Skip to main content
Erschienen in: Cancer Chemotherapy and Pharmacology 4/2009

01.09.2009 | Original Article

Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane

verfasst von: Sabry M. Attia, Alaa A. Al-Anteet, Nouf M. Al-Rasheed, Abdulqader A. Alhaider, Mohammed M. Al-harbi

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2009

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The objective of the current investigation is to determine whether non-toxic doses of the catalytic topoisomerase-II inhibitor, dexrazoxane, have influence on the genomic damage induced by the anticancer topoisomerase-II poison, etoposide, on mice bone marrow cells.

Method

The scoring of micronuclei, chromosomal aberrations, and mitotic activity were undertaken as markers of cyto- and genotoxicity. Oxidative damage markers such as reduced glutathione and lipid peroxidation were assessed as a possible mechanism underlying this amelioration.

Results

Dexrazoxane pre-treatment significantly reduced the etoposide-induced micronuclei formation, chromosomal aberrations, and also the suppression of erythroblast proliferation in bone marrow cells of mice. These effects were dose dependent. Etoposide induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of etoposide challenge ameliorated these biochemical markers.

Conclusion

Based on our data presented, strategies can be developed to decrease the etoposide-induced genomic damage in normal cells using dexrazoxane.
Literatur
1.
Zurück zum Zitat Adler ID (1984) Cytogenetic tests in mammals. In: Venitt S, Parry JM (eds) Mutagenicity testing: a practical approach. IRL Press, Oxford, pp 275–306 Adler ID (1984) Cytogenetic tests in mammals. In: Venitt S, Parry JM (eds) Mutagenicity testing: a practical approach. IRL Press, Oxford, pp 275–306
2.
Zurück zum Zitat Agarwal K, Mukherjee A, Sen S (1994) Etoposide (VP-16): cytogenetic studies in mice. Environ Mol Mutagen 23(3):190–193PubMedCrossRef Agarwal K, Mukherjee A, Sen S (1994) Etoposide (VP-16): cytogenetic studies in mice. Environ Mol Mutagen 23(3):190–193PubMedCrossRef
3.
Zurück zum Zitat Andoh T, Ishida R (1998) Catalytic inhibitors of DNA topoisomerase II. Biochim Biophys Acta 1400:155–171PubMed Andoh T, Ishida R (1998) Catalytic inhibitors of DNA topoisomerase II. Biochim Biophys Acta 1400:155–171PubMed
4.
Zurück zum Zitat Ashby J, Tinwell H, Glover P et al (1994) Potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: comparison to Salmonella responses. Environ Mol Mutagen 24:51–60PubMedCrossRef Ashby J, Tinwell H, Glover P et al (1994) Potent clastogenicity of the human carcinogen etoposide to the mouse bone marrow and mouse lymphoma L5178Y cells: comparison to Salmonella responses. Environ Mol Mutagen 24:51–60PubMedCrossRef
5.
Zurück zum Zitat Attia SM (2008) Abatement by naringin of lomefloxacin-induced genomic instability in mice. Mutagenesis 23(6):515–521PubMedCrossRef Attia SM (2008) Abatement by naringin of lomefloxacin-induced genomic instability in mice. Mutagenesis 23(6):515–521PubMedCrossRef
6.
Zurück zum Zitat Attia SM, Kliesch U, Schriever-Schwemmer G et al (2003) Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow micronucleus test complemented by fluorescence in situ hybridization with the mouse minor satellite DNA probe. Environ Mol Mutagen 41:99–103PubMedCrossRef Attia SM, Kliesch U, Schriever-Schwemmer G et al (2003) Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow micronucleus test complemented by fluorescence in situ hybridization with the mouse minor satellite DNA probe. Environ Mol Mutagen 41:99–103PubMedCrossRef
7.
Zurück zum Zitat Attia SM, Schmid TE, Badary OA et al (2002) Molecular cytogenetic analysis in mouse sperm of chemically induced aneuploidy: studies with topoisomerase II inhibitors. Mutat Res 520:1–13PubMed Attia SM, Schmid TE, Badary OA et al (2002) Molecular cytogenetic analysis in mouse sperm of chemically induced aneuploidy: studies with topoisomerase II inhibitors. Mutat Res 520:1–13PubMed
8.
Zurück zum Zitat Boos G, Stopper H (2000) Genotoxicity of several clinically used topoisomerase II inhibitors. Toxicol Lett 116(1–2):7–16PubMedCrossRef Boos G, Stopper H (2000) Genotoxicity of several clinically used topoisomerase II inhibitors. Toxicol Lett 116(1–2):7–16PubMedCrossRef
9.
Zurück zum Zitat Chen M, Beck WT (1995) Differences in inhibition of chromosome separation and G2 arrest by DNA topoisomerase II inhibitors merbarone and VM-26. Cancer Res 55:1509–1516PubMed Chen M, Beck WT (1995) Differences in inhibition of chromosome separation and G2 arrest by DNA topoisomerase II inhibitors merbarone and VM-26. Cancer Res 55:1509–1516PubMed
10.
Zurück zum Zitat Choudhury RC, Palo AK, Sahu PJ (2004) Cytogenetic risk assessment of etoposide from mouse bone marrow. Appl Toxicol 24:115–122CrossRef Choudhury RC, Palo AK, Sahu PJ (2004) Cytogenetic risk assessment of etoposide from mouse bone marrow. Appl Toxicol 24:115–122CrossRef
11.
Zurück zum Zitat Cierniak A, Papiez M, Kapiszewska M (2004) Modulatory effect of quercetin on DNA damage, induced by etoposide in bone marrow cells and on changes in the activity of antioxidant enzymes in rats. Rocz Akad Med Bialymst 49(Suppl. 1):167–169PubMed Cierniak A, Papiez M, Kapiszewska M (2004) Modulatory effect of quercetin on DNA damage, induced by etoposide in bone marrow cells and on changes in the activity of antioxidant enzymes in rats. Rocz Akad Med Bialymst 49(Suppl. 1):167–169PubMed
12.
Zurück zum Zitat Drake FH, Hofmann GA, Mong SM et al (1989) In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone. Cancer Res 49(10):2578–2583PubMed Drake FH, Hofmann GA, Mong SM et al (1989) In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone. Cancer Res 49(10):2578–2583PubMed
13.
Zurück zum Zitat Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 74:214–226 Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 74:214–226
14.
Zurück zum Zitat Felix CA (2001) Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 36(5):525–535PubMedCrossRef Felix CA (2001) Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 36(5):525–535PubMedCrossRef
15.
Zurück zum Zitat Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521PubMedCrossRef Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521PubMedCrossRef
16.
Zurück zum Zitat Hasinoff BB, Kuschak TI, Yalowich JC et al (1995) A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 50:953–958PubMedCrossRef Hasinoff BB, Kuschak TI, Yalowich JC et al (1995) A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 50:953–958PubMedCrossRef
17.
Zurück zum Zitat Hasinoff BB, Yalowich JC, Ling Y et al (1996) The effect of dexrazoxane (ICRF-187) on doxorubicin- and daunorubicin mediated growth inhibition of Chinese hamster ovary cells. Anticancer Drugs 7:558–567PubMedCrossRef Hasinoff BB, Yalowich JC, Ling Y et al (1996) The effect of dexrazoxane (ICRF-187) on doxorubicin- and daunorubicin mediated growth inhibition of Chinese hamster ovary cells. Anticancer Drugs 7:558–567PubMedCrossRef
18.
Zurück zum Zitat Hofland KF, Thougaard AV, Dejligbjerg M et al (2005) Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors. Clin Cancer Res 11(18):6722–6729PubMedCrossRef Hofland KF, Thougaard AV, Dejligbjerg M et al (2005) Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors. Clin Cancer Res 11(18):6722–6729PubMedCrossRef
19.
Zurück zum Zitat Hofland KF, Thougaard V, Sehested M et al (2005) Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin. Cancer Res 11:3915–3924CrossRef Hofland KF, Thougaard V, Sehested M et al (2005) Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin. Cancer Res 11:3915–3924CrossRef
20.
Zurück zum Zitat Holm B, Jensen PB, Sehested M (1996) ICRF-187 rescue in etoposid treatment in vivo. A model targeting high dose topoisomerase II poisons to CNS tumors. Cancer Chemother Pharmacol 38:203–209PubMedCrossRef Holm B, Jensen PB, Sehested M (1996) ICRF-187 rescue in etoposid treatment in vivo. A model targeting high dose topoisomerase II poisons to CNS tumors. Cancer Chemother Pharmacol 38:203–209PubMedCrossRef
21.
Zurück zum Zitat Humeniuk R, Kaczmarek L, Peczynska-Czoch W et al (2003) Cytotoxicity and cell cycle effects of novel indolo[2, 3-b]quinoline derivatives. Oncol Res 13(5):269–277PubMed Humeniuk R, Kaczmarek L, Peczynska-Czoch W et al (2003) Cytotoxicity and cell cycle effects of novel indolo[2, 3-b]quinoline derivatives. Oncol Res 13(5):269–277PubMed
22.
Zurück zum Zitat Kagan VE, Kuzmenko AI, Tyurina YY et al (2001) Pro-oxidant and antioxidant mechanisms of etoposide in HL-60 cells: role of myeloperoxidase. Cancer Res 61:7777–7784PubMed Kagan VE, Kuzmenko AI, Tyurina YY et al (2001) Pro-oxidant and antioxidant mechanisms of etoposide in HL-60 cells: role of myeloperoxidase. Cancer Res 61:7777–7784PubMed
23.
Zurück zum Zitat Kagan VE, Yalowich JC, Borisenko GG et al (1999) Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. Mol Pharmacol 56:494–506PubMed Kagan VE, Yalowich JC, Borisenko GG et al (1999) Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. Mol Pharmacol 56:494–506PubMed
24.
Zurück zum Zitat Kaiserová H, den Hartog GJ, Simůnek T et al (2006) Iron is not involved in oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin. Br J Pharmacol 149(7):920–930PubMedCrossRef Kaiserová H, den Hartog GJ, Simůnek T et al (2006) Iron is not involved in oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin. Br J Pharmacol 149(7):920–930PubMedCrossRef
25.
Zurück zum Zitat Kapiszewska M, Cierniak A, Elas M et al (2007) Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. Toxicol In Vitro 21(6):1020–1030PubMedCrossRef Kapiszewska M, Cierniak A, Elas M et al (2007) Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. Toxicol In Vitro 21(6):1020–1030PubMedCrossRef
26.
Zurück zum Zitat Kapiszewska M, Cierniak A, Papiez MA et al (2007) Prolonged quercetin administration diminishes the etopoide-induced DAN damage in bone marrow cells of rats. Drug Chem Toxicol 30:67–81PubMedCrossRef Kapiszewska M, Cierniak A, Papiez MA et al (2007) Prolonged quercetin administration diminishes the etopoide-induced DAN damage in bone marrow cells of rats. Drug Chem Toxicol 30:67–81PubMedCrossRef
27.
Zurück zum Zitat Langer SW, Sehested M, Jensen PB (2001) Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol 12:405–410PubMedCrossRef Langer SW, Sehested M, Jensen PB (2001) Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol 12:405–410PubMedCrossRef
28.
Zurück zum Zitat Lebrecht D, Geist A, Ketelsen UP et al (2007) Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 151(6):771–778PubMedCrossRef Lebrecht D, Geist A, Ketelsen UP et al (2007) Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Br J Pharmacol 151(6):771–778PubMedCrossRef
29.
Zurück zum Zitat Lowry OM, Rosebrough NJ, Fare AL et al (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275PubMed Lowry OM, Rosebrough NJ, Fare AL et al (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275PubMed
30.
Zurück zum Zitat Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRef Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRef
31.
Zurück zum Zitat Mo YY, Beck WT (1999) DNA damage signals induction of Fas ligand in tumor cells. Mol Pharmacol 55:216–222PubMed Mo YY, Beck WT (1999) DNA damage signals induction of Fas ligand in tumor cells. Mol Pharmacol 55:216–222PubMed
32.
Zurück zum Zitat Ohkawa H, Ohishi N, Yagi K (1979) Assay of lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedCrossRef Ohkawa H, Ohishi N, Yagi K (1979) Assay of lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358PubMedCrossRef
33.
Zurück zum Zitat Pearlman M, Jendiroba D, Pagliaro L et al (2003) Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. Leuk Res 27:617–626PubMedCrossRef Pearlman M, Jendiroba D, Pagliaro L et al (2003) Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. Leuk Res 27:617–626PubMedCrossRef
34.
Zurück zum Zitat Pearlman M, Jendiroba D, Pagliaro L et al (2003) Dexrazoxane’s protection of jejunal crypt cells in the jejunum of C3Hf/Kam mice from doxorubicin-induced toxicity. Cancer Chemother Pharmacol 52:477–481PubMedCrossRef Pearlman M, Jendiroba D, Pagliaro L et al (2003) Dexrazoxane’s protection of jejunal crypt cells in the jejunum of C3Hf/Kam mice from doxorubicin-induced toxicity. Cancer Chemother Pharmacol 52:477–481PubMedCrossRef
35.
Zurück zum Zitat Ritov VB, Goldman R, Stoyanovsky DA et al (1995) Antioxidant paradoxes of phenolic compounds: peroxyl radical scavenger and lipid antioxidant, etoposide (VP-16), inhibits sarcoplasmic reticulum Ca(2+)-ATPase via thiol oxidation by its phenoxyl radical. Arch Biochem Biophys 321:140–152PubMedCrossRef Ritov VB, Goldman R, Stoyanovsky DA et al (1995) Antioxidant paradoxes of phenolic compounds: peroxyl radical scavenger and lipid antioxidant, etoposide (VP-16), inhibits sarcoplasmic reticulum Ca(2+)-ATPase via thiol oxidation by its phenoxyl radical. Arch Biochem Biophys 321:140–152PubMedCrossRef
36.
Zurück zum Zitat Sehested M, Jensen PB, Sørensen BS et al (1993) Antagonistic effect of the cardioprotector (+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16). Biochem Pharmacol 46(3):389–393PubMedCrossRef Sehested M, Jensen PB, Sørensen BS et al (1993) Antagonistic effect of the cardioprotector (+)-1, 2-bis(3, 5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16). Biochem Pharmacol 46(3):389–393PubMedCrossRef
37.
Zurück zum Zitat Siitonen T, Alaruikka P, Mantymaa P et al (1999) Protection of acute myeloblastic leukemia cells against apoptotic cell death by high glutathione and gamma-glutamylcysteine synthetase levels during etoposide-induced oxidative stress. Ann Oncol 10:1361–1367PubMedCrossRef Siitonen T, Alaruikka P, Mantymaa P et al (1999) Protection of acute myeloblastic leukemia cells against apoptotic cell death by high glutathione and gamma-glutamylcysteine synthetase levels during etoposide-induced oxidative stress. Ann Oncol 10:1361–1367PubMedCrossRef
38.
Zurück zum Zitat Smith PJ, Soués S, Gottlieb T et al (1994) Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small-cell lung cancer cells. Br J Cancer 70:914–921PubMed Smith PJ, Soués S, Gottlieb T et al (1994) Etoposide-induced cell cycle delay and arrest-dependent modulation of DNA topoisomerase II in small-cell lung cancer cells. Br J Cancer 70:914–921PubMed
39.
Zurück zum Zitat Swain SM, Vici P (2004) The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol 130:1–7PubMedCrossRef Swain SM, Vici P (2004) The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol 130:1–7PubMedCrossRef
40.
Zurück zum Zitat Swain SM, Whaley F, Gerber MC et al (1997) Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15:1333–1340PubMed Swain SM, Whaley F, Gerber MC et al (1997) Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15:1333–1340PubMed
41.
Zurück zum Zitat Topcu Z (2001) DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther 26:405–416PubMedCrossRef Topcu Z (2001) DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther 26:405–416PubMedCrossRef
42.
Zurück zum Zitat Turner SD, Wijnhoven SW, Tinwell H et al (2001) Assays to predict the genotoxicity of the chromosomal mutagen etoposide-focussing on the best assay. Mutat Res 493(1–2):139–147PubMed Turner SD, Wijnhoven SW, Tinwell H et al (2001) Assays to predict the genotoxicity of the chromosomal mutagen etoposide-focussing on the best assay. Mutat Res 493(1–2):139–147PubMed
44.
Zurück zum Zitat Wang L, Eastmond DA (2002) Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Environ Mol Mutagen 39(4):348–356PubMedCrossRef Wang L, Eastmond DA (2002) Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Environ Mol Mutagen 39(4):348–356PubMedCrossRef
45.
Zurück zum Zitat Zima T, Tesar V, Crkovská J et al (1998) ICRF-187 (dexrazoxan) protects from adriamycin-induced nephrotic syndrome in rats. Nephrol Dial Transplant 13(8):1975–1979PubMedCrossRef Zima T, Tesar V, Crkovská J et al (1998) ICRF-187 (dexrazoxan) protects from adriamycin-induced nephrotic syndrome in rats. Nephrol Dial Transplant 13(8):1975–1979PubMedCrossRef
Metadaten
Titel
Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane
verfasst von
Sabry M. Attia
Alaa A. Al-Anteet
Nouf M. Al-Rasheed
Abdulqader A. Alhaider
Mohammed M. Al-harbi
Publikationsdatum
01.09.2009
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 4/2009
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-009-0934-8

Weitere Artikel der Ausgabe 4/2009

Cancer Chemotherapy and Pharmacology 4/2009 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.