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. 1980 Jan;77(1):467–471. doi: 10.1073/pnas.77.1.467

DNA crosslinking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas.

L C Erickson, M O Bradley, J M Ducore, R A Ewig, K W Kohn
PMCID: PMC348292  PMID: 6928639

Abstract

Normal (IMR-90) and simian virus 40-transformed (VA-13) human embryo cells were treated with antitumor nitrosoureas, and the effects on cell viability and cell DNA were compared. All six nitrosoureas tested were more toxic to VA-13 cells than to IMR-90 cells as measured by decrease in cell proliferation or in colony formation. The nitrosoureas capable of generating alkylisocyanates produced a smaller difference between the cell types than did derivatives lacking this capacity. DNA damage was measured by alkaline elution in cells treated with four chloroethylnitrosoureas. Whereas VA-13 cells exhibited dose-dependent interstrand crosslinking, little or none was detected in IMR-90 cells. The IMR-90 cells, however, exhibited at least as much DNA-protein crosslinking as did VA-13 cells. The results can be interpreted in terms of a possible difference in DNA repair between the cell lines.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abelson H. T., Karlan D., Penman S. A comparison of the effects of alkylating agents 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and nitrogen mustard on nuclear RNA synthesis and processing. Biochim Biophys Acta. 1974 May 31;349(3):389–401. doi: 10.1016/0005-2787(74)90125-7. [DOI] [PubMed] [Google Scholar]
  2. Baril B. B., Baril E. F., Laszlo J., Wheeler G. P. Inhibition of rat liver DNA polymerase by nitrosoureas and isocyanates. Cancer Res. 1975 Jan;35(1):1–5. [PubMed] [Google Scholar]
  3. Bradley M. O., Kohn K. W., Sharkey N. A., Ewig R. A. Differential cytotoxicity between transformed and normal human cells with combinations of aminonucleoside and hydroxyurea. Cancer Res. 1977 Jul;37(7 Pt 1):2126–2131. [PubMed] [Google Scholar]
  4. Carter S. K., Wasserman T. H. The nitrosoureas--thoughts for the future. Cancer Treat Rep. 1976 Jun;60(6):807–811. [PubMed] [Google Scholar]
  5. Chuang R. Y., Laszlo J., Keller P. Effects of nitrosoureas on human DNA polymerase activities from acute and chronic granulocytic leukemia cells. Biochim Biophys Acta. 1976 Apr 2;425(4):463–468. doi: 10.1016/0005-2787(76)90010-1. [DOI] [PubMed] [Google Scholar]
  6. Colvin M., Brundrett R. B., Cowens W., Jardine I., Ludlum D. B. A chemical basis for the antitumor activity of chloroethylnitrosoureas. Biochem Pharmacol. 1976 Mar 15;25(6):695–699. doi: 10.1016/0006-2952(76)90246-x. [DOI] [PubMed] [Google Scholar]
  7. Erickson L. C., Bradley M. O., Kohn K. W. Differential inhibition of the rejoining of X-ray-induced DNA strand breaks in normal and transformed human fibroblasts treated with 1,3-bis(2-chloroethyl)-1-nitrosourea in vitro. Cancer Res. 1978 Mar;38(3):672–677. [PubMed] [Google Scholar]
  8. Erickson L. C., Bradley M. O., Kohn K. W. Measurements of DNA damage in Chinese hamster cells treated with equitoxic and equimutagenic doses of nitrosoureas. Cancer Res. 1978 Oct;38(10):3379–3384. [PubMed] [Google Scholar]
  9. Erickson L. C., Bradley M. O., Kohn K. W. Strand breaks in DNA from normal and transformed human cells treated with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1977 Oct;37(10):3744–3750. [PubMed] [Google Scholar]
  10. Erickson L. C., Osieka R., Kohn K. W. Differential repair of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea-induced DNA damage in two human colon tumor cell lines. Cancer Res. 1978 Mar;38(3):802–808. [PubMed] [Google Scholar]
  11. Ewig R. A., Kohn K. W. DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard, 1,3-bis(2-chloroethyl)-1-nitrosourea, and other nitrosoureas. Cancer Res. 1977 Jul;37(7 Pt 1):2114–2122. [PubMed] [Google Scholar]
  12. Ewig R. A., Kohn K. W. DNA-protein cross-linking and DNA interstrand cross-linking by haloethylnitrosoureas in L1210 cells. Cancer Res. 1978 Oct;38(10):3197–3203. [PubMed] [Google Scholar]
  13. Fornace A. J., Jr, Kohn K. W., Kann H. E., Jr Inhibition of the ligase step of excision repair by 2-chloroethyl isocyanate, a decomposition product of 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 1978 Apr;38(4):1064–1069. [PubMed] [Google Scholar]
  14. GIRARDI A. J., JENSEN F. C., KOPROWSKI H. SV40-INDUCED TRANFORMATION OF HUMAN DIPLOID CELLS: CRISIS AND RECOVERY. J Cell Physiol. 1965 Feb;65:69–83. doi: 10.1002/jcp.1030650110. [DOI] [PubMed] [Google Scholar]
  15. Kann H. E., Jr Comparison of biochemical and biological effects of four nitrosoureas with differing carbamoylating activities. Cancer Res. 1978 Aug;38(8):2363–2366. [PubMed] [Google Scholar]
  16. Kann H. E., Jr, Kohn K. W., Lyles J. M. Inhibition of DNA repair by the 1,3-bis(2-chloroethyl)-1-nitrosourea breakdown product, 2-chloroethyl isocyanate. Cancer Res. 1974 Feb;34(2):398–402. [PubMed] [Google Scholar]
  17. Kann H. E., Jr, Kohn K. W., Widerlite L., Gullion D. Effects of 1,3-bis(2-chloroethyl)-1-nitrosourea and related compounds on nuclear RNA metabolism. Cancer Res. 1974 Aug;34(8):1982–1988. [PubMed] [Google Scholar]
  18. Kohn K. W., Erickson L. C., Ewig R. A., Friedman C. A. Fractionation of DNA from mammalian cells by alkaline elution. Biochemistry. 1976 Oct 19;15(21):4629–4637. doi: 10.1021/bi00666a013. [DOI] [PubMed] [Google Scholar]
  19. Kohn K. W., Ewig R. A. DNA-protein crosslinking by trans-platinum(II)diamminedichloride in mammalian cells, a new method of analysis. Biochim Biophys Acta. 1979 Mar 28;562(1):32–40. doi: 10.1016/0005-2787(79)90123-0. [DOI] [PubMed] [Google Scholar]
  20. Kohn K. W. Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. Cancer Res. 1977 May;37(5):1450–1454. [PubMed] [Google Scholar]
  21. Montgomery J. A. Chemistry and structure-activity studies of the nitrosoureas. Cancer Treat Rep. 1976 Jun;60(6):651–664. [PubMed] [Google Scholar]
  22. Nichols W. W., Murphy D. G., Cristofalo V. J., Toji L. H., Greene A. E., Dwight S. A. Characterization of a new human diploid cell strain, IMR-90. Science. 1977 Apr 1;196(4285):60–63. doi: 10.1126/science.841339. [DOI] [PubMed] [Google Scholar]
  23. Osieka R., Houchens D. P., Goldin A., Johnson R. K. Chemotherapy of human colon cancer xenografts in athymic nude mice. Cancer. 1977 Nov;40(5 Suppl):2640–2650. doi: 10.1002/1097-0142(197711)40:5+<2640::aid-cncr2820400938>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  24. Panasci L. C., Green D., Nagourney R., Fox P., Schein P. S. A structure-activity analysis of chemical and biological parameters of chloroethylnitrosoureas in mice. Cancer Res. 1977 Aug;37(8 Pt 1):2615–2618. [PubMed] [Google Scholar]
  25. Reed D. J., May H. E., Boose R. B., Gregory K. M., Beilstein M. A. 2-chloroethanol formation as evidence for a 2-chloroethyl alkylating intermediate during chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea. Cancer Res. 1975 Mar;35(3):568–576. [PubMed] [Google Scholar]
  26. Schabel F. M., Jr Nitrosoureas: a review of experimental antitumor activity. Cancer Treat Rep. 1976 Jun;60(6):665–698. [PubMed] [Google Scholar]
  27. Thomas C. B., Osieka R., Kohn K. W. DNA cross-linking by in vivo treatment with 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea of sensitive and resistant human colon carcinoma xenograms in nude mice. Cancer Res. 1978 Aug;38(8):2448–2454. [PubMed] [Google Scholar]
  28. Wheeler K. T., Deen D. F., Wilson C. B., Williams M. E., Sheppard S. BCNU-modification of the in vitro radiation response in 9L brain tumor cells of rats. Int J Radiat Oncol Biol Phys. 1977 Jan-Feb;2(1-2):79–88. doi: 10.1016/0360-3016(77)90011-6. [DOI] [PubMed] [Google Scholar]

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