Investigational New Drugs

, Volume 23, Issue 3, pp 235–239 | Cite as

Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy

  • Dean Lim
  • Robert J. MorganJr.
  • Steven Akman
  • Kim Margolin
  • Brian I. Carr
  • Lucille Leong
  • Oluwole Odujinrin
  • James H. Doroshow


Based on the activity of menadione (M) in the human tumor stem cell assay, we conducted a phase I trial of M in patients with advanced cancer. Forty patients (19 men, 21 women) were treated with 90 courses of M; 82 treatment courses are evaluable for toxicity. The median patient age, Karnofsky performance status, and number of prior chemotherapy regimens were 61 years (range 32–74 years), 80% (range 50–100%), and two, respectively. M was given by a short (1–5 h) intravenous infusion every 3 weeks, starting at 40 mg/m2 and escalating by modified Fibonacci scheme to 1360 mg/m2. Toxicity was graded according to the Southwest Oncology Group toxicity scale with defined hypersensitivity reaction (HSR) scales. No grade ≧2 hematologic toxicity was observed. Non-hematologic toxicity consisted of a HSR syndrome of paresthesiae of the extremities, facial flushing, burning of the eyes and mucous membranes, chest pain and dyspnea. HSR was defined as Grade I toxicity by the presence of facial numbness, flushing, and/or a tingling sensation or burning of the eyes and mucous membranes. Grade II toxicity was defined as the presence of the same above symptoms plus chest tightness, paresthesiae of extremities and/or dyspnea and chest pain. These toxicities were grade 1 in 3 of 4 patients at a dose of 840 mg/m2. At 1360 mg/m2, 2 of 13 patients suffered grade 1 HSR and 7 of 13 grade 2 HSR No objective partial or complete responses were observed. Plasma menadione concentrations peaked at 1.9–7.4 μ M during the infusion in 3 patients receiving 1360 mg/m2. Further phase 1 and 2 combination trials using longer infusion durations have resulted from this trial.

Key words

Phase I solid tumor pharmacokinetics menadione menadiol 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Thor H, Smith MT, Hartszell P, Bellomo G, Jewell SA, Orrenius S: The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the implications of oxidative stress in intact cells. J Biol Chem 257: 12419–12425, 1982PubMedGoogle Scholar
  2. 2.
    Lind C, Hochstein P, Ernster L: DT-diaphorase as a quinone reductase: A cellular control device against semiquinone and superoxide radical formation. Archives Biochem & Biophy 216: 178–185, 1982Google Scholar
  3. 3.
    Akman SA, Doroshow JH, Dietrich MF, Chlebowski RT, Block JS: Synergistic cytotoxicity between menadione and dicumarol vs. murine leukemia L1210. J Pharm Exper Therapeut 240: 486–491, 1987Google Scholar
  4. 4.
    Chlebowski RT, Dietrich M, Akman S, Block JB: Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation. Cancer Treatment Reports 69: 527–532, 1985PubMedGoogle Scholar
  5. 5.
    Prasad KN, Edwards-Prasad J, Sakamoto A: Vitamin K3 (menadione) inhibits the growth of mammalian tumor cells in culture. Life Sciences 29: 1387–1392, 1981CrossRefPubMedGoogle Scholar
  6. 6.
    Akman SA, Dietrich, M, Chlebowski, RT, Limberg P, Block JB: Modulation of cytotoxicity of menadione sodium bisulfite versus leukemia L1210 by the acid-soluble thiol pool. Cancer Res 45: 5257–5262, 1985PubMedGoogle Scholar
  7. 7.
    Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 47: 207–214, 1981PubMedGoogle Scholar
  8. 8.
    Yang WH, Purchase EC, Rivingston RN: Positive skin tests and Prausnitz-Kustner reactions in metabisulfite-sensitive subjects. J Allergy Clin Immuno 79: 15, 1987Google Scholar
  9. 9.
    Riggs BS, Harcherlroad FP Jr, Poole C: Allergic reaction to sulfiting agents. Annals Emergency Medicine. 15: 77–79, 1986Google Scholar
  10. 10.
    Sprenger JD, Altman LC, Marshall SG, Pierson WE, Koenig JQ: Studies of neutrophil chemotactic factor of anaphylaxis in metabisulfite sensitivity. Annals Allergy 62: 117–121, 1989Google Scholar
  11. 11.
    Margolin KA, Akman SA, Leong LA, Morgan RJ, Somlo G, Raschko JW, Ahn C, Doroshow JH: Phase I study of mitomycin C and menadione in advanced solid tumors. Cancer Chemother Pharmacol 36: 293–298, 1995PubMedGoogle Scholar
  12. 12.
    Su YZ, Duarte TE, Dill PE, Weisenthal LM: Selective enhancement by Menadiol of in vitro drug activity in human lymphatic neoplasms. Cancer Treat Rep 71: 619, 1987PubMedGoogle Scholar
  13. 13.
    Durse L, Rajagopalan S, Eliot HM, Covey JM, Sinha BK: DNA interstrand crosslink and free radical formation in a human multidrug-resistant cell line from mitomycin C and its analogues. Cancer Res 50: 648, 1990PubMedGoogle Scholar
  14. 14.
    Keizer H, De Leeuw SJ, Van Rijn J, Pinedo HM, Joenje H: Effect of artificial electron acceptors on the cytotoxicity of mitomycin C and doxorubicin in human lung tumor cells. Eur J Cancer Clin Oncol 25: 1113, 1989CrossRefPubMedGoogle Scholar
  15. 15.
    Nishikawa Y, Carr B, Wang M, Kar S, Finn F, Dowd P, Zheng Z, Kerns J, Naganathan S: Growth Inhibition of hepatoma cells induced by vitamin K and its analogs. J Biol Chem 270: 28304–28310, 1995CrossRefPubMedGoogle Scholar
  16. 16.
    Tetef M, Margolin K, Ahn C, Akman S, Chow W, Coluzzi P, Leong L, Morgan Jr RJ, Raschko J, Shibata S, Somlo G, Doroshow JH: Mitomycin C and menadione for the treatment of advanced gastrointestinal cancer: A phase II trial. J Cancer Res Clin Oncol 121: 103–106, 1995CrossRefPubMedGoogle Scholar
  17. 17.
    Tetef M, Margolin K, Ahn C, Akman S, Chow W, Leong L, Morgan RJ Jr, Raschko J, Somlo G, Doroshow JH: Mitomycin C and menadione for the treatment of lung cancer: A phase II trial. Invest New Drugs 13: 157–162, 1995CrossRefPubMedGoogle Scholar
  18. 18.
    Siderova YA, Grishanova AY: Dose- and time-dependent effects of menadione on enzymes of xenobiotic metabolism in rat liver. Bull Exp Biol Med 137: 231–234, 2004CrossRefPubMedGoogle Scholar
  19. 19.
    Taper HS, Jamison JM, Gilloteaux J, Summers JL, Calderon PB: Inhibition of the development of metastases by dietary vitamin C combination. Life Sci 75: 955–967, 2004CrossRefPubMedGoogle Scholar
  20. 20.
    von Gruenigen VE, Jamison JM, Gilloteaux J, Lorimer HE, Summers M, Pollard RR, Gwin CA, Summers JL: The in vitro antitumor activity of vitamins C and K3 against ovarian carcinoma. Anticancer Res 23: 3279–3287, 2003PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Dean Lim
    • 1
    • 5
  • Robert J. MorganJr.
    • 1
  • Steven Akman
    • 2
  • Kim Margolin
    • 1
  • Brian I. Carr
    • 3
  • Lucille Leong
    • 1
  • Oluwole Odujinrin
    • 4
  • James H. Doroshow
    • 1
  1. 1.Department of Medical Oncology and Therapeutics ResearchCity of Hope National Medical CenterDuarteUSA
  2. 2.Division of Hematology/OncologyWake Forest University, Baptist Medical CenterWinston Salem
  3. 3.University of Pittsburgh, Physician FacultyPittsburgh
  4. 4.Cell Therapeutics, Inc.Seattle
  5. 5.Department of Medical Oncology & Therapeutics ResearchDuarteUSA

Personalised recommendations