Views
4 years ago

29 - A Lazarowski - Diciembre 2004

  • Text
  • Drogas
  • Epilepsia
  • Resistance
  • Multidrug
  • Pacientes
  • Niveles
  • Lazarowski
  • Casos
  • Epilepsy
  • Cerebral
Proteínas de resistencia múltiple a drogas en epilepsia refractaria

Alberto

Alberto Lazarowski FIGURA 7 • • • Sangre Cyt.P450 G Hepatocitos MRP Metabolitos Canalículos La acción conjunta de los genes de metabolización y excresión, contribuyen a la disminución de la concentración plasmática de drogas. 99m Tc-SESTAMIBI • Drogas 67 Ga Pgp-170 • • La alta expresión de los transportadores P-gp y MRP en el sistema gastrointestinal, influye significativamente en la cinética de las drogas terapéuticas. La imagen cambiante del 99m Tc-MIBI, muestra el transporte activo de eliminación hepato-biliar-intestinal acorde con los sitios de expresión de los transportadores. Del mismo modo, puede observarse un lavado activo del trazador en un caso de linfoma No-Hodking refractario, que contrasta con imagen persistente con 67Ga, indicando que dicho linfoma es refractario al tratamiento (80, 81). con una mayor expresión intestinal de esta proteína, lo cual está asociado con valores más bajos de digoxina en sangre respecto a los otros grupos polimórficos T3435T o C3435T (76, 77). No se sabe qué tipo polimórfico corresponde a los casos aquí presentados; sin embargo, Siddiqui A. y cols. (78) mostraron en varios casos de pacientes epilépticos, que el grupo C3435C se asociaba a los casos refractarios. Recientemente, la detección del polimorfismo del gen MDR-1 C3435C, fue relacionada con bajos niveles plasmáticos de DFH en voluntarios sanos (79), proporcionando una base molecular y genética a los hallazgos aquí descriptos. Conclusiones Debe destacarse que, a pesar del creciente conocimiento de los mecanismos íntimos del fenómeno MDR, aún representa un verdadero escollo en el adecuado control de las crisis en pacientes con fenotipo refractario. La naturaleza constitutiva e inducible de la P-gp, como la posible concurrencia de otras proteínas con similares propiedades, tales como MRP-1, BCRP (breast cancer resistance protein), y MVP/LRP (lung resistanse protein), estas últimas de muy reciente descripción en la patología epiléptica, sugieren que distintos mecanismos pueden participar simultánea e independientemente, para dar origen al fenotipo refractario. La alta expresión cerebral de estas proteínas en los casos de ER no es la única característica de este fenómeno, sino que probablemente también deba considerarse su sobreexpresión "sistémica", principalmente en los órganos excretores, con alto impacto en la farmacocinética de las distintas drogas. La suma de las propiedades funcionales de estas diferentes proteínas, y su expresión en distintos tipos celulares de las áreas epileptógenas, puede dar como resultante una amplia red celular altamente refractaria, y la configuración de un mapa proteico cerebral farmacorresistente. Referencias bibliográficas 1. National Institute of Health. Consensus Conference. Surgery for Epilepsy. JAMA 1990;264:729-33. 2. Biedler N, Riehm W. Cellular resistance to actinomycin D hamster cells in vitro. Cross resistance, radioautographic, and cytogenetics studies. Cancer Res 1990;30:1174-84. 3. Ling V. Does P-Glycoprotein predict response to chemotherapy? J Natl Cancer Inst 1989;81:84-5. 4. Gottesman MM, Pastan I. The multidrug transporter, a double-edge sword. J Biol Chem 1988;263:12163-5. 5. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Ann Rev Biochem 1993;62:385-427. 6. Bosch I, Croopy JM. P-glycoprotein structure and evolutionary homolgies. In: Martin Clynes editor. Mutiple drug resistance in cancer 2, Mollecular, Cellular and Clinical Aspects. Kluwer Academic Publishers. Cytotechnology 1998;27:1-30. 7. Baichwal V, Liu D, Ames GF. The ATP-bining component of a prokaryotic traffic ATPasa is exposed to the peroplasmatic (external) suface. Proc Nat Acad Sci USA 1993;90:620-24. 8. Cordon-Cardo C. Immunological analysis of P-Glycoprotein expression in normal and tumor tissues in human. In Roninson IB editor. Molecular and cellular biology of multidrug resistance in tumor cells. New York: Premium Press; 1991. p. 303-318. 9. Smit JW, Duin E, Steen H, Oosting R, Roggeveld J, Meijer DK. Interaction between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level. Br J Pharmacol 1998;123:361-370. 10. Bates SE. Drug resistance: still on learning curve. Clin Cancer Res 1999;5:3346-8. 11. Litman T, Druley T, Stein WD, Bates SE. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significans. Cell Mol Lif Sci 2001;58:931-59. 12. Mickley LA, Bates SE., Richert ND, Currier S, Tanaka S, Foss F, et al. Modulation of the expression of a multidrug resistance gene (mdr-1/P-glycoprotein) by differentiating agents. J Biol Chem 1989; 264: 18031-40. 13. Stein U, Walther W, Shoemaker RH. Vincristine induction of mutant and wild-type human multidrug resistance promoters is cell-type-specific and dose dependent. J Cancer Res Clin Oncol. 1996;122:275-82. 14. Cornwell MM, Smith DE. A signal transduction pathway for activation of the mdr1 Promoter involves the proto-oncogene c-raf kinase. J Biol Chem 1993; 268:15347-50. 15. Goldsmith ME, Gudas JM, Schneider E, Cowan KH. Wild type p53 stimulates expression from the human multidrug resistance promoter in a p53-negative cell line. J Biol Chem 1995;270:1894-8. 16. Zhou G, Kuo MT. NF- B-mediated induction of mdr1b expression by insulin in rat hepatoma cells. J Biol Chem 1997;272:15174-83. 17. Combates NJ, Rzepka RW, Pan Chen YN, Cohen D. NF-IL6, a member of the C/EBP family of transcription factors, binds and trans-activates the human MDR1 gene promoter. J Biol Chem 1994; 269:29715-19. 18. Comerford K, Wallace T, Karhausen J, Louis N, Montalto M, Coglan S. Hypoxia-inducible factor-1- dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 2002;62:3387-94. 19. Robinson LJ, Roberts WK, Lamming D, Stemberg SS, Roepe PD. Human MDR1 protein overexpression delay the apoptotic cascade in Chinase hamster ovary fibroblasts. Biochemistry 1997;36:11169-78. 20. Abolhoa A, Wilson AE, Ross H, Danenberg P, Burt M, Scotto KW. Rapid activation of MDR1 gene expression in human metastatic sarcoma following in vivo exposure to doxorubicin. Clin Cancer Res 1999;5:3352-56. 21. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willinghan MC. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170 Evidence for localization in brain capillaries and cross reactivity with muscle protein. J Histochem Cytochem 1989; 37:159-64. 22. Schinkel AH. The roles of P-glycoprotein and MRP1 in the blood-brain and blood-cerebrospinal fluid barriers. Adv Exp Med Biol 2001;500:365-72. 23. Cordon-Cardo C, O'Brien JP, Casals D, Rittman- Grauer L, Biedler JL, Melamed MR, et al. Multidrug resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Nat Acad Sci U S A 1989;86:695-8. 24. Zhang Y, Han H, Elmquist WF, Miller DW. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 2000;876:148-53. 25. Golden PL, Pardrige WM. P-glycoprotein on astrocytes foot processe of unfixed isolated human brain capillaries. Brain Res 1999;819:143-6. 26. de Boer AG, van der Sandt ICJ, Gaillard PJ. The role of drug transporters at the blood-brain-barrier. Ann Rev Pharmachol Toxicol 2003;43:629-56.

Psicofarmacología 5:29, diciembre 2004 27. Tsuji A, Terasaki T, Takabatake Y, Tamai I, Yamashita J, Moritani S, et al. P-glycoprotein as the drug efflux in primary cultured brain capillary endothelial cells. Life Sci 1992;51:1427-37. 28. Tsuji A, Tamai I. Blood-brain barrier function of P-glycoprotein. Adv Drug Delivery Rev 1997;25: 287-98. 29. Tetsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T. Functional involvement of P-glycoprotein in blood brain barrier. J Biol Chem 1992;267: 20383-91. 30. Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Delivery Rev 1999;36:179-94. 31. Schinkel AH. The roles of P-glycoprotein and MRP1 in the blood-brain and blood-cerebrospinal fluid barriers. Adv Exp Med Biol 2001;500:365-72. 32. Tamai I, Tsuji A. Transporter-mediated permeation of drug across the blood-brain barrier. J Pharm Sci 2000; 89:1371-88. 33. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Eng J Med 2000;342:314-9. 34. Tishler D, Weinberg K, Hinton D, Barbaro N, Geralyn A, Corey R. MDR1 Gene expression in brain of patient with medically intractable epilepsy. Epilepsia 1995;36:1-6. 35. Lazarowski A, Sevlever G, Taratuto A, Massaro M, Rabinowicz A. Tuberous Sclerosis associated with MDR-1 expression and drug-resistant epilepsy. Ped Neurol 1999;21:731-4. 36. D'Giano C, Sevlever G, Lazarowski A, Taratuto A, Leiguarda R, Pomata H, et al. Expression of P-glycoprotein and related proteins in brain of patients with refractory temporal lobe epilepsy. Epilepsia 1997;38(Suppl):7,41. 37. Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 2001;42:1501-6. 38. Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 2002;125:22-31. 39. Sisodiya S, Thom M. Widespread upregulation of drug-resistance proteins in fatal human status epilepticus. Epilepsia 2003;44:261-4. 40. Lazarowski A, Lubieniecki F, Camarero S, Pomata H, Bartuluchi M, Sevlever G, et al. Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr Neurol 2004;30:102-6. 41. Lazarowski A, Massaro M, Schteinschnaider A, Intruvini S, Sevlever G, Rabinowicz A. Neuronal MDR-1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy. Ther Drug Monit 2004;26:44-6. 42. Loscher W, Schimth D. New horizons in the development of antiepileptic drugs. Epilepsy Res 2003;50:3-16. 43. Loscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic resistance systems, their properties and clinical significance. Drugs J Pharmacol Exp Ther 2002; 301:7-14. 44. Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, et al. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance. J Neurosc 2002;22: 5833-9. 45. Kwan P, Still G, Butler E, Gant T, Meldrum B, Brodie M. Regional Expression of Multidrug Resistance Gene in Genetically epilepsy-prone Rat Brain after Single Audiogenic Seizure. Epilepsia 2002;43:1318-23. 46. Seegers U, Potschka H, Loscher W. Expression of the Multidrug Transporter P-glycoprotein in brain capillary endothelial cells and brain parenchyma of amygdala-kindled rats. Epilepsia 2002;43:675-84. 47. Seegers U, Potschka H, Loscher W. Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy. Epilepsy Res 2002;51:257-68. 48. Lazarowski A, Girardi E, Ramos A, García-Rivello H, Brusco A. MDR-1 gene expression (Pgp-170) in different brain areas in an experimental epilepsy model. J Epilepsy Clin Neurophysiol 2002;8:101E4. 49. Lazarowski A, Ramos AJ, Garcia-Rivello H, Brusco A, Girardi E. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. Cell Mol Neurobiol 2004;24:77-85. 50. Zhang L, Ong W, Lee T. Induction of P-glycoprotein expression in astrocytes following intracerebroventricular kainate injection. Exp Brain Res 1999;126:509-16. 51. Lazarowski A, Girardi.E, RamosAJ, García-Rivello H, Brusco A. Neuronal MDR-1 gene encoded P-Glycoprotein (P-170) Expression in 3-Mercaptopropionic Acid-induced Seizures in rats. Epilepsia 2002;43 Supl 7:11-12. 52. Girardi E, Lazarowski A. Lack protection of Phenytoin in rats with high induced brain expression of MDR-1 gene. III Latin American Congress of Epilepsy México; 2004 Jul 1-5; México. Rev Mex Neuroci 2004;5:210-P36 ISSN 165-5044. 53. Rabinowicz A, Salvat J, Leiguarda R, Demonty F, Salvat F, Cervio A, et al. Use of antiepileptic drugs in non-traumatic neurosurgical procedures. Is there any best route and time of administration? Clin Neuropharmacol 1997;20:438-41. 54. Schinkel AH,Wagenaar E, Mol CA, van Deemter L. P-Glycoprotein in the blood-brain barrier of mice influences the brain penetration and the pharmacological activity of many drugs. J Clin Invest 1996;97:2517-24. 55. Doppenschmitt S, Langguth P, Regarth C, Andersson T. Characterization of binding properties to human P-glycoprotein development of a (3H) verapamil-binding assay. J Pharmachol Exp Ther 1999;288:348-57. 56. Hunter J, Hirst R. Intestinal secretion of drugs: the role of P-glycoprotein, and related drug efflux system in limiting oral drug absorption. Adv Drug Delivery Rev 1997;25:129-57. 57. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 1981;41:1967-72. 58. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y. Circumvention of vinblastine and adriamycine resistance in vivo and in vitro by calcium blockers. Cancer Res 1983;43:2905-10. 59. Tsuruo T. Reversal of multidrug resistance by calcium channel blockers and other agents. In: Ronninson IB editor. Molecular and Cellular Biology of Multidrug Resistancce in Tumor Cells. New York: Plenum Press; 1991. p. 349-72. 60. Abernethy D, Schwartz J. Calcium-antagonist drugs. N Eng J Med 1999;341:1447-57. 61. De Sarro GB, Meldrum BS, Nistico G. Anticonvulsivant effects of some calcium entry blockers in DBA/2 mice. Br J Pharmacol 1988;93: 247-56. 62. Meyer FB, Cascino GD, Whisnant JP, Sharbrough FW, Ivnik RJ. Nimodipine as an add-on therapy for intractable epilepsy. Mayo Clin Proc 1995;7:623-7. 63. Meyer FB, Anderson RE, Sundt TM Jr, Sharbrough FW. Selective central nervous system calcium channel blockers - a new class of anticonvulsivant agents. Mayo Clin Proc 1986;61:239-47. 64. Morocutti C, Pierelli F, Sanarelli L, Stefano E, Peppe A, Mattioli GL. Antiepileptic effects of calcium antagonist (nimodipine) on cefazoline-induced epileptogenic foci in rabbits. Epilepsia 1986;27: 498-503. 65. Balakrishnan S, Pandhi P, Bhargava VK. Effect of nimodipine on efficacy of commonly used antiepileptic drugs in rats. Indian J Exp Biol 1988;36:51-4. 66. Balakrishnan S, Pandhi O. Effects pf nimodipine on the cognitive dysfunction induced by phenytoin and valproic acid in rats. Methods Find Exp Clin Pharmachol 1997;19:693-7. 67. Larkin JC, McKee PJ, Backlaw J, Thompson GG, Morgan JC, Brodie MJ. Nimodipine in refractory epilepsy: a placebo-controled, add-on study. Epilepsy Res 1991;9:71-7. 68. De Falco FA, Bartiromo U, Majello L, DiGeronimo G, Mundo P. Calcium antagonist nimodipine in intractable epilepsy. Epilepsia 1992;33:343-5. 69. Brant L, Saveland H, Ljunggreen B, Andersson KE. Control of epilepsy partials continuans with intravenous nimodipine: report of two cases. J Neurosurg 1988;69:949-50. 70. Lazarowski A, Schteinshnaider A, Intruvini S, Sevlever G, Massaro M. Corrección de niveles subterapéticos de drogas anticonvulsivantes y control de crisis con terapia adyuvante con nimodipina en niños con epilepsia refractaria. XIX Congreso Argentino de Neurología Infantil. Sociedad Argentina de Neurología Infantil (SANI); 1998 Oct 8-9; San Miguel de Tucumán, Argentina. 71. Zhang Y, Guo X, Lin ET, Benet LZ. Overlapping substrates specifities of cytochrome P4503A and P-glycoprotein for novel cysteine protease inhibitor. Drug Metab Dispos 1998;26:360-6. 72. Jansen PL, Muller M. Genetic cholestasis: lesson from the molecular physiology of bile formation. Can J Gastroenterol 2000;3:233-8. 73. Kerb R, Hoffmeyer S, Brinkman U. ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2000;2:51-64. 74. de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, et al. Mutation in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998;95:282-7. 75. Paulusma C, Kool M, Bosma PJ, Scheffer GL, Ter BF. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin- Johnson syndrome. Hepatology 1997;25:1539-42. 76. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al. Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473-8. 77. Brinkmann U, Eichelbaum M. Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 2001; 1:59-64. 78. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with Polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003; 3348:1442-8. 79. Kerb R, Aynacioglu AS, Brockmoller J, Schlagenhaufer R, Bauer S, Szekeres T, et al. The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels. Pharmacogenomics J 2001;1:204-10. 80. Lazarowski A, Solimano J, Riveros D, Garay G, Dupont J, Fernández J, et al. 99 mTc-SESTAMIBI scintigraphy in non Hodgkin Lymphoma as a predictive indicator for chemotherapy sensitivity. 41th Annual Meeting of American Society of Hematology; 1999 Dec 3-7; New Orleans, Louisiana, USA. Blood 1999;(Supple 1) part 1: 84a:367. 81. Dupont J, Lazarowski A, Solimano J,Riveros D, Florin M, Garay G, et al. Evaluación de la respuesta a la quimioterapia con el uso de la captación centellográfica de 99 mTc-SESTAMIBI en linfomas y su utilización en la predicción de quimio-sensibilidad. Premio Bienal de la Academia Nacional de Medicina: "Elsa Arini de Masnata: Radioisótopos en Hematología". Academia Nacional de Medicina de Buenos Aires; 2002 Oct 31; Bs As, Argentina.

Biblioteca

Av. García del Río 2585 Piso 12 A - C.A.B.A
+54 11 2092 1646 | info@sciens.com.ar

Editorial Sciens, Todos los Derechos Reservados 2015