This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kosano, H. Articles by Nagata, N. Search for Related Content PubMed PubMed Citation Articles by Kosano, H. Articles by Nagata, N.

Growth-inhibitory Action of an Estrogen-Chlorambucil Conjugate (KM2210) in Human Breast Cancer Cell Line MCF-7: Its Relation to Reduction of Estrogen Receptor and Transforming Growth Factor- Secretion

Third Department of Internal Medicine, National Defense Medical College, 3-2, Namiki, Tokorozawa-ski, Saitama 359 [H. K., N. N.]; Department of Surgery, School of Medicine, Keio University, Tokyo 160 [T. K., O. A.]; First Department of Internal Medicine, Osaka Medical College, Osaka 569 [N. O.]; Mitsubishi Yuka Bio-Clinical Laboratories, Inc., Tokyo 174 [S. Y.]; and Department of Hygiene and Public Health, Nippon Medical School, Tokyo 113, [H. I.] Japan

We investigated the effects of a benzoate of an estradiol-chlorambucil conjugate (KM2210) and chlorambucil on growth, estrogen receptor, and secretion of transforming growth factor (TGF)- in the hormone-dependent human breast cancer cell line MCF-7. In the presence of 10^–10–10^–6 M KM2210, the estrogen-induced growth of MCF-7 was completely inhibited. Inhibited growth of MCF-7 treated with 10^–8 or 10^–6 M KM2210 for 4 days was not rescued by removal of the drug and the addition of estradiol. By treatment of MCF-7 with KM2210 for 4 days, estrogen receptor-binding sites were decreased at 10^–8 M and were not detected at 10^–6 M but were unaltered by 10^–8 M chlorambucil. Moreover, estrogen receptor immunoreactivity and the level of estrogen receptor mRNA were decreased through treatment with 10^–6 M KM2210 for 4 days. These suppressions occurred prior to the onset of inhibitory action on MCF-7 growth. Secretion of TGF- from MCF-7 was decreased by 4 days of treatment with 10^–8 and 10^–6 M KM2210 but not with chlorambucil. The addition of exogenous TGF- generally restored the growth of MCF-7 treated with 10^–8 M KM2210.

We concluded that KM2210 has irreversible or at least long-standing inhibitory effect on estrogen-dependent growth of MCF-7. It is conceivable that the decrease of estrogen receptor renders the cell unable to respond to estrogen with increased TGF- secretion and succeeding cell growth.

¹ To whom requests for reprints should be addressed.

Received 5/28/91. Accepted 12/17/91.