Skip to main content

Advertisement

SpringerLink
Log in

Oxidative damage to guanine nucleosides following combination chemotherapy with 5-fluorouracil and oxaliplatin

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Recent in vitro and animal studies have suggested that the cytotoxicity of 5-fluorouracil and oxaliplatin is linked to increased formation of reactive oxygen species (ROS). This prospective study was undertaken to examine the generation of oxidative stress, in 106 colorectal cancer patients, by 5-fluorouracil and oxaliplatin combination (FOLFOX) therapy as measured by urinary excretion of 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro-guanosine (8-oxoGuo).

Methods

The amounts of 8-oxoGuo and 8-oxodG were measured in 3 spot urine samples from 106 patients by using ultra performance liquid chromatography and tandem mass spectrometry. Furthermore, we collected information on other clinical and demographic variables hypothesized to be associated with oxidative stress. Repeated measures linear mixed models were used to model the relationship between urinary concentrations of 8-oxoGuo and 8-oxodG and the treatment effect and the other variables.

Results

The analysis showed that chemotherapy increased the excretion of 8-oxoGuo and 8-oxodG around 15% (P < 0.0001 and P = 0.02, respectively) though there was a significant interaction with CRP levels. Additionally, we found that sex, smoking status, age, and c-reactive protein were related to urinary excretion of 8-oxoGuo and 8-oxodG in colorectal cancer patients.

Conclusion

These results indicate that FOLFOX induces ROS in patients and that ROS-generating mechanisms interact.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alexandre J, Nicco C, Chereau C et al (2006) Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J Natl Cancer Inst 98:236–244

    Article  PubMed  CAS  Google Scholar 

  2. Dahan L, Sadok A, Formento JL, Seitz JF, Kovacic H (2009) Modulation of cellular redox state underlies antagonism between oxaliplatin and cetuximab in human colorectal cancer cell lines. Br J Pharmacol 158:610–620

    Article  PubMed  CAS  Google Scholar 

  3. Hwang IT, Chung YM, Kim JJ et al (2007) Drug resistance to 5-FU linked to reactive oxygen species modulator 1. Biochem Biophys Res Commun 359:304–310

    Article  PubMed  CAS  Google Scholar 

  4. Hwang PM, Bunz F, Yu J et al (2001) Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat Med 7:1111–1117

    Article  PubMed  CAS  Google Scholar 

  5. Kopetz S, Lesslie DP, Dallas NA et al (2009) Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res 69:3842–3849

    Article  PubMed  CAS  Google Scholar 

  6. Laurent A, Nicco C, Chereau C et al (2005) Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res 65:948–956

    PubMed  CAS  Google Scholar 

  7. Lim SC, Choi JE, Kang HS, Han SI (2010) Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer 126:1582–1595

    PubMed  CAS  Google Scholar 

  8. Liu G, Chen X (2002) The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene 21:7195–7204

    Article  PubMed  CAS  Google Scholar 

  9. Preston TJ, Henderson JT, McCallum GP, Wells PG (2009) Base excision repair of reactive oxygen species-initiated 7, 8-dihydro-8-oxo-2’-deoxyguanosine inhibits the cytotoxicity of platinum anticancer drugs. Mol Cancer Ther 8:2015–2026

    Article  PubMed  CAS  Google Scholar 

  10. Shibata T, Kokubu A, Gotoh M et al (2008) Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135:1358–1368

    Google Scholar 

  11. Ueta E, Yoneda K, Yamamoto T, Osaki T (1999) Manganese superoxide dismutase negatively regulates the induction of apoptosis by 5-fluorouracil, peplomycin and gamma-rays in squamous cell carcinoma cells. Jpn J Cancer Res 90:555–564

    Article  PubMed  CAS  Google Scholar 

  12. Burdon RH (1995) Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18:775–794

    Article  PubMed  CAS  Google Scholar 

  13. Benhar M, Dalyot I, Engelberg D, Levitzki A (2001) Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 21:6913–6926

    Article  PubMed  CAS  Google Scholar 

  14. Chung YM, Bae YS, Lee SY (2003) Molecular ordering of ROS production, mitochondrial changes, and caspase activation during sodium salicylate-induced apoptosis. Free Radic Biol Med 34:434–442

    Article  PubMed  CAS  Google Scholar 

  15. Li PF, Dietz R, von HR (1999) p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J 18:6027–6036

    Article  PubMed  CAS  Google Scholar 

  16. Pierce GB, Parchment RE, Lewellyn AL (1991) Hydrogen peroxide as a mediator of programmed cell death in the blastocyst. Differentiation 46:181–186

    Article  PubMed  CAS  Google Scholar 

  17. Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN (1998) Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J 332(Pt 1):43–50

    PubMed  CAS  Google Scholar 

  18. Murrell GA, Francis MJ, Bromley L (1990) Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 265:659–665

    PubMed  CAS  Google Scholar 

  19. Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299

    Article  PubMed  CAS  Google Scholar 

  20. Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798

    PubMed  CAS  Google Scholar 

  21. Toyokuni S, Okamoto K, Yodoi J, Hiai H (1995) Persistent oxidative stress in cancer. FEBS Lett 358:1–3

    Article  PubMed  CAS  Google Scholar 

  22. Joseph EK, Chen X, Bogen O, Levine JD (2008) Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 9:463–472

    Article  PubMed  CAS  Google Scholar 

  23. Weimann A, Belling D, Poulsen HE (2002) Quantification of 8-oxo-guanine and guanine as the nucleobase, nucleoside and deoxynucleoside forms in human urine by high-performance liquid chromatography-electrospray tandem mass spectrometry. Nucleic Acids Res 30:E7

    Article  PubMed  Google Scholar 

  24. Henriksen T, Hillestrom PR, Poulsen HE, Weimann A (2009) Automated method for the direct analysis of 8-oxo-guanosine and 8-oxo-2’-deoxyguanosine in human urine using ultraperformance liquid chromatography and tandem mass spectrometry. Free Radic Biol Med 47:629–635

    Article  PubMed  CAS  Google Scholar 

  25. Dizdaroglu M, Olinski R, Doroshow JH, Akman SA (1993) Modification of DNA bases in chromatin of intact target human cells by activated human polymorphonuclear leukocytes. Cancer Res 53:1269–1272

    PubMed  CAS  Google Scholar 

  26. Ohba M, Shibanuma M, Kuroki T, Nose K (1994) Production of hydrogen peroxide by transforming growth factor-beta 1 and its involvement in induction of egr-1 in mouse osteoblastic cells. J Cell Biol 126:1079–1088

    Article  PubMed  CAS  Google Scholar 

  27. Peddie CM, Wolf CR, McLellan LI, Collins AR, Bowen DT (1997) Oxidative DNA damage in CD34 + myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-alpha concentration. Br J Haematol 99:625–631

    Article  PubMed  CAS  Google Scholar 

  28. Kayanoki Y, Fujii J, Suzuki K, Kawata S, Matsuzawa Y, Taniguchi N (1994) Suppression of antioxidative enzyme expression by transforming growth factor-beta 1 in rat hepatocytes. J Biol Chem 269:15488–15492

    PubMed  CAS  Google Scholar 

  29. Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 61:4756–4760

    PubMed  CAS  Google Scholar 

  30. Prieme H, Loft S, Klarlund M, Gronbaek K, Tonnesen P, Poulsen HE (1998) Effect of smoking cessation on oxidative DNA modification estimated by 8-oxo-7, 8-dihydro-2’-deoxyguanosine excretion. Carcinogenesis 19:347–351

    Article  PubMed  CAS  Google Scholar 

  31. Fano G, Mecocci P, Vecchiet J et al (2001) Age and sex influence on oxidative damage and functional status in human skeletal muscle. J Muscle Res Cell Motil 22:345–351

    Article  PubMed  CAS  Google Scholar 

  32. Mecocci P, Fano G, Fulle S et al (1999) Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle. Free Radic Biol Med 26:303–308

    Article  PubMed  CAS  Google Scholar 

  33. Hofer T, Seo AY, Prudencio M, Leeuwenburgh C (2006) A method to determine RNA and DNA oxidation simultaneously by HPLC-ECD: greater RNA than DNA oxidation in rat liver after doxorubicin administration. Biol Chem 387:103–111

    Article  PubMed  CAS  Google Scholar 

  34. Kong Q, Lin CL (2010) Oxidative damage to RNA: mechanisms, consequences, and diseases. Cell Mol Life Sci 67:1817–1829

    Article  PubMed  CAS  Google Scholar 

  35. Crohns M, Saarelainen S, Erhola M, Alho H, Kellokumpu-Lehtinen P (2009) Impact of radiotherapy and chemotherapy on biomarkers of oxidative DNA damage in lung cancer patients. Clin Biochem 42:1082–1090

    Article  PubMed  CAS  Google Scholar 

  36. Siomek A, Tujakowski J, Gackowski D et al (2006) Severe oxidatively damaged DNA after cisplatin treatment of cancer patients. Int J Cancer 119:2228–2230

    Article  PubMed  CAS  Google Scholar 

  37. Weimann A, Riis B, Poulsen HE (2004) Oligonucleotides in human urine do not contain 8-oxo-7, 8-dihydrodeoxyguanosine. Free Radic Biol Med 36:1378–1382

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

No conflicts of interest to disclose for any author.

Author information

Authors and Affiliations

  1. Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, 20 Tagensvej, 2200, Copenhagen, Denmark

    Shoaib Afzal, Trine Henriksen, Allan Weimann & Henrik Enghusen Poulsen

  2. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Shoaib Afzal & Henrik Enghusen Poulsen

  3. Department of Oncology, Rigshospitalet, Copenhagen, Denmark

    Søren Astrup Jensen & Jens Benn Sørensen

  4. Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark

    Trine Henriksen, Allan Weimann & Henrik Enghusen Poulsen

Authors
  1. Shoaib Afzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Søren Astrup Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens Benn Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Trine Henriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Allan Weimann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henrik Enghusen Poulsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shoaib Afzal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Afzal, S., Jensen, S.A., Sørensen, J.B. et al. Oxidative damage to guanine nucleosides following combination chemotherapy with 5-fluorouracil and oxaliplatin. Cancer Chemother Pharmacol 69, 301–307 (2012). https://doi.org/10.1007/s00280-011-1700-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1700-2

Keywords

Search

Navigation