Tris (1-aziridinyl) phosphine oxide (TEPA) and tris (1-aziridinyl) phosphine sulfide (thio-TEPA) induced base pair mutations in the Ames mutagenic assay. Thio-TEPA required metabolic activation while TEPA was active without metabolic activation. Growth of a human vaginal carcinoma (A431), a human breast carcinoma (MDAMB-231), and a human cervical carcinoma (HeLa) were inhibited in soft agar in vitro at concentrations which induced mutagenesis in the Ames Assay. A fourth line, JEG choriocarcinoma, was sensitive to the antigrowth properties of both drugs at concentrations below that which induced mutagenesis. These data suggest that as more antineoplastic agents become available, and as mean survival times increase, knowledge of the relative in vitro sensitivity of a patient's neoplasm to a specific antineoplastic drug (i.e., dose required for growth inhibition) as a function of its mutagenic index might be useful for prediction of clinical remission, as well as the risk of secondary neoplasm induction.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- TEPA:
-
tris (1-aziridinyl) phosphine oxide
- thio-TEPA:
-
tris (1-aziridinyl) phosphine sulfide
- MEM:
-
Minimal Essential Media
References
ADLER, I.D., RAMARAO, G. AND EPSTEIN, S.S. (1971). In vivo cytogenetic effects of trimethyl phosphate and of TEPA on bone marrow cells of male rats. Mutat. Res. 13: 263–273.
ALLAN, W.S.A. (1970). Acute myeloid leukemia after treatment with cytostatic agents. Lancet ii: 775.
ALLRED, A.L. (1961). Electronegativity values from thermochemical data. J. Inorg. Nuclear Chem. 17: 215–221.
ALLRED, A.L. AND ROCHOW, E.G. (1958). A scale of electronegativity based on electrostatic force. J. Inorg. Nuclear Chem. 5: 264–268.
AMES, B.N., McCANN, J. AND YAMASAKI, E. (1975). Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res. 31: 347–364.
CALABRESI, P. AND PARKS, R.E. JR. (1980). Antiproliferative agents and drugs. In Pharmacological Basis of Therapeutics (A.E. Gilman et al., eds.) 1256–1314. Macmillan, NY.
COHEN, S.D. AAND MURPHY, S.D. (1972). Inactivation of malaoxon by mouse liver. Proc. Soc. Exp. Biol. Med. 139: 1385–1389.
COHEN, S.D. AND MURPHY, S.D. (1974). A simplified bioassay for organophosphate detoxification and interactions. Toxicol. Appl. Pharmacol. 27: 537–550.
EPSTEIN, S.S., ARNOLD, E., STEINBERG, K., MACKINTOSH, D., SHAFNER, H. AND BISHOP, Y. (1970). Mutagenic and antifertility effects of TEPA and METEPA in mice. Toxicol. Appl. Pharmacol. 17: 23–40.
EPSTEIN, S. S. AND SHAFNER, H. (1968). Chemical Mutagens in the Environment. Nature 219: 385–386.
FINTER, N.B. (1969). Dye uptake methods for measuring viral cytopathogenicity and their application to interferon assays. J. Gen. Virol. 5: 419–427.
GARFIELD, D.H. (1970). Acute erythromegakaryocytic leukemia after treatment with cyto static agents. Lancet ii: 1037.
GREENSPAN, E.M. AND TUNG, B.G. (1974). Acute myeloblastic leukemia after cure of ovarian cancer. JAMA 230: 418–420.
HAMBURGER, A. AND SALMON, S.E. (1977). Primary Bioassay of Human Myeloma Stem Cells. J. Clin. Invest. 60: 846–854.
JACKSON, J., FOX, B.W. AND CRAIG, A.W. (1959). The effect of alkylating agents on male fertility. Brit. J. Pharmacol. 14: 149–157.
KASLOW, R.A., WISCH, N. AND GLASS, J.L. (1972). Acute leukemia following cytostatic therapy. JAMA 219: 75–76.
LAUWERYS, R.R. AND MURPHY, S.D. (1969). Comparison of assay methods for studying o-odiethyl, o-p-nitrophenyl phosphate (paraoxon) detoxification in vitro. Biochem. Pharmacol. 18: 789–800.
MACHEMER, L. AND HESS, R. (1971). Comparative dominant lethal studies with phenylbutazone, thio-TEPA and MMS in the mouse. Experientia 27: 1050–1057.
MARON, D.M. AND AMES, B. (1983). Revised methods for the Salmonella mutagenicity test. Mutat. Red. 113: 173–215.
McCANN, J., CHOI, E., YAMASAKI, E. AND AMES, B.N. (1975). Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. (U.S.A.) 72: 5135–5139.
NEAL, R.A. (1967). Studies on the Metabolism of Diethyl 4-Nitrophenyl Phosphorothionate (Parathion) in vitro. Biochem. J. 1032: 183.
NUZKDIN, N.I. AND NIZHNIK, G.V. (1968) Fertilization and embryonic development of rabbits after treatment of spermatozoa in vitro with chemical mutagens. Dokl. Biol. Sci. 181: 419–422.
PERLMAN, M. AND WALKER, R. (1973). Acute leukemia following cytotoxic chemotherapy. JAMA 224: 250.
PRITCHARD, H.O. AND SKINNER, H.A. (1955). The concept of electronegativity. Chem. Rev. 55: 745–786.
RUFFNER, B.W. (1974). Androgen role in erythroleukemia after treatment with alkylating agents. Ann. Int. Med. 81: 118–119.
SIKIC, B.I. AND TABER, R.L. (1981). Human tumor clonogenic assays. An overview. Cancer Chemother. Pharmacol. 6: 201–203.
SOLOMON, R.B. AND FIRAT, D. (1971). Acute leukemia following treatment with irradiation and alkylating agents. N.Y. State J. Med. 71: 2422–2425.
SRAM, R.J., BENES, Y. AND ZUDOVA, Z. (1970). Induction of dominant lethals in mice by TEPA and HEMPA. Folia Biol. (Praha) 16: 407–416.
SRAM, R.J., ZUDOVA, Z. AND BENES, Y. (1970). Induction of translocations in mice by TEPA. Folia Biol. (Praha) 16: 367–368.
SYPKENS-SMIT, G.C. AND MEYLER, L. (1970). Acute myeloid leukemia after treatment with cytostatic agents. Lancet, ii: 58–62.
TANIGAWA, N., KERN, D.H., HIKASA, Y. AND MORTON, D.L. (1982). Rapid assay for evaluating the chemosensitivity of human tumors in soft agar culture. Cancer Res. 42: 2159–2164.
ZETTERBERG, G. (1971). Bacteriophage development in lysogenic Escherichia coli and mutations in fungi induced with analogs of tris (1-aziridinyl)-phosphate oxide, TEPA. Hereditas 68: 245–254.
Author information
Authors and Affiliations
Additional information
This study was supported by PHS grant No. CA 30321 awarded by the National Cancer Institute (DHHS).
Rights and permissions
About this article
Cite this article
Breau, A.P., Field, L. & Mitchell, W.M. Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA. Cell Biol Toxicol 1, 21–30 (1984). https://doi.org/10.1007/BF00125562
Issue Date:
DOI: https://doi.org/10.1007/BF00125562