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Nitrosourea and nitrosocarbamate derivatives of the antiestrogen tamoxifen as potential estrogen receptor-mediated cytotoxic agents in human breast cancer cells

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Summary

We have prepared two analogs of the antiestrogen tamoxifen that incorporate known DNA-crosslinking functions, a chloroethyl nitrosourea and a nitrosocarbamate moiety, and we have tested their bioactivities in cultures of human breast cancer cells. Both compounds bind to the estrogen receptor from MCF-7 cells, with relative binding affinities of 0.18% for the nitrosocarbamate derivative and 0.35% for the nitrosourea derivative, while the affinity of tamoxifen is 1.8%, and that of estradiol is set at 100%. The tamoxifen-nitrosocarbamate compound demonstrated a dose-related cytotoxicity by the colony formation and cell proliferation assays that was not blocked by estradiol in either estrogen receptor-positive MCF-7 cells or estrogen receptor-negative MDA-MB-231 cells, and thus, was not studied further. Tamoxifen-nitrosourea (TAM-NU) showed dose-related cytotoxicity in MCF-7 cells that was blocked by estradiol, whereas its activity in MDA-MB-231 cells was unaffected by estradiol. N-2-(4-t-butylphenoxy)ethyl-N′-chloroethyl-N′-nitrosourea (BPE-NU), a control compound which contains the nitrosourea moiety but does not bind to the estrogen receptor, had no effect on cell proliferation or colony formation in MCF-7 cells, but was very inhibitory in the receptor-negative MDA-MB-231 cells. In contrast, TAM-NU was more active in the receptor-positive MCF-7 cells than in the MDA-MB-231 line. Thus, because TAM-NU appears to be active selectively against the receptor-positive cell line, and because this activity is suppressible by estradiol, its cytotoxic effect seems to be mediated via the estrogen receptor. However, since TAM-NU is active only in prolonged treatment protocols, it appears likely that its cytotoxic activity results from the hormone antagonistic effect of the hydrolysis product of TAM-NU (bis-desmethyltamoxifen), rather than from a direct receptor-mediated, DNA-directed cytotoxic action of TAM-NU itself. This study stresses the need for the use of appropriate control compounds and cell systems in order to assess whether the toxic activity displayed by hormone-cytotoxic conjugates is mediated by receptor interactions and whether it operates through the intended toxic mechanism.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, 524 Burrill Hall, University of Illinois, 407 South Goodwin Avenue, 61801, Urbana, Illinois, USA

    Lisa L. Wei & Benita S. Katzenellenbogen

  2. Department of Chemistry, University of Illinois, 61801, Urbana, Illinois, USA

    David W. Robertson, David M. Simpson & John A. Katzenellenbogen

  3. University of Illinois College of Medicine, 61801, Urbana, Illinois, USA

    Lisa L. Wei, Benita S. Katzenellenbogen, David W. Robertson, David M. Simpson & John A. Katzenellenbogen

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  1. Lisa L. Wei
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  2. Benita S. Katzenellenbogen
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  3. David W. Robertson
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  4. David M. Simpson
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  5. John A. Katzenellenbogen
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Wei, L.L., Katzenellenbogen, B.S., Robertson, D.W. et al. Nitrosourea and nitrosocarbamate derivatives of the antiestrogen tamoxifen as potential estrogen receptor-mediated cytotoxic agents in human breast cancer cells. Breast Cancer Res Tr 7, 77–90 (1986). https://doi.org/10.1007/BF01806792

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