Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 3, pp 765–775 | Cite as

Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial

  • J. L. Welsh
  • B. A. Wagner
  • T. J. van’t Erve
  • P. S. Zehr
  • D. J. Berg
  • T. R. Halfdanarson
  • N. S. Yee
  • K. L. Bodeker
  • J. Du
  • L. J. RobertsII
  • J. Drisko
  • M. Levine
  • G. R. Buettner
  • J. J. CullenEmail author
Original Article



Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma.


Nine subjects received twice-weekly intravenous ascorbate (15–125 g) employing Simon’s accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored.


Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months.


Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.


Pancreatic neoplasm Ascorbic acid Clinical trial Phase 1 Gemcitabine Drug toxicity 



The authors thank the John (Jack) Widness lab and the Sysmex Corporation, Kobe, Japan, for the use of XE-2100 and XT-2000 automated hematology analyzers. The authors also thank the Holden Comprehensive Cancer Center for its support for the clinical trial. TJvE gratefully acknowledges support from the Iowa Superfund Research Program (P42 ES013661) Training Core. The content is solely the responsibility of the authors and does not represent views of the National Institutes of Health. The University of Iowa ESR Facility provided invaluable support. This work was supported by the National Institutes of Health [grant numbers GM42056, GM073929, P42ES013661, P30 CA086862, CA137230, and CA148062], the Medical Research Service of the Department of Veterans Affairs, the Holden Comprehensive Cancer Center, and the Susan L. Bader Foundation of Hope. Dr. Mark Levine is supported by the Intramural Research Program NIDDK, NIH.

Conflict of interest

  The authors have declared no conflicts of interest.

Supplementary material

280_2013_2070_MOESM1_ESM.tif (93 kb)
Supplemental Fig. 1. Patient weight changes while receiving ascorbate + gemcitabine therapy. The bar graph demonstrates the mean patient weight at baseline and at removal from the study. Error bars represent the variability in the distribution of patients’ weights. Supplementary material 1 (TIFF 93 kb)
280_2013_2070_MOESM2_ESM.doc (30 kb)
Supplementary material 2 (DOC 29 kb)


  1. 1.
    Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236PubMedCrossRefGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29PubMedCrossRefGoogle Scholar
  3. 3.
    Winstead ER (2009) Pancreatic cancer report urges changes in clinical trials. NCI Cancer BulletinGoogle Scholar
  4. 4.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol Off J Am Soc Clin Oncol 15(6):2403–2413Google Scholar
  5. 5.
    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825PubMedCrossRefGoogle Scholar
  6. 6.
    Buettner GR, Jurkiewicz BA (1996) Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res 145(5):532–541PubMedCrossRefGoogle Scholar
  7. 7.
    Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR et al (2005) Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA 102(38):13604–13609PubMedCrossRefGoogle Scholar
  8. 8.
    Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E et al (2007) Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA 104(21):8749–8754PubMedCrossRefGoogle Scholar
  9. 9.
    Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH et al (2010) Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res 16(2):509–520PubMedCrossRefGoogle Scholar
  10. 10.
    Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M et al (2011) Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 50(11):1610–1619PubMedCrossRefGoogle Scholar
  11. 11.
    Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR et al (1996) Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 93(8):3704–3709PubMedCrossRefGoogle Scholar
  12. 12.
    Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A et al (2004) Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 140(7):533–537PubMedGoogle Scholar
  13. 13.
    Levine M, Padayatty SJ, Espey MG, Vitamin C (2011) a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2(2):78–88PubMedCrossRefGoogle Scholar
  14. 14.
    Vislisel JM, Schafer FQ, Buettner GR (2007) A simple and sensitive assay for ascorbate using a plate reader. Anal Biochem 365(1):31–39PubMedCrossRefGoogle Scholar
  15. 15.
    Venkataraman S, Martin SM, Schafer FQ, Buettner GR (2000) Detailed methods for the quantification of nitric oxide in aqueous solutions using either an oxygen monitor or EPR. Free Radic Biol Med 29(6):580–585PubMedCrossRefGoogle Scholar
  16. 16.
    Buettner GR, Kiminyo KP (1992) Optimal EPR detection of weak nitroxide spin adduct and ascorbyl free radical signals. J Biochem Biophys Methods 24(1–2):147–151PubMedCrossRefGoogle Scholar
  17. 17.
    Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ 2nd (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA 87(23):9383–9387PubMedCrossRefGoogle Scholar
  18. 18.
    Kadiiska MB, Gladen BC, Baird DD, Germolec D, Graham LB, Parker CE et al (2005) Biomarkers of oxidative stress study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning? Free Radic Biol Med 38(6):698–710PubMedCrossRefGoogle Scholar
  19. 19.
    Kadiiska MB, Gladen BC, Baird DD, Graham LB, Parker CE, Ames BN et al (2005) Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning. Free Radic Biol Med 38(6):711–718PubMedCrossRefGoogle Scholar
  20. 20.
    Park HJ, Mah E, Bruno RS (2010) Validation of high-performance liquid chromatography-boron-doped diamond detection for assessing hepatic glutathione redox status. Anal Biochem 407(2):151–159PubMedCrossRefGoogle Scholar
  21. 21.
    Jones DP, Liang Y (2009) Measuring the poise of thiol/disulfide couples in vivo. Free Radic Biol Med 47(10):1329–1338PubMedCrossRefGoogle Scholar
  22. 22.
    Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30(11):1191–1212PubMedCrossRefGoogle Scholar
  23. 23.
    Buettner GR, Jurkiewicz BA (1993) Ascorbate free radical as a marker of oxidative stress: an EPR study. Free Radic Biol Med 14(1):49–55PubMedCrossRefGoogle Scholar
  24. 24.
    Buettner GR, Wagner BA (2011) Rodgers VG. An approach to understand the role of reactive species in defining the cellular redox environment, Cell Biochem Biophys Quant Redox BiolGoogle Scholar
  25. 25.
    Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K et al (2008) Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 19(11):1969–1974PubMedCrossRefGoogle Scholar
  26. 26.
    Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ et al (2012) Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE 7(1):e29794PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • J. L. Welsh
    • 1
  • B. A. Wagner
    • 2
  • T. J. van’t Erve
    • 2
  • P. S. Zehr
    • 3
  • D. J. Berg
    • 3
    • 4
  • T. R. Halfdanarson
    • 3
    • 4
  • N. S. Yee
    • 5
  • K. L. Bodeker
    • 2
  • J. Du
    • 2
  • L. J. RobertsII
    • 6
  • J. Drisko
    • 7
  • M. Levine
    • 8
  • G. R. Buettner
    • 2
    • 3
  • J. J. Cullen
    • 1
    • 2
    • 3
    • 9
    Email author
  1. 1.Department of Surgery, 1528 JCP—UIHCThe University of Iowa Carver College of MedicineIowa CityUSA
  2. 2.Department of Radiation OncologyThe University of Iowa Carver College of MedicineIowa CityUSA
  3. 3.The Holden Comprehensive Cancer CenterThe University of IowaIowa CityUSA
  4. 4.Department of Internal MedicineThe University of Iowa Carver College of MedicineIowa CityUSA
  5. 5.Penn State Hershey Cancer InstituteHerseyUSA
  6. 6.Vanderbilt-Ingram Cancer CenterVanderbilt UniversityNashvilleUSA
  7. 7.Integrative MedicineUniversity of Kansas Medical CenterKansas CityUSA
  8. 8.Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institutes of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  9. 9.The Veterans’ Affairs Medical CenterIowa CityUSA

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