Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 3, pp 703–707 | Cite as

The small-molecule TNF-α inhibitor, UTL-5g, delays deaths and increases survival rates for mice treated with high doses of cisplatin

  • Jiajiu Shaw
  • Joseph Media
  • Ben Chen
  • Fredrick Valeriote
Short Communication



UTL-5g is a novel small-molecule chemoprotector that lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by cisplatin through TNF-α inhibition among other factors. The objective of this study was to investigate whether UTL-5g can reduce the overall acute toxicity of cisplatin and increase cisplatin tolerability in mice.

Materials and methods

BDF1 female mice were treated individually with UTL-5g (suspended in Ora-Plus) by oral gavage at 60 mg/kg, 30 min before i.p. injection of cisplatin at 10, 15, and 20 mg/kg, respectively, on Day 0. Starting from Day 1, individual mice were again treated daily by the same dose of UTL-5g for 4 consecutive days. Survivals and body weights were monitored.


UTL-5g treatment increased the survival rate and delayed the time to death for mice treated with 150 % of the maximum tolerated dose (MTD) of cisplatin (15 mg/kg). Likewise, at 200 % of the MTD of cisplatin (20 mg/kg), treatment of UTL-5g increased the survival rate and delayed the time to death. Treatment of UTL-5g did not have a significant effect on weight loss induced by cisplatin, indicating that body weight may not be a sensitive-enough measure for chemoprotection of UTL-5g against cisplatin.


In summary, UTL-5g delayed deaths and increased survival rates of mice treated by high doses of cisplatin, indicating that UTL-5g is capable of reducing the overall acute toxicity of cisplatin and increased cisplatin tolerability in mice; this is in line with the specific chemoprotective effects of UTL-5g previously reported. Further investigation of UTL-5g in combination with cisplatin is warranted.


UTL-5g Cisplatin Maximum tolerated dose Toxicity Animal death/survival Body weight 



This work was supported by NIH/NCI Grant 5R44CA141749-03.

Conflict of interest



  1. 1.
    Madias NE, Harrington JT (1978) Platinum nephrotoxicity. Am J Med 65(2):307–314PubMedCrossRefGoogle Scholar
  2. 2.
    Cavalli F, Tschopp L, Sonntag RW, Zimmermann A (1978) A case of liver toxicity following cis-dichlorodiammineplatinum(II) treatment. Cancer Treat Rep 62(12):2125–2126PubMedGoogle Scholar
  3. 3.
    Cersosimo RJ (1993) Hepatotoxicity associated with cisplatin chemotherapy. Ann Pharmacother 27(4):438–441PubMedGoogle Scholar
  4. 4.
    Pollera CF, Ameglio F, Nardi M, Vitelli G, Marolla P (1987) Cisplatin-induced hepatic toxicity. J Clin Oncol 5(2):318–319PubMedGoogle Scholar
  5. 5.
    Subbiah U, Raghunathan M (2008) Chemoprotective action of resveratrol and genistein from apoptosis induced in human peripheral blood lymphocytes. J Biomol Struct Dyn 25(4):425–434PubMedCrossRefGoogle Scholar
  6. 6.
    Li R, Bianchet MA, Talalay P, Amzel LM (1995) The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. Proc Natl Acad Sci USA 92(19):8846–8850PubMedCrossRefGoogle Scholar
  7. 7.
    Psotova J, Chlopcikova S, Miketova P, Hrbac J, Simanek V (2004) Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytother Res 18(7):516–521. doi: 10.1002/ptr.1462 PubMedCrossRefGoogle Scholar
  8. 8.
    Markman M (1998) Amifostine in reducing cisplatin toxicity. Semin Oncol 25(5):522–524PubMedGoogle Scholar
  9. 9.
    Phillips KA, Tannock IF (1998) Design and interpretation of clinical trials that evaluate agents that may offer protection from the toxic effects of cancer chemotherapy. J Clin Oncol 16(9):3179–3190PubMedGoogle Scholar
  10. 10.
    Korst AE, Gall HE, Vermorken JB, van der Vijgh WJ (1996) Pharmacokinetics of amifostine and its metabolites in the plasma and ascites of a cancer patient. Cancer Chemother Pharmacol 39(1–2):162–166PubMedCrossRefGoogle Scholar
  11. 11.
    Culy CR, Spencer CM (2001) Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs 61(5):641–684PubMedCrossRefGoogle Scholar
  12. 12.
    Volckova E, Dudones LP, Bose RN (2002) HPLC determination of binding of cisplatin to DNA in the presence of biological thiols: implications of dominant platinum-thiol binding to its anticancer action. Pharm Res 19(2):124–131. doi: 10.1023/A:1014268729658 PubMedCrossRefGoogle Scholar
  13. 13.
    Sadowitz PD, Hubbard BA, Dabrowiak JC, Goodisman J, Tacka KA, Aktas MK, Cunningham MJ, Dubowy RL, Souid AK (2002) Kinetics of cisplatin binding to cellular DNA and modulations by thiol-blocking agents and thiol drugs. Drug Metab Dispos 30(2):183–190PubMedCrossRefGoogle Scholar
  14. 14.
    Shaw J, Chen B, Huang W-H, Lee A-R, Media J, Valeriote F (2011) The small-molecule TNF-A modulator, UTL-5g, reduces side effects induced by cisplatin and enhances the therapeutic effect of cisplatin in vivo. J Exp Ther Oncol 9(2):129–137PubMedGoogle Scholar
  15. 15.
    Leite EA, Lana AM, Junior AD, Coelho LG, De Oliveira MC (2012) Acute toxicity study of cisplatin loaded long-circulating and pH-sensitive liposomes administered in mice. J Biomed Nanotechnol 8(2):229–239PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jiajiu Shaw
    • 1
  • Joseph Media
    • 2
  • Ben Chen
    • 1
  • Fredrick Valeriote
    • 2
  1. 1.21st Century Therapeutic, Inc.FerndaleUSA
  2. 2.Henry Ford Health SystemDetroitUSA

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