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Basic Sciences

Evidence for Enzymatic Activation and Oxygen Involvement in Cytotoxicity and Antitumor Activity of N,N′,N″-Triethylenethiophosphoramide

Beverly A. Teicher, David J. Waxman, Sylvia A. Holden, Yenyun Wang, Lynn Clarke, Enrique Alvarez Sotomayor, Steven M. Jones and Emil Frei III
Beverly A. Teicher
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David J. Waxman
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Sylvia A. Holden
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Yenyun Wang
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Lynn Clarke
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Enrique Alvarez Sotomayor
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Steven M. Jones
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Emil Frei III
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DOI:  Published September 1989
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Abstract

The cytotoxicity of N,N′,N″-triethylenethiophosphoramide (thiotepa) was studied in vitro in the MCF-7 human breast carcinoma cell line and in vivo using the EMT6 mouse mammary tumor model, under various conditions of oxygenation and in the presence and absence of Aroclor 1254-induced liver preparations. The cytotoxicity of thiotepa toward exponentially growing MCF-7 cells was markedly dependent on the presence of oxygen during the period of drug exposure, with 3 log greater cell kill at 500 µm thiotepa being observed when the cells were normally oxygenated compared with hypoxic cells. Incubation of thiotepa with an Aroclor 1254-induced rat liver S-9 homogenate, in the presence of a NADPH-regenerating system, resulted in an 8-fold increase in cytotoxicity towards the MCF-7 cells over a wide range of drug concentrations. Thiotepa was shown to be metabolized under these conditions in a NADPH- and O2-dependent reaction that was catalyzed by one or more microsomal cytochrome P-450 enzymes that were present in the S-9 fraction. The thiotepa metabolite triethylene phosphoramide, which hydrolyzes significantly faster than thiotepa, was significantly less cytotoxic toward the MCF-7 cells than was thiotepa itself, suggesting that it is unlikely to be the S-9 metabolite responsible for the observed increase in drug cytotoxicity. Moreover, triethylene phosphoramide cytotoxicity was only partially O2 dependent and was largely unaffected by incubation in the presence of the S-9 preparation, indicating a mechanism of action distinct from that of thiotepa. Tumor cell survival experiments with the EMT6 mouse mammary carcinoma system revealed that a 3.6-fold increase in thiotepa cytotoxicity was obtained by prior administration of the liver inducer Aroclor 1254 to the tumor-bearing animals, 5 days before drug treatment. Finally, the therapeutic effectiveness of thiotepa was significantly enhanced (3- to 5.8-fold increase in tumor growth delay) when an increase in oxygenation was achieved, by carbogen breathing, in animals given the perfluorochemical emulsion Fluosol-DA. These findings establish that the cytotoxic effects of thiotepa are oxygen dependent and may involve, at least in part, metabolic processes catalyzed by cytochrome P-450 enzymes.

Footnotes

  • ↵1 This work was supported by grants from Lederle Laboratories, Pearl River, NY (B. A. T.); by National Cancer Institute Grant 1PO1-CA-38493 (E. F.); and by American Cancer Society Grant BC-462 (D. J. W.).

  • ↵2 To whom requests for reprints should be addressed.

  • Received April 12, 1989.
  • Revision received June 9, 1989.
  • Accepted June 15, 1989.
  • ©1989 American Association for Cancer Research.
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September 1989
Volume 49, Issue 18
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Evidence for Enzymatic Activation and Oxygen Involvement in Cytotoxicity and Antitumor Activity of N,N′,N″-Triethylenethiophosphoramide
Beverly A. Teicher, David J. Waxman, Sylvia A. Holden, Yenyun Wang, Lynn Clarke, Enrique Alvarez Sotomayor, Steven M. Jones and Emil Frei III
Cancer Res September 15 1989 (49) (18) 4996-5001;

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Evidence for Enzymatic Activation and Oxygen Involvement in Cytotoxicity and Antitumor Activity of N,N′,N″-Triethylenethiophosphoramide
Beverly A. Teicher, David J. Waxman, Sylvia A. Holden, Yenyun Wang, Lynn Clarke, Enrique Alvarez Sotomayor, Steven M. Jones and Emil Frei III
Cancer Res September 15 1989 (49) (18) 4996-5001;
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