Patienten:..“Nebel im Hirn…“..“Gedächtnisverlust“..
Study suggests way to offset chemobrain memory loss
Cancer patients have complained for years about the mental fog known as chemobrain. New research shows that injections of N-acetyl cysteine (NAC) can prevent the memory loss that breast cancer chemotherapy drugs induce.
Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats <
Zeitschrift Metabolic Brain Disease
Verlag Springer Netherlands
ISSN 0885-7490 (Print) 1573-7365 (Online)
Heft Volume 23, Number 3 / September 2008
Kategorie Original Paper
DOI 10.1007/s11011-008-9100-y
Seiten 325-333
Fachgebiete Biomedizin & Life Sciences
SpringerLink Date Samstag, 9. August 2008
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Original Paper
Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats
Gregory W. Konat1 , Michal Kraszpulski1, Isaac James1, Han-Ting Zhang2 and Jame Abraham3
(1) Department of Neurobiology and Anatomy, West Virginia University School of Medicine, 4052 HSCN, P.O. Box 9128, Morgantown, WV 26506-9128, USA
(2) Department of Behavioral Medicine and Psychiatry, West Virginia University School of Medicine, Morgantown, WV, USA
(3) Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV, USA
Received: 13 March 2008 Accepted: 8 June 2008 Published online: 9 August 2008
Abstract Although cognitive dysfunction manifested by severe memory and attention deficits has been reported in up to 70% of cancer patients undergoing chemotherapy, the mechanisms of this serious side effect have not been defined. In particular, it has not been decisively resolved whether the dysfunction is attributable to the chemotherapy or to the malignancy itself. In the present study we tested whether cognitive dysfunction can be induced in an experimental setting by the administration of commonly used chemotherapeutics to rats. Female 10 month old Sprague–Dawley rats were injected intraperitoneally with a combination of 2.5 mg/kg of adriamycin (ADR) and 25 mg/kg of cytoxan (CTX). A total of four doses were given at weekly intervals. The control group was treated with saline only. No mortality and no apparent morbidity were observed in either group. However, the chemotherapeutic treatment severely impaired memory function of rats as measured by a passive avoidance test. This memory deficiency was fully prevented by the administration of an antioxidant, N-acetyl cysteine (NAC) injected subcutaneously three times a week at 200 mg/kg in the course of chemotherapeutic treatment. These results indicate that chemotherapeutic agents alone, i.e., in the absence of malignancy, damage the brain resulting in memory dysfunction. Moreover, the results strongly indicate that the damaging effect is mediated by oxidative stress, as memory dysfunction is preventable by the co-administration of NAC.
Keywords Adriamycin – Cytoxan – N-Acetyl cysteine – Memory impairment
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Gregory W. Konat
Email: gkonat@wvu.edu
References
Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7:192–201
Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, Silberfarb PM (2002) Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 20:485–493
Bhatia AL, Manda K, Patni S, Sharma AL (2006) Prophylactic action of linseed (Linum usitatissimum) oil against cyclophosphamide-induced oxidative stress in mouse brain. J Med Food 9:261–264
Bhattacharya A, Lawrence RA, Krishnan A, Zaman K, Sun D, Fernandes G (2003) Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. J Am Coll Nutr 22:388–399
Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C (2007) Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer Treat Rev 33(5):407–18
Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18:2695–2701
Chuang RY, Chuang LF (1979) Inhibition of chicken myeloblastosis RNA polymerase II activity by adriamycin. Biochemistry 18:2069–2073
Cummings J, Anderson L, Willmott N, Smyth JF (1991) The molecular pharmacology of doxorubicin in vivo. Eur J Cancer 27:532–535
De Beer EL, Bottone AE, Voest EE (2001) Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. Eur J Pharmacol 415:1–11
Durken M, Agbenu J, Finckh B, Hubner C, Pichlmeier U, Zeller W, Winkler K, Zander A, Kohlschutter A (1995) Deteriorating free radical-trapping capacity and antioxidant status in plasma during bone marrow transplantation. Bone Marrow Transplant 15:757–762
Durken M, Herrnring C, Finckh B, Nagel S, Nielsen P, Fischer R, Berger HM, Moison RM, Pichlmeier U, Kohlschutter B, Zander AR, Kohlschutter A (2000) Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation. Free Radic Biol Med 28:887–894
Erhola M, Kellokumpu-Lehtinen P, Metsa-Ketela T, Alanko K, Nieminen MM (1996) Effects of anthracyclin-based chemotherapy on total plasma antioxidant capacity in small cell lung cancer patients. Free Radic Biol Med 21:383–390
Friedman OM, Wodinsky I, Myles A (1976) Cyclophosphamide (NSC-26271)-related phosphoramide mustards—recent advances and historical perspective. Cancer Treat Rep 60:337–346
Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741
Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2003) Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357–3365
Goodman J, Hochstein P (1977) Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun 77:797–803
Hu YJ, Chen Y, Zhang YQ, Zhou MZ, Song XM, Zhang BZ, Luo L, Xu PM, Zhao YN, Zhao YB, Cheng G (1997) The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 56:331–341
Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K (1992) Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 12:599–606
Joshi G, Sultana R, Tangpong J, Cole MP, St Clair DK, Vore M, Estus S, Butterfield DA (2005) Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radic Res 39:1147–1154
Joshi G, Hardas S, Sultana R, St Clair DK, Vore M, Butterfield DA (2007) Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain. J Neurosci Res 85:497–503
Julka D, Sandhir R, Gill KD (1993) Adriamycin-induced oxidative stress in rat central nervous system. Biochem Mol Biol Int 29:807–820
Kehrer JP, Biswal SS (2000) The molecular effects of acrolein. Toxicol Sci 57:6–15
Kennedy DD, Tucker KL, Ladas ED, Rheingold SR, Blumberg J, Kelly KM (2004) Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia. Am J Clin Nutr 79:1029–1036
Kennedy DD, Ladas EJ, Rheingold SR, Blumberg J, Kelly KM (2005) Antioxidant status decreases in children with acute lymphoblastic leukemia during the first six months of chemotherapy treatment. Pediatr. Blood Cancer 44:378–385
Lamm DL, Riggs DR, Shriver JS, vanGilder PF, Rach JF, DeHaven JI (1994) Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 151:21–26
Lockwood K, Moesgaard S, Hanioka T, Folkers K (1994) Apparent partial remission of breast cancer in ‘high risk’ patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med 15(Suppl):s231–s240
Meyers CA, Albitar M, Estey E (2005) Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104:788–793
Olson RD, Mushlin PS (1990) Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4:3076–3086
Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85:640–650
Simone CB, Simone NL, Simone V, Simone CB (2007a) Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med 13:22–28
Simone CB, Simone NL, Simone V, Simone CB (2007b) Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2. Altern Ther Health Med 13:40–47
Singal PK, Li T, Kumar D, Danelisen I, Iliskovic N (2000) Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 207:77–86
Sladek NE (1971) Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Res 31:901–908
Sladek NE (1972a) Therapeutic efficacy of cyclophosphamide as a function of inhibition of its metabolism. Cancer Res 32:1848–1854
Sladek NE (1972b) Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Res 32:535–542
Stankiewicz A, Skrzydlewska E, Makiela M (2002) Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabol Drug Interact 19:67–82
Tanaka M, Yoshida S (1980) Mechanism of the inhibition of calf thymus DNA polymerases alpha and beta by daunomycin and adriamycin. J Biochem (Tokyo) 87:911–918
Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF (1984) Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466–468
van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 90:210–218
Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA (2004a) ‘Chemobrain’ in breast carcinoma?: a prologue. Cancer 101:466–475
Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004b) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100:2292–2299
Zhang HT, Zhao Y, Huang Y, Dorairaj NR, Chandler LJ, O’Donnell JM (2004) Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 29:1432–1439
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