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

Summary

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.

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References

  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

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