Drugs

, Volume 71, Issue 11, pp 1385–1396 | Cite as

Cellular Redox Pathways as a Therapeutic Target in the Treatment of Cancer

Leading Article

Abstract

The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage.

There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.

References

  1. 1.
    Connors T. Anticancer drug development: the way forward. Oncologist 1996; 1(3): 180–1PubMedGoogle Scholar
  2. 2.
    Rang HP, Dale MM, Ritter JM. Pharmacology. 4th ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  3. 3.
    Fruehauf JP, Meyskens Jr FL. Reactive oxygen species: a breath of life or death? Clin Cancer Res 2007; 13(3): 789–94PubMedCrossRefGoogle Scholar
  4. 4.
    Lu J, Chew EH, Holmgren A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci USA 2007; 104(30): 12288–93PubMedCrossRefGoogle Scholar
  5. 5.
    Chen J, Stubbe J. Bleomycins: towards better therapeutics. Nat Rev Cancer 2005; 5(2): 102–12PubMedCrossRefGoogle Scholar
  6. 6.
    Chow MS, Liu LV, Solomon EI. Further insights into the mechanism of the reaction of activated bleomycin with DNA. Proc Natl Acad Sci USA 2008; 105(36): 13241–5PubMedCrossRefGoogle Scholar
  7. 7.
    Fribley A, Zeng Q, Wang CY. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 2004; 24(22): 9695–704PubMedCrossRefGoogle Scholar
  8. 8.
    Berndtsson M, Hagg M, Panaretakis T, et al. Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer 2007; 120(1): 175–80PubMedCrossRefGoogle Scholar
  9. 9.
    Wondrak GT. Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Antioxid Redox Signal 2009; 11(12): 3013–69PubMedCrossRefGoogle Scholar
  10. 10.
    Oh SY, Sohn YW, Park JW, et al. Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. Mol Cancer Ther 2007; 6(8): 2178–87PubMedCrossRefGoogle Scholar
  11. 11.
    Alexandre J, Batteux F, Nicco C, et al. Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 2006; 119(1): 41–8PubMedCrossRefGoogle Scholar
  12. 12.
    Alexandre J, Hu Y, Lu W, et al. Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 2007; 67(8): 3512–7PubMedCrossRefGoogle Scholar
  13. 13.
    Loft S, Poulsen HE. Cancer risk and oxidative DNA damage in man. J Mol Med 1996; 74(6): 297–312PubMedCrossRefGoogle Scholar
  14. 14.
    Ballatori N, Krance SM, Notenboom S, et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 2009; 390(3): 191–214PubMedCrossRefGoogle Scholar
  15. 15.
    Electronic Medicines Compendium (eMC). Epirubicin summary of product characteristics [online]. Available from URL: http://emc.medicines.org.uk/medicine/18609/SPC/Epirubicin+Hydrochloride+2+mg+ml+Injection+(Hospira+UK+Ltd)/ [Accessed 2010 Feb 3]
  16. 16.
    Electronic Medicines Compendium (eMC). Doxorubicin summary of product characteristics [online]. Available from URL: http://emc.medicinesorguk/medicine/8270/SPC/Doxorubicin%20hydrochloride%2050mg%20Powder%20for%20Injection%20(Hospira%20UK%20Ltd)/ [Accessed 2010 Feb 5]
  17. 17.
    Pfizer Inc. Doxorubicin (Adriamycin) prescribing information [online]. Available from URL: http://www.pfizercom/files/products/uspi_adriamycinpdf [Accessed 2010 Sep 29]
  18. 18.
    Pfizer Inc. Epirubicin (Ellence) prescribing information [online]. Available from URL: http://media.pfizercom/files/products/uspi_ellencepdf [Accessed 2010 Feb 3]
  19. 19.
    Zelnak A. Overcoming taxane and anthracycline resistance. Breast J 2010; 16(3): 309–12PubMedCrossRefGoogle Scholar
  20. 20.
    Townsend DM. S-glutathionylation: indicator of cell stress and regulator of the unfolded protein response. Mol Interv 2007; 7(6): 313–24PubMedCrossRefGoogle Scholar
  21. 21.
    Giles GI. The redox regulation of thiol dependent signaling pathways in cancer. Curr Pharm Des 2006; 12(34): 4427–43PubMedCrossRefGoogle Scholar
  22. 22.
    Tew KD, Townsend DM. Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol 2011; 15(1): 156–61PubMedCrossRefGoogle Scholar
  23. 23.
    Qin XJ, Hudson LG, Liu W, et al. Dual actions involved in arsenite-induced oxidative DNA damage. Chem Res Toxicol 2008; 21(9): 1806–13PubMedCrossRefGoogle Scholar
  24. 24.
    Ames BN, Shigenaga MK, Gold LS. DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 1993; 101 Suppl. 5: 35–44PubMedCrossRefGoogle Scholar
  25. 25.
    Moller P, Wallin H. Adduct formation, mutagenesis and nucleotide excision repair of DNA damage produced by reactive oxygen species and lipid peroxidation product. Mutat Res 1998; 410(3): 271–90PubMedCrossRefGoogle Scholar
  26. 26.
    Clerkin JS, Naughton R, Quiney C, et al. Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 2008; 266(1): 30–6PubMedCrossRefGoogle Scholar
  27. 27.
    Trachootham D, Lu W, Ogasawara MA, et al. Redox regulation of cell survival. Antioxid Redox Signal 2008; 10(8): 1343–74PubMedCrossRefGoogle Scholar
  28. 28.
    Schumacker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 2006; 10(3): 175–6PubMedCrossRefGoogle Scholar
  29. 29.
    Chandra J, Samali A, Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 2000; 29(3–4): 323–33PubMedCrossRefGoogle Scholar
  30. 30.
    Ghezzi P, Casagrande S, Massignan T, et al. Redox regulation of cyclophilin A by glutathionylation. Proteomics 2006; 6(3): 817–25PubMedCrossRefGoogle Scholar
  31. 31.
    Townsend DM, Pazoles CJ, Tew KD. NOV-002, a mimetic of glutathione disulfide. Expert Opin Investig Drugs 2008; 17(7): 1075–83PubMedCrossRefGoogle Scholar
  32. 32.
    Griffith OW. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 1982; 257(22): 13704–12PubMedGoogle Scholar
  33. 33.
    Tew KD. TLK-286: a novel glutathione S-transferase-activated prodrug. Expert Opin Investig Drugs 2005; 14(8): 1047–54PubMedCrossRefGoogle Scholar
  34. 34.
    Edelman MJ. Novel cytotoxic agents for non-small cell lung cancer. J Thorac Oncol 2006; 1(7): 752–5PubMedCrossRefGoogle Scholar
  35. 35.
    Ruscoe JE, Rosario LA, Wang T, et al. Pharmacologic or genetic manipulation of glutathione S-transferase P1-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 2001; 298(1): 339–45PubMedGoogle Scholar
  36. 36.
    Raza A, Galili N, Smith S, et al. Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood 2009; 113(26): 6533–40PubMedCrossRefGoogle Scholar
  37. 37.
    Dvorakova K, Payne CM, Tome ME, et al. Induction of oxidative stress and apoptosis in myeloma cells by the aziridine-containing agent imexon. Biochem Pharmacol 2000; 60(6): 749–58PubMedCrossRefGoogle Scholar
  38. 38.
    Electronic Medicines Compendium (eMC). Antabuse summary of product characteristics [online]. Available from URL: http://emc.medicinesorguk/medicine/519/SPC/Antabuse+Tablets++200mg/ [Accessed 2010 Feb 17]
  39. 39.
    Drugs.com. Disulfiram prescribing information [online]. Available from URL: http://www.drugscom/pro/disulfiramhtml [Accessed 2010 Feb 17]
  40. 40.
    Baker AF, Dragovich T, Tate WR, et al. The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma. J Lab Clin Med 2006; 147(2): 83–90PubMedCrossRefGoogle Scholar
  41. 41.
    Hausheer FH, Shanmugarajah D, Leverett BD, et al. Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase. Cancer Chemother Pharmacol 2010; 65(5): 941–51PubMedCrossRefGoogle Scholar
  42. 42.
    Hausheer F, Bain S, Perry M, et al. Comprehensive meta-analysis of survival outcomes from two randomized multicenter trials in first-line advanced non-small cell lung cancer in patients treated with the novel investigational antitumor-enhancing and chemoprotective agent Tavocept. Eur J Clin Med Oncol 2009; 1: 7–19Google Scholar
  43. 43.
    Magda D, Miller RA. Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin Cancer Biol 2006; 16(6): 466–76PubMedCrossRefGoogle Scholar
  44. 44.
    Quintas-Cardama A, Verstovsek S, Freireich E, et al. Chemical and clinical development of darinaparsin, a novel organic arsenic derivative. Anticancer Agents Med Chem 2008; 8: 904–9PubMedCrossRefGoogle Scholar
  45. 45.
    Novelos Therapeutics. Study of NOV-002 in combination with chemotherapy to treat lung cancer [ClinicalTrials. gov identifier: NCT00347412]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  46. 46.
    Fidias P, Ciuleanu TA, Gladkov O, et al. A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carboplatin (C) versus paclitaxel and carboplatin alone for the treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28 (18s): Abstract LBA7007Google Scholar
  47. 47.
    Montero AJ, Diaz-Montero CM, Slingerland J, et al. Phase 2 study of neoadjuvant treatment with cellular redox modulator NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel (AC T) in patients with stage II-IIIHER-2 (−) breast cancer [abstract P1-11-05]. 33rd Annual Breast Cancer Symposium; 2010 Dec 8–12; San Antonio (TX)Google Scholar
  48. 48.
    Krasner CN, Seiden MV, Penson RT, et al. NOV-002 plus carboplatin in platinum-resistant ovarian cancer [abstract no. 5593]. J Clin Oncol 2008; 26 (May 20 Suppl.): 315sGoogle Scholar
  49. 49.
    Gumireddy K, Pazoles C, Vulfson E, et al. Inhibition of tumor cell invasion and ErbB2/PI3K signalling pathways by the glutathione disulfide-mimetic NOV-002 [abstract 1807]. Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver (CO)Google Scholar
  50. 50.
    Townsend DM, Bowers R, Pazoles CJ, et al. NOV-002 suppresses tumor cell growth by modulating redox-sensitive cell signaling. Mol Cancer Ther 2009; 8 (12 Suppl. 1): Abstract C301Google Scholar
  51. 51.
    Bowers R, Townsend D, Manevich Y, et al. The redox modulator NOV-002 inhibits proliferation of ovarian tumor cells but increases proliferation of myeloid cells. Proceedings of the 101st Annual Meeting of the American Association for Cancer Research [abstract 1615]; 2010 Apr 17–21; Washington (DC)Google Scholar
  52. 52.
    Montero AJ, Naga O, Xu M, et al. Nov-002, a cellular redox modulator, enhances the antitumor effect of adoptively transferred T cells in a murine melanoma model. Mol Cancer Ther 2009; 8 (12 Suppl. 1): Abstract C238Google Scholar
  53. 53.
    Pazoles CJ, Gerstein H. NOV-002, a chemoprotectant/immunomodulator, added to first-line carboplatin/paclitaxel in advanced non-small cell lung cancer (NSCLC): a randomized phase 1/2, open-label, controlled study [abstract 17021]. J Clin Oncol 2006; 2418S Pt 1 (Jun 20 Suppl.): 668sGoogle Scholar
  54. 54.
    University of Miami Sylvester Comprehensive Cancer Center. Oxidized glutathione (NOV-002), doxorubicin, cyclophosphamide, and docetaxel in treating women with newly diagnosed stage IIB, or stage IIIC breast cancer [ClinicalTrials.gov identifier: NCT00499122]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  55. 55.
    Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003; 21(22): 4165–74PubMedCrossRefGoogle Scholar
  56. 56.
    von Minckwitz G, Rezai M, Loibl S, et al. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 2010; 28(12): 2015–23CrossRefGoogle Scholar
  57. 57.
    Arrick BA, Griffith OW, Cerami A. Inhibition of glutathione synthesis as a chemotherapeutic strategy for trypanosomiasis. J Exp Med 1981; 153(3): 720–5PubMedCrossRefGoogle Scholar
  58. 58.
    Martensson J, Jain A, Stole E, et al. Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress. Proc Natl Acad Sci USA 1991; 88(20): 9360–4PubMedCrossRefGoogle Scholar
  59. 59.
    Marengo B, De CC, Verzola D, et al. Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma. Free Radic Biol Med 2008; 44(3): 474–82PubMedCrossRefGoogle Scholar
  60. 60.
    Bailey HH, Ripple G, Tutsch KD, et al. Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. J Natl Cancer Inst 1997; 89(23): 1789–96PubMedCrossRefGoogle Scholar
  61. 61.
    O’Dwyer PJ, Hamilton TC, La Creta FP, et al. Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J Clin Oncol 1996; 14(1): 249–56PubMedGoogle Scholar
  62. 62.
    Children’s Hospital Los Angeles. Chemotherapy in treating children with neuroblastoma [ClinicalTrials.gov identifier: NCT00002730]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  63. 63.
    New Approaches to Neuroblastoma Therapy Consortium. Melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children with resistant or recurrent neuroblastoma. ClinicalTrials.gov identifier: NCT00005835 [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00005835?term=NCT00005835&rank=1 [Accessed 2010 Apr 27]
  64. 64.
    Duke University. Buthionine sulfoximine and an isolated limb infusion of melphalan in treating patients with persistent or recurrent stage III malignant melanoma [ClinicalTrials.gov identifier: NCT00661336]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  65. 65.
    Hsu CH, Chen CL, Hong RL, et al. Prognostic value of multidrug resistance: 1, glutathione-S-transferase-pi and p53 in advanced nasopharyngeal carcinoma treated with systemic chemotherapy. Oncology 2002; 62(4): 305–12PubMedCrossRefGoogle Scholar
  66. 66.
    Shiga H, Heath EI, Rasmussen AA, et al. Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. Clin Cancer Res 1999; 5(12): 4097–104PubMedGoogle Scholar
  67. 67.
    Su F, Hu X, Jia W, et al. Glutathion S transferase pi indicates chemotherapy resistance in breast cancer. J Surg Res 2003; 113(1): 102–8PubMedCrossRefGoogle Scholar
  68. 68.
    Sequist LV, Fidias PM, Temel JS, et al. Phase 1-2a multi-center dose-ranging study of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy for patients with advanced non-small cell lung cancer. J Thorac Oncol 2009; 4(11): 1389–96PubMedCrossRefGoogle Scholar
  69. 69.
    Vergote I, Finkler N, del Campo J, et al. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45(13): 2324–32PubMedCrossRefGoogle Scholar
  70. 70.
    Raza A, Galili N, Smith S, et al. Phase 1multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra(R), TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome. Blood 2009 Jun 25; 113(26): 6533–40PubMedCrossRefGoogle Scholar
  71. 71.
    Telik. Phase 2 study comparing two dose schedules of Telintra™ in myelodysplastic syndrome (MDS) [ClinicalTrials.gov identifier: NCT00700206]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  72. 72.
    Telik. Study of ezatiostat (Telintra tablets) for treatment of severe chronic neutropenia [ClinicalTrials.gov identifier: NCT00909584]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  73. 73.
    Moulder S, Dhillon N, Ng C, et al. A phase I trial of imexon, a pro-oxidant, in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer. Invest New Drugs 2010; 28: 634–40PubMedCrossRefGoogle Scholar
  74. 74.
    Cohen SJ, Zalupski MM, Modiano MR, et al. A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer. Cancer Chemother Pharmacol 2009; 66: 287–94PubMedCrossRefGoogle Scholar
  75. 75.
    Cohen SJ, Zalupski MM, Conkling P, et al. A phase II randomized double blind multicenter trial of gemcitabine (Gem) plus imexon (IMX) versus Gem plus placebo (P) in patients with chemotherapy-naïve pancreatic adenocarcinoma (PC). J Clin Oncol 2010; 28 (15s): abstract 4076Google Scholar
  76. 76.
    Cvek B. Targeting malignancies with disulfiram (anta-buse): multidrug resistance, angiogenesis, and proteasome. Curr Cancer Drug Targets 2011; 11(3): 332–7PubMedCrossRefGoogle Scholar
  77. 77.
    Kona FR, Buac D, Burger AM. Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies. Curr Cancer Drug Targets 2011; 11(3): 338–46PubMedCrossRefGoogle Scholar
  78. 78.
    Cen D, Brayton D, Shahandeh B, et al. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem 2004; 47(27): 6914–20PubMedCrossRefGoogle Scholar
  79. 79.
    University of California. Disulfiram in metastatic melanoma [ClinicalTrials.gov identifier: NCT00256230]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  80. 80.
    Hadassah Medical Organization. Initial assessment of the effect of the addition of disulfiram (Antabuse) to standard chemotherapy in lung cancer [ClinicalTrials.gov identifier: NCT00312819]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  81. 81.
    University of Utah. Phase I study of disulfiram and copper gluconate for the treatment of refractory solid tumors involving the liver [ClinicalTrials.gov identifier NCT00742911]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  82. 82.
    Verma S, Stewart DJ, Maroun JA, et al. A randomized phase II study of cisplatin alone versus cisplatin plus disulfiram. Am J Clin Oncol 1990; 13(2): 119–24PubMedCrossRefGoogle Scholar
  83. 83.
    Ramanathan RK, Fakih M, Mani S, et al. Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers. Cancer Chemother Pharmacol 2006; 57(4): 465–74PubMedCrossRefGoogle Scholar
  84. 84.
    Oncothyreon Inc. A trial of PX-12 in patients with a histologically or cytologically confirmed diagnosis of advanced or metastatic cancer [ClinicalTrials.gov identifier: NCT00736372]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  85. 85.
    Boven E, Verschraagen M, Hulscher TM, et al. BNP7787, a novel protector against platinum-related toxicities, does not affect the efficacy of cisplatin or carboplatin in human tumour xenografts. Eur J Cancer 2002; 38(8): 1148–56PubMedCrossRefGoogle Scholar
  86. 86.
    Roswell Park Cancer Institute. Dimesna in treating patients with solid tumors who are undergoing treatment with cisplatin and paclitaxel [ClinicalTrials.gov identifier: NCT00003569]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  87. 87.
    BioNumerik Pharmaceuticals I. Phase 3 study of tavocept vs placebo in patients with newly diagnosed or relapsed advanced (stage IIIB/IV) primary adenocarcinoma of the lung treated with docetaxel or paclitaxel plus cisplatin [ClinicalTrials.gov identifier: NCT00966914]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  88. 88.
    Amato RJ, Jac J, Hernandez-McClain J. Motexafin gadolinium for the treatment of metastatic renal cell carcinoma: phase II study results. Clin Genitourin Cancer 2008; 6(2): 73–8PubMedCrossRefGoogle Scholar
  89. 89.
    Mehta MP, Shapiro WR, Phan SC, et al. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys 2009; 73(4): 1069–76PubMedCrossRefGoogle Scholar
  90. 90.
    Pharmacyclics. Study of motexafin gadolinium (MGd) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma [ClinicalTrials.gov identifier: NCT00100711]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  91. 91.
    Pharmacyclics. A study of motexafin gadolinium for the treatment of chronic lymphocytic leukemia (CLL) [ClinicalTrials.gov identifier: NCT00076401]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  92. 92.
    Pharmacyclics. Trial of motexafin gadolinium and peme-trexed (Alimta®) for second line treatment in patients with non-small cell lung cancer [ClinicalTrials.gov identifier: NCT00365183]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  93. 93.
    Pharmacyclics. Study of motexafin gadolinium for the treatment of renal cell (kidney) cancer [ClinicalTrials.gov identifier: NCT00134186]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  94. 94.
    Radiation Therapy Oncology Group. Motexafin gadolinium, temozolomide, and radiation therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma [ClinicalTrials.gov identifier: NCT00305864]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  95. 95.
    European Medicines Agency. Trisenox summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000388/WC500042844.pdf [Accessed 2010 Sep 29]
  96. 96.
    US Food and Drug Administration. Trisenox package insert and prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2000/21248lbl.pdf [Accessed 2011 Mar 24]
  97. 97.
    University of California. Evaluation of disulfiram plus arsenic trioxide in patients with metastatic melanoma and at least one prior systemic therapy [ClinicalTrials.gov identifier: NCT00571116]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  98. 98.
    ZIOPHARM. Phase I study of oral darinaparsin (ZIO-101-C) in advanced solid tumors and non-Hodgkin’s lymphomas [ClinicalTrials.gov identifier: NCT00591422]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  99. 99.
    ZIOPHARM. Phase I study of oral ZIO-101-C in advanced solid tumors and lymphomas [ClinicalTrials.gov identifier: NCT00592163]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  100. 100.
    ZIOPHARM. Phase II study of ZIO-101 in advanced blood and bone marrow cancers [ClinicalTrials.gov identifier: NCT00421213]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]
  101. 101.
    Wu J, Henderson C, Feun L, et al. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Invest New Drugs 2009; 28(5): 670–6PubMedCrossRefGoogle Scholar
  102. 102.
    Mann KK, Wallner B, Lossos IS, et al. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs 2009; 18(11): 1727–34PubMedCrossRefGoogle Scholar
  103. 103.
    Diaz-Montero CM, Paphitis N, Onicescu G, et al. Daily injections of the glutathione disulfide mimetic NOV-002 ameliorates hematologic toxicities from neoadjuvant chemotherapy in breast cancer patients enrolled in the NEO-NOVO trial, and significantly increases circulating dendritic cells [abstract 2141]. 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2008 Dec 10–14; San Antonio (TX)Google Scholar
  104. 104.
    Diaz-Montero CM, Perez A, Zidan AA, et al. Immunomodulatory activity of NOV-002 potentiates the anti-tumor efficacy of cyclophosphamide in the CT26 murine colon cancer model. Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17–21; Washington (DC)Google Scholar
  105. 105.
    Vergote I, Finkler N, del Campo J, et al. Single agent, canfosfamide (C, TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): phase 3 study results [abstract LBA5528]. J Clin Oncol 2010; 25 (18s Jun 20 Suppl.): 953sGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Miami Sylvester Comprehensive Cancer CenterMiamiUSA
  2. 2.Department of Oncology and RadiotherapyMedical University of GdanskGdanskPoland

Personalised recommendations