.: Tumour necrosis factor (TNF) production by T cell receptor-primed T lymphocytes is a target for low dose methotrexate in rheumatoid arthritis. Clin. Exp. Immunol. 1999; 118: 137-146.
  • 37. Weinstein G.D., Jeffes E., McCullough J.L.: Cytotoxic and immunologic effects of methotrexate in psoriasis. J. Invest. Dermatol. 1990; 95 (5 supl.): 49S-52S.
  • 38. Seitz M., Dayer J.M.: Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment. Rheumatology (Oxford) 2000; 39: 637-645.
  • 39. Albertioni F., Lindemalm S., Eriksson S. i wsp.: Relationship between cladribine (CdA) plasma, intracellular CdA-5’-triphosphate (CdATP) concentration, deoxycytidine kinase (dCK), and chemotherapeutic activity in chronic lymphocytic leukemia (CLL). Adv. Exp. Med. Biol. 1998; 431: 693-697.
  • 40. Hartman WR., Hentosh P: The antileukemia drug 2-chloro-2’-deoxyadenosine: an intrinsic transcriptional antagonist. Mol. Pharmacol. 2004; 65: 227-234.
Document Type
article
Publication order reference
YADDA identifier
bwmeta1.element.psjd-9ab199b5-73fd-48df-b352-f09ad66d9669
Identifiers
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.