Skip to main content

Advertisement

SpringerLink
Log in

Pyridoxine to protect from oxaliplatin-induced neurotoxicity without compromising antitumour effect

  • Short Communication
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Oxaliplatin (OHP) in combination with 5-fluorouracil/leucovorin (FOLFOX) is clinically used as frontline therapy in patients with advanced colorectal carcinoma (CRC), with response rates ranging from 46 to 71%. This combination is now considered a standard treatment for metastatic CRC and also in the post-operative adjuvant setting. Reversible, cumulative, peripheral sensory neuropathy is the principal dose-limiting toxicity of OHP therapy. Pyridoxine (vitamin B6) has been shown to reduce cisplatin and fluoropyrimidine-related neurotoxicity but its administration with OHP has not yet been studied. Low doses of pyridoxine are free of side effects; it can be given orally. If pyridoxine administration with oxaliplatin has no adverse effect on OHP cytotoxicity effects, it will be a simple and cost-effective way to minimise OHP-induced neurotoxicity.

Methods

In vitro simultaneous combination of OHP and pyridoxine was studied in 6 CRC cell lines (HT29, Widr, SW480, HCT116, H630 and SW1116), in an ovarian cancer cell line (A2780) and its cisplatin-resistant subline (ADDP) and in an oestrogen-dependent breast cancer cell line (MCF-7). Three fixed concentrations of pyridoxine: 1, 10 and 25 μM were combined with varying concentrations of OHP, and the growth inhibitory effects were evaluated using the MTT cell growth assay.

Results

Oxaliplatin induced consistent cytotoxicity in all cell lines with GI50 values between 0.23 and 7.6 μM. Addition of pyridoxine at concentrations of 1–25 μM does not affect OHP cytotoxicity.

Conclusions

Administration of pyridoxine, at concentrations extending across possible therapeutic plasma levels in humans, does not antagonise OHP antitumour effects in a range of relevant tumour cell lines. This study provides a foundation for clinical studies to test whether pyridoxine can minimise OHP-related neurotoxicity, and clinicians can be confident that pyridoxine is very unlikely to reverse the antitumour effects of OHP, as seems to be the case with Ca/Mg infusions. This could prove to be a cost-effective way to minimise OHP-related neurotoxicity, allowing more effective less toxic treatment and better outcomes in patients.

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

Fig. 1

References

  1. Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, Fojo T (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the national cancer institute’s anticancer drug screen panel. Biochem Pharmacol 52:1855–1865

    Article  PubMed  CAS  Google Scholar 

  2. Tashiro T, Kawada Y, Sakurai Y, Kidani Y (1989) Antitumour activity of a new platinum complex, oxalato (trans-1-1,2-diaminocyclo-hexane) platinum (II): new experimental data. Biomed Pharmacother 43:251–260

    Article  PubMed  CAS  Google Scholar 

  3. Culy CR, Clemett D, Wiseman LR (2000) Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60:895–924

    Article  PubMed  CAS  Google Scholar 

  4. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947

    PubMed  Google Scholar 

  5. de Gramont A, Vignoud J, Tournigand C, Louvet C, Andre T, Varette C, Raymond E, Moreau S, Le Bail N, Krulik M (1997) Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214–219

    Article  PubMed  Google Scholar 

  6. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351

    Article  PubMed  CAS  Google Scholar 

  7. Chollet P, Bensmaine MA, Brienza S, Deloche C, Cure H, Caillet H, Cvitkovic E (1996) Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 10:1065–1070

    Google Scholar 

  8. Machover D, Diaz-Rubio E, de Gramont A, Schilf A, Giastiaburu JJ, Brienza S, Itzhaki M, Metzger G, N’Daw D, Vignoud J, Abad A, Francois E, Gamelin E, Marty M, Sastre J, Seitz JF, Ychou M (1996) Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95–98

    PubMed  CAS  Google Scholar 

  9. Pasetto LM, D’Andrea MR, Rossi E, Monfardini S (2006) Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hematol 59:159–168

    Article  PubMed  Google Scholar 

  10. Holmes J, Stanko J, Varchenko M, Ding H, Madden VJ, Bagnell CR, Wyrick SD, Chaney SG (1998) Comparative neurotoxicity of oxaliplatin, cisplatin, and ormaplatin in a Wistar rat model. Toxicol Sci 46:342–351

    PubMed  CAS  Google Scholar 

  11. Gregg RW, Molepo JM, Monpetit VJ, Mikael NZ, Redmond D, Gadia M, Stewart DJ (1992) Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol 10:795–803

    PubMed  CAS  Google Scholar 

  12. Gamelin L, Boisdron-Celle M, Delva R, Guerin-Meyer V, Ifrah N, Morel A, Gamelin E (2004) Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 10:4055–4061

    Article  PubMed  CAS  Google Scholar 

  13. Grolleau F, Gamelin L, Boisdron-Celle M, Lapied B, Pelhate M, Gamelin E (2001) A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 85:2293–2297

    PubMed  CAS  Google Scholar 

  14. Hochster HS, Grothey A, Childs BH (2007) Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 25:4028–4029

    Article  PubMed  Google Scholar 

  15. Eckel F, Schmelz R, Adelsberger H, Erdmann J, Quasthoff S, Lersch C (2002) Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study. Dtsch Med Wochenschr 3:78–82

    Article  Google Scholar 

  16. Grothey A (2005) Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer 1:38–46

    Article  Google Scholar 

  17. Wang WS, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Chiou TJ, Liu JH, Yen CC, Chen PM (2007) Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 12:312–319

    Article  PubMed  CAS  Google Scholar 

  18. Wiernik PH, Yeap B, Vogl SE, Kaplan BH, Comis RL, Falkson G, Davis TE, Fazzini E, Cheuvart B, Horton J (1992) Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group. Cancer Invest 10:1–9

    Article  PubMed  CAS  Google Scholar 

  19. Abushullaih S, Saad ED, Munsell M, Hoff PM (2002) Incidence and severity of hand-foot syndrome in colorectal cancer patients treated with capecitabine: a single-institution experience. Cancer Invest 20:3–10

    Article  PubMed  CAS  Google Scholar 

  20. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1998) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601

    Google Scholar 

Download references

Acknowledgments

We are grateful for financial support from The Margaret Mitchell Research Grant Scheme of Calvary Mater Newcastle Hospital, NSW, Australia.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Calvary Mater Newcastle Hospital, Locked bag No 7, Hunter Regional Mail Centre, Newcastle, NSW, 2310, Australia

    Madhu B. Garg & Stephen P. Ackland

  2. Faculty of Health, University of Newcastle, Callaghan, NSW, 2308, Australia

    Stephen P. Ackland

  3. Hunter Medical Research Institute, Newcastle, NSW, Australia

    Madhu B. Garg & Stephen P. Ackland

Authors
  1. Madhu B. Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen P. Ackland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen P. Ackland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garg, M.B., Ackland, S.P. Pyridoxine to protect from oxaliplatin-induced neurotoxicity without compromising antitumour effect. Cancer Chemother Pharmacol 67, 963–966 (2011). https://doi.org/10.1007/s00280-010-1476-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-010-1476-9

Keywords

Search

Navigation