Skip to main content

Advertisement

SpringerLink
Log in

Comparative Safety and Pharmacokinetic Evaluation of Three Oral Selenium Compounds in Cancer Patients

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Selenium (Se) compounds have demonstrated anticancer properties in both preclinical and clinical studies, with particular promise in combination therapy where the optimal form and dose of selenium has yet to be established. In a phase I randomised double-blinded study, the safety, tolerability and pharmacokinetic (PK) profiles of sodium selenite (SS), Se-methylselenocysteine (MSC) and seleno-l-methionine (SLM) were compared in patients with chronic lymphocytic leukaemia and a cohort of patients with solid malignancies. Twenty-four patients received 400 μg of elemental Se as either SS, MSC or SLM for 8 weeks. None of the Se compounds were associated with any significant toxicities, and the total plasma Se AUC of SLM was markedly raised in comparison to MSC and SS. DNA damage assessment revealed negligible genotoxicity, and some minor reductions in lymphocyte counts were observed. At the dose level used, all three Se compounds are well-tolerated and non-genotoxic. Further analyses of the pharmacodynamic effects of Se on healthy and malignant peripheral blood mononuclear cells will inform the future evaluation of higher doses of these Se compounds. The study is registered under the Australian and New Zealand Clinical Trials Registry No: ACTRN12613000118707.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Velicer CM, Ulrich CM (2008) Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 26(4):665–673

    Article  CAS  Google Scholar 

  2. Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach LA, Marshall JR, Clark LC (2002) Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomark Prev 11(7):630–639

    CAS  Google Scholar 

  3. Rayman MP (2005) Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc 64(4):527–542

    Article  CAS  Google Scholar 

  4. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD III, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the selenium and vitamin E Cancer prevention trial (SELECT). JAMA 301(1):39–51

    Article  CAS  Google Scholar 

  5. Muecke R, Schomburg L, Buentzel J, Kisters K, Micke O, German Working Group Trace E, Electrolytes in O (2010) Selenium or no selenium—that is the question in tumor patients: a new controversy. Integr Cancer Ther 9(2):136–141

    Article  CAS  Google Scholar 

  6. Bhattacharya A (2011) Methylselenocysteine: a promising antiangiogenic agent for overcoming drug delivery barriers in solid malignancies for therapeutic synergy with anticancer drugs. Expert Opin Drug Deliv 8(6):749–763

    Article  CAS  Google Scholar 

  7. Zakharia Y, Bhattacharya A, Rustum YM (2018) Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development. Oncotarget 9(12):10765–10783

    Article  Google Scholar 

  8. Evans SO, Khairuddin PF, Jameson MB (2017) Optimising selenium for modulation of cancer treatments. Anticancer Res 37(12):6497–6509

    CAS  PubMed  Google Scholar 

  9. Fakih M, Cao S, Durrani FA, Rustum YM (2005) Selenium protects against toxicity induced by anticancer drugs and augments antitumor activity: a highly selective, new, and novel approach for the treatment of solid tumors. Clin Colorectal Cancer 5(2):132–135

    Article  Google Scholar 

  10. Li Z, Carrier L, Belame A, Thiyagarajah A, Salvo VA, Burow ME, Rowan BG (2009) Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast Cancer Res Treat 118(1):33–43

    Article  CAS  Google Scholar 

  11. Schueller P, Puettmann S, Micke O, Senner V, Schaefer U, Willich N (2004) Selenium influences the radiation sensitivity of C6 rat glioma cells. Anticancer Res 24(5A):2913–2917

    CAS  PubMed  Google Scholar 

  12. Wallenberg M, Misra S, Bjornstedt M (2014) Selenium cytotoxicity in cancer. Basic Clin Pharmacol Toxicol 114(5):377–386

    Article  CAS  Google Scholar 

  13. Fischer JL, Mihelc EM, Pollok KE, Smith ML (2007) Chemotherapeutic selectivity conferred by selenium: a role for p53-dependent DNA repair. Mol Cancer Ther 6(1):355–361

    Article  CAS  Google Scholar 

  14. Sieja K, Talerczyk M (2004) Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol 93(2):320–327

    Article  CAS  Google Scholar 

  15. Asfour IA, El Shazly S, Fayek MH, Hegab HM, Raouf S, Moussa MA (2006) Effect of high-dose sodium selenite therapy on polymorphonuclear leukocyte apoptosis in non-Hodgkin's lymphoma patients. Biol Trace Elem Res 110(1):19–32

    Article  CAS  Google Scholar 

  16. Jahangard-Rafsanjani Z, Gholami K, Hadjibabaie M, Shamshiri AR, Alimoghadam K, Sarayani A, Mojtahedzadeh M, Ostadali-Dehaghi M, Ghavamzadeh A (2013) The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial. Bone Marrow Transplant 48(6):832–836

    Article  CAS  Google Scholar 

  17. Muecke R, Schomburg L, Glatzel M, Berndt-Skorka R, Baaske D, Reichl B, Buentzel J, Kundt G, Prott FJ, Devries A, Stoll G, Kisters K, Bruns F, Schaefer U, Willich N, Micke O, German Working Group Trace E, Electrolytes in Oncology A (2010) Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 78(3):828–835

    Article  CAS  Google Scholar 

  18. Cao S, Durrani FA, Toth K, Rustum YM (2014) Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer 110(7):1733–1743

    Article  CAS  Google Scholar 

  19. Ip C, Hayes C, Budnick RM, Ganther HE (1991) Chemical form of selenium, critical metabolites, and cancer prevention. Cancer Res 51(2):595–600

    CAS  PubMed  Google Scholar 

  20. Brodin O, Eksborg S, Wallenberg M, Asker-Hagelberg C, Larsen EH, Mohlkert D, Lenneby-Helleday C, Jacobsson H, Linder S, Misra S, Bjornstedt M (2015) Pharmacokinetics and toxicity of sodium selenite in the treatment of patients with carcinoma in a phase I clinical trial: the SECAR study. Nutrients 7(6):4978–4994

    Article  CAS  Google Scholar 

  21. Valdiglesias V, Pasaro E, Mendez J, Laffon B (2010) In vitro evaluation of selenium genotoxic, cytotoxic, and protective effects: a review. Arch Toxicol 84(5):337–351

    Article  CAS  Google Scholar 

  22. Muecke R, Micke O, Schomburg L, Glatzel M, Reichl B, Kisters K, Schaefer U, Huebner J, Eich HT, Fakhrian K, Adamietz IA, Buentzel J, German Working Group Trace E, Electrolytes in Oncology A (2014) Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. Integr Cancer Ther 13(6):463–467

    Article  CAS  Google Scholar 

  23. Buntzel J, Riesenbeck D, Glatzel M, Berndt-Skorka R, Riedel T, Mucke R, Kisters K, Schonekaes KG, Schafer U, Bruns F, Micke O (2010) Limited effects of selenium substitution in the prevention of radiation-associated toxicities. Results of a randomized study in head and neck cancer patients. Anticancer Res 30(5):1829–1832

    CAS  PubMed  Google Scholar 

  24. Cao S, Durrani FA, Rustum YM (2004) Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res 10(7):2561–2569

    Article  CAS  Google Scholar 

  25. Fakih MG, Pendyala L, Smith PF, Creaven PJ, Reid ME, Badmaev V, Azrak RG, Prey JD, Lawrence D, Rustum YM (2006) A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors. Clin Cancer Res 12(4):1237–1244

    Article  CAS  Google Scholar 

  26. Fakih MG, Pendyala L, Brady W, Smith PF, Ross ME, Creaven PJ, Badmaev V, Prey JD, Rustum YM (2008) A phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol 62(3):499–508

    Article  CAS  Google Scholar 

  27. Mix M, Singh AK, Tills M, Dibaj S, Groman A, Jaggernauth W, Rustum Y, Jameson MB (2015) Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck. World J Clin Oncol 6(5):166–173

    Article  Google Scholar 

  28. Mix M, Ramnath N, Gomez J, de Groot C, Rajan S, Dibaj S, Tan W, Rustum Y, Jameson MB, Singh AK (2015) Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer. World J Clin Oncol 6(5):156–165

    Article  Google Scholar 

  29. Corcoran NM, Martin D, Hutter-Paier B, Windisch M, Nguyen T, Nheu L, Sundstrom LE, Costello AJ, Hovens CM (2010) Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J Clin Neurosci 17(8):1025–1033

    Article  CAS  Google Scholar 

  30. Asfour IA, El Tehewi MM, Ahmed MH, Abdel-Sattar MA, Moustafa NN, Hegab HM, Fathey OM (2009) High-dose sodium selenite can induce apoptosis of lymphoma cells in adult patients with non-Hodgkin's lymphoma. Biol Trace Elem Res 127(3):200–210

    Article  CAS  Google Scholar 

  31. Marshall JR, Ip C, Romano K, Fetterly G, Fakih MG, Jovanovic BD, Perloff M, Crowell J, Davis W Jr, Christy R, Dew A, Coomes M, Bergan RC (2011) Methyl Selenocysteine: single-dose pharmacokinetics in men. Cancer Prev Res (Phila) 4(11):1938–1944

    Article  CAS  Google Scholar 

  32. Marshall JR, Burk RF, Payne Ondracek R, Hill KE, Perloff M, Davis W, Pili R, George S, Bergan R (2017) Selenomethionine and methyl selenocysteine: multiple-dose pharmacokinetics in selenium-replete men. Oncotarget 8(16):26312–26322

    Article  Google Scholar 

  33. Stevens J, Juliger S, Summer K, Fitzgibbon J, Lister A, Joel S (2008) Methylseleninic acid demonstrates anti-leukaemic activity and sensitises AML cells to the effects of cytotoxic agents by initiating the unfolded protein response. Congress of the European Hematology Association Copenhagen Denmark June Haematologica 93s1 115 116 12–15

  34. Evans SO, Jameson MB, Cursons RT, Peters LM, Bird S, Jacobson GM (2016) Development of a qPCR method to measure mitochondrial and genomic DNA damage with application to chemotherapy-induced DNA damage and cryopreserved cells. Biology (Basel) 5 (4)

  35. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111(12):5446–5456

    Article  CAS  Google Scholar 

  36. Corcoran NM, Hovens CM, Michael M, Rosenthal MA, Costello AJ (2010) Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer. Br J Cancer 103(4):462–468

    Article  CAS  Google Scholar 

  37. Asfour IA, Fayek M, Raouf S, Soliman M, Hegab HM, El-Desoky H, Saleh R, Moussa MA (2007) The impact of high-dose sodium selenite therapy on Bcl-2 expression in adult non-Hodgkin's lymphoma patients: correlation with response and survival. Biol Trace Elem Res 120(1–3):1–10

    Article  CAS  Google Scholar 

  38. Lu J, Jiang C, Kaeck M, Ganther H, Vadhanavikit S, Ip C, Thompson H (1995) Dissociation of the genotoxic and growth inhibitory effects of selenium. Biochem Pharmacol 50(2):213–219

    Article  CAS  Google Scholar 

  39. Li GX, Hu H, Jiang C, Schuster T, Lu J (2007) Differential involvement of reactive oxygen species in apoptosis induced by two classes of selenium compounds in human prostate cancer cells. Int J Cancer 120(9):2034–2043

    Article  CAS  Google Scholar 

  40. Letavayova L, Vlasakova D, Spallholz JE, Brozmanova J, Chovanec M (2008) Toxicity and mutagenicity of selenium compounds in Saccharomyces cerevisiae. Mutat Res 638(1–2):1–10

    Article  CAS  Google Scholar 

  41. Biswas S, Talukder G, Sharma A (2000) Chromosome damage induced by selenium salts in human peripheral lymphocytes. Toxicol in Vitro 14(5):405–408

    Article  CAS  Google Scholar 

  42. Wu J, Lyons GH, Graham RD, Fenech MF (2009) The effect of selenium, as selenomethionine, on genome stability and cytotoxicity in human lymphocytes measured using the cytokinesis-block micronucleus cytome assay. Mutagenesis 24(3):225–232

    Article  CAS  Google Scholar 

  43. Yang H, Jia X (2014) Safety evaluation of Se-methylselenocysteine as nutritional selenium supplement: acute toxicity, genotoxicity and subchronic toxicity. Regul Toxicol Pharmacol 70(3):720–727

    Article  CAS  Google Scholar 

  44. Laffon B, Valdiglesias V, Pasaro E, Mendez J (2010) The organic selenium compound selenomethionine modulates bleomycin-induced DNA damage and repair in human leukocytes. Biol Trace Elem Res 133(1):12–19

    Article  CAS  Google Scholar 

  45. Seo YR, Sweeney C, Smith ML (2002) Selenomethionine induction of DNA repair response in human fibroblasts. Oncogene 21(23):3663–3669

    Article  CAS  Google Scholar 

  46. de Rosa V, Erkekoglu P, Forestier A, Favier A, Hincal F, Diamond AM, Douki T, Rachidi W (2012) Low doses of selenium specifically stimulate the repair of oxidative DNA damage in LNCaP prostate cancer cells. Free Radic Res 46(2):105–116

    Article  Google Scholar 

  47. Bera S, De Rosa V, Rachidi W, Diamond AM (2013) Does a role for selenium in DNA damage repair explain apparent controversies in its use in chemoprevention? Mutagenesis 28(2):127–134

    Article  CAS  Google Scholar 

  48. Suzuki KT, Shiobara Y, Itoh M, Ohmichi M (1998) Selective uptake of selenite by red blood cells. Analyst 123(1):63–67

    Article  CAS  Google Scholar 

  49. Rayman MP, Infante HG, Sargent M (2008) Food-chain selenium and human health: spotlight on speciation. Br J Nutr 100(2):238–253

    Article  CAS  Google Scholar 

  50. Aguilar F, Charrondiere UR, Dusemund B, Galtier P, Gilbert J, Gott DM, Grilli S, Guertler R, Cass GEN, Koenig J, Lambre C, Larsen JC, Leblanc JC, Mortensen A, Parent-Massin D, Pratt I, Rietjens IMCM, Stankovic I, Tobback P, Verguieva T, Woutersen R (2009) Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food on L-selenomethionine as a source of selenium added for nutritional purposes to food supplements, following a request from the European Commission. EFSA J 1082:1–38

    Google Scholar 

  51. Patterson BH, Levander OA, Helzlsouer K, McAdam PA, Lewis SA, Taylor PR, Veillon C, Zech LA (1989) Human selenite metabolism: a kinetic model. Am J Phys 257(3 Pt 2):R556–R567

    CAS  Google Scholar 

  52. Chintala S, Najrana T, Toth K, Cao S, Durrani FA, Pili R, Rustum YM (2012) Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition. BMC Cancer 12:293

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the patients and families who participated in this study.

Funding

Funding sources (Waikato Medical Research Foundation, Genesis Oncology Trust, Cycle for Life).

Author information

Authors and Affiliations

  1. Department of Biological Sciences, University of Waikato, Hamilton, New Zealand

    Stephen O. Evans, Gregory M. Jacobson & Steve Bird

  2. Waikato Clinical Campus, University of Auckland, Hamilton, New Zealand

    Stephen O. Evans & Michael B. Jameson

  3. Regional Cancer Centre, Waikato Hospital, Private Bag 3200, Hamilton, 3240, New Zealand

    Hugh J. B. Goodman & Michael B. Jameson

Authors
  1. Stephen O. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory M. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hugh J. B. Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steve Bird
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael B. Jameson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SOE contributed to study design, sample collection, performed the experiments, analysed the data and wrote the manuscript. GMJ contributed to experimental design, laboratory experiments and contributed to the manuscript. SB contributed to experimental design and contributed to the manuscript. HJBG contributed to study conduct, patient assessment and to the manuscript. MBJ, as study PI, conceived the project, wrote the trial protocol, oversaw the clinical and experimental aspects of the study (including patient assessment), assisted with data collection, analysis and interpretation and co-wrote the study manuscript.

Corresponding author

Correspondence to Michael B. Jameson.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Ethics Approval

Ethical approval was obtained through Northern A Health and Disability Ethics Committee (HDEC) (13/NTA/172). All procedures performed in this study were in accordance with the ethical standards of the Waikato DHB research committee and HDEC and with the 1964 Declaration of Helsinki and its later amendments.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

ESM 1

(DOCX 474 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Evans, S.O., Jacobson, G.M., Goodman, H.J.B. et al. Comparative Safety and Pharmacokinetic Evaluation of Three Oral Selenium Compounds in Cancer Patients. Biol Trace Elem Res 189, 395–404 (2019). https://doi.org/10.1007/s12011-018-1501-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-018-1501-0

Keywords

Search

Navigation