Cancer Chemotherapy and Pharmacology

, Volume 15, Issue 3, pp 185–191 | Cite as

On the search for new anticancer drugs 14: The plasma pharmacokinetics and tissue distribution of spin-labeled thio-TEPA (SL-O-TT)

  • Peter L. Gutierrez
  • Brian E. Cohen
  • George Sosnovsky
  • Thomas A. Davis
  • Merrill J Egorin
Original Articles Pharmacokinetics, thio-TEPA


We defined the plasma and tissue concentrations and pharmacokinetics of SL-O-TT, a spin-labeled analog of thio-TEPA, in 35–44-g male Swiss Wesbster mice that had received spin-labeled thio-TEPA at a dosage of 10 mg/kg. Concentrations of spin-labeled thio-TEPA in ethyl acetate extracts of tissue and plasma were determined by gas-liquid chromatography and electron spin resonance spectroscopy. Plasma concentrations of spinlabeled thio-TEPA declined in a biexponential fashion that was well described by the equation: Ç = 21.5e-0.276t + 2.30e-0.026t indicating a half-life alpha of 2.5 min and a half-life beta of 26.6 min. After 2h there was still spin-labeled thio-TEPA in plasma, but not in tissues. In tissues, no spin-labeled thio-TEPA was detected with gas-liquid chromatography 15 min after injection, but with electron-spin resonance label was found in lung and skeletal muscle. the main metabolite of spin-labeled thio-TEPA is spin-labeled TEPA, where oxidative desulfurization is invoked as the main metabolic mechanism. Reduction of the spin label to the hydroxylamine was also observed with time.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Craig AW, Fox BM, Jackson H (1959) Metabolic studies of 32P-labeled triethylenethiophosphoramide. biochem Pharmacol 3:42Google Scholar
  2. 2.
    Drew JE, Marshall VF (1968) The effects of topical thio-TEPA on the recurrence rate of superficial bladder cancers. J Urol 99:740Google Scholar
  3. 3.
    Egorin MJ, Akman SR, Gutierrez PL (1984) The plasma pharmacokinetics and tissue distribution of thio-TEPA in mice. Cancer Treat Rep 68:1265Google Scholar
  4. 4.
    Egorin M, Cohen B, Kohlhepp E, Gutierrez P (1985) Gas-liquid chromatographic analysis of thio-TEPA and TEPA in biological samples. J Chromatr (in press)Google Scholar
  5. 5.
    Emanuel NM, Konovalova NP, Djachkovskaya RF (1976) Toxicity, antitumor activity and pharmacokinetics of spinlabeled thio-TEPA analogs. Cancer Treat Rep 60:1605Google Scholar
  6. 6.
    Grochow L, Grossman S, Garrett S, Murray K, Trump D, Colvin M (1982) Pharmacokinetics of intraventricular thio-TEPA (TT) in patients with meningeal carcinomatosis. Proc Am Soc Clin Oncol 1:19Google Scholar
  7. 7.
    Gutierrez PL, Konieczny M, Sosnovsky G (1981) In the search for new antitumor drugs II. Antitumor activity, toxicity and electron spin resonance of spin-labeled Thio-TEPA derivatives. Z Naturforsch 36b:1612Google Scholar
  8. 8.
    Gutin PH, Levi JA, Wiernik PH, Walker MD (1977) Treatment of malignant meningeal disease with intrathecal Thio-TEPA: A phase II study. Cancer Treat Rep 61:885Google Scholar
  9. 9.
    Hart RD, Perloff M, Holland JF (1981) One-day VATH therapy for advanced breast cancer refractory to prior chemotherapy. Cancer 48:1522Google Scholar
  10. 10.
    Heath DF (1961) Organophosphorus poisons. Pergamon, New YorkGoogle Scholar
  11. 11.
    Hyde J (1963) Experimental techniques in EPR. In: Proceedings Seventh Annual EPR-NMR Workshop, Palo Alto Nov. 11–15, p 15Google Scholar
  12. 12.
    Jones HC, Swinney J (1961) Thio-TEPA in the treatment of tumors of the bladder. Lancet II:615Google Scholar
  13. 13.
    Konieczny M, Gutierrez PL, Sosnovsky G (1983a) In the search for new anticancer drugs. IV: Antitumor activity of seleno-TEPA. Z Naturforsch 38b:1138Google Scholar
  14. 14.
    Konieczny M, Gutierrez PL, Sosnovsky G (1983b) In the search for new anticancer drugs. V: Study of the binding of spin labeled thio-TEPA to cells. Z Naturforsch 38b:1142Google Scholar
  15. 15.
    Konovalova NP, Bogdanov GN, Miller VB, Neiman M, Rozantsev G, Emanuel NM (1964) Antitumor activity of stable free radicals. Dokl Akad Nauk SSSR 157:707Google Scholar
  16. 16.
    National Bladder Cancer Collaborative Group A (1977) The role of intravesical thio-TEPA in the management of superficial bladder cancer. Cancer Res 37:2916Google Scholar
  17. 17.
    Perloff M, Hart RD, Holland JF (1977) Vinblastine, Adriamycin, thio-TEPA, and Halotestin (VATH): Therapy for advanced breast cancer refractory to prior therapy. Cancer 39:1289Google Scholar
  18. 18.
    Sosnovsky G, Konieczny M (1977a) Improvements in the preparation of spin-labeled phosphorus compounds of potential cytotoxicity. Z Naturforsch 32b:87Google Scholar
  19. 19.
    Sosnovsky G, Konieczny M (1977b) Preparation of 4-phosphorylated 1,4-dihydroxy-2,3,6,6-tetramethylpiperidines by reduction of nitroxyls with L-ascorbic acid. Synthesis 9:619Google Scholar
  20. 20.
    Sykes M, Karnofsky D, Phillipps F, Burchenal J (1953) Clinical studies of triethylenephosphoramide and diethylenephosphoramide compounds with nitrogen mustard-like activity. Cancer 6:142Google Scholar
  21. 21.
    Trump DL, Grossman SA, Thompson G, Murray K, Wharam M (1982) Treatment of neoplastic meningitis with intraventricular thio-TEPA and methotrexate. Cancer Treat Rep 66: 1549Google Scholar
  22. 22.
    Veenema RJ, Dean AL Jr, Roberts M, Fingerhut B, Chowhury BK, Tarassoly H (1962) Bladder carcinoma treated by direct instillation of thio-TEPA. J Urol 88:60Google Scholar
  23. 23.
    Veenema RJ, Dean AL Jr, Uson AC, Roberts M, Longo F (1969) Thio-TEPA bladder instillations: Therapy and prophylaxis for superficial bladder tumors. J Urol 101:711Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • Peter L. Gutierrez
    • 1
  • Brian E. Cohen
    • 1
  • George Sosnovsky
    • 2
  • Thomas A. Davis
    • 1
  • Merrill J Egorin
    • 1
  1. 1.Division of Developmental TherapeuticsUniversity of Maryland Cancer CenterBaltimoreUSA
  2. 2.Department of ChemistryUniversity of Wisconsin at MilwaukeeMilwaukeeUSA

Personalised recommendations