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Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase

  • Original Articles
  • Trimidox, Ribonucleotide Reductase, Antitumor Activity
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Abstract

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 μM, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 μM. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 μM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 μM for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 μM, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC50 values of 12 and 87 μM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82 in male mice and 112% in female mice). The antitumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.

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Abbreviations

Didox:

N,3,4-trihydroxybenzamide

MTT:

{3-[4,5-dimethyl-thiazo-2yl]}-2,5-diphenyl tetrazolium bromide

PBS:

phosphate-buffered saline

trimidox:

3,4,5-trihydroxybenzamidoxime HCl

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Authors and Affiliations

  1. Institute of Medical Chemistry, University of Vienna, Austria

    Thomas Szekeres & Monika Fritzer

  2. Molecules for Health Inc., 23227, Richmond, VA, USA

    Bart van't Riet & Howard L. Elford

  3. Laboratory for Experimental Oncology, Indiana University School of Medicine, 702 Barnhill Drive, 46202-5200, Indianapolis, IN, USA

    Kamran Gharehbaghi, Michael Woody, Arun Srivastava & Hiremagalur N. Jayaram

Authors
  1. Thomas Szekeres
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  2. Kamran Gharehbaghi
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  3. Monika Fritzer
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  4. Michael Woody
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  5. Arun Srivastava
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  6. Bart van't Riet
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  7. Hiremagalur N. Jayaram
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  8. Howard L. Elford
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Szekeres, T., Gharehbaghi, K., Fritzer, M. et al. Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase. Cancer Chemother. Pharmacol. 34, 63–66 (1994). https://doi.org/10.1007/BF00686113

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  • DOI: https://doi.org/10.1007/BF00686113

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