Individual and combined effects of alpha-difluoromethylornithine and ovariectomy on the growth and polyamine milieu of experimental breast cancer in rats.

Despite considerable evidence suggesting a critical role of polyamines in the hormonal control of breast cancer growth in vitro, their role in in vivo tumor growth is not established. In these experiments, we evaluated the individual and combined effects of the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) and ovariectomy on the growth and cellular levels of ornithine decarboxylase (ODC) and polyamines of N-nitrosomethylurea-induced rat mammary tumors. Despite a similar suppressive effect on ODC activity, the two treatments had a different effect on polyamine levels. As expected, DFMO selectively suppressed putrescine, whereas spermidine and spermine levels were minimally or not affected at all. Since quantitatively putrescine contributes the least to overall polyamine pools, the DFMO effect on this latter parameter was modest. In contrast, ovariectomy, by suppressing the more abundant spermidine and spermine, produced a more profound suppression of total polyamine pools. This finding is in agreement with the notion that hormones not only control ODC activity, but also other enzymes involved in the synthesis of the distal polyamines. Ovariectomy was also more potent than DFMO administration in inhibiting N-nitrosomethylurea-induced mammary tumor growth. No major additive/synergistic effects were observed between DFMO and ovariectomy on tumor growth and cellular levels of ODC activity and polyamines. DFMO administration lowered the tumor level of progesterone receptors and appeared to potentiate the suppressive effect of ovariectomy. In contrast, neither treatment, alone or in combination, altered tumor levels of estrogen receptors. DFMO administration did not affect circulating levels of estradiol and prolactin or uterine and ovarian weights, thus suggesting that its effects were not indirectly mediated through alterations of the endocrine milieu of the host.

[1]  A. Pegg,et al.  Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. , 1988, Cancer research.

[2]  T. Thomas,et al.  Additive growth-inhibitory effects of DL-alpha-difluoromethylornithine and antiestrogens on MCF-7 breast cancer cell line. , 1987, Biochemical and biophysical research communications.

[3]  B. Katzenellenbogen,et al.  An evaluation of the involvement of polyamines in modulating MCF-7 human breast cancer cell proliferation and progesterone receptor levels by estrogen and antiestrogen. , 1987, Journal of steroid biochemistry.

[4]  L. Demers,et al.  Effects of progestins on growth of experimental breast cancer in culture: interaction with estradiol and prolactin and involvement of the polyamine pathway. , 1987, Cancer research.

[5]  J. Hammond,et al.  Polyamines and autocrine control of tumor growth by prolactin in experimental breast cancer in culture. , 1986, Endocrinology.

[6]  L. Demers,et al.  Polyamines and hormonal regulation of N-nitrosomethylurea-induced rat mammary tumor growth in vivo. , 1986, Cancer research.

[7]  L. Meeker,et al.  Effect of tamoxifen and D,L-2-difluoromethylornithine on the growth, ornithine decarboxylase activity and polyamine content of mammary carcinomas induced by 1-methyl-1-nitrosourea. , 1986, Carcinogenesis.

[8]  H. Rochefort,et al.  Autocrine stimulation by estradiol-regulated growth factors of rat hormone-responsive mammary cancer: interaction with the polyamine pathway. , 1986, Cancer research.

[9]  R. Shiu,et al.  Role of polyamines in estradiol-induced growth of human breast cancer cells. , 1985, Cancer research.

[10]  A. Manni,et al.  Polyamines as mediators of the effect of prolactin and growth hormone on the growth of N-nitroso-N-methylurea-induced rat mammary tumor cultured in vitro in soft agar. , 1985, Journal of the National Cancer Institute.

[11]  A. Manni,et al.  Polyamines as mediators of estrogen action on the growth of experimental breast cancer in rats. , 1984, Journal of the National Cancer Institute.

[12]  S. Shapiro,et al.  Two direct radioimmunoassays for 17 beta-estradiol evaluated for use in monitoring in vitro fertilization. , 1984, Clinical chemistry.

[13]  A. Manni,et al.  Reversal of the antiproliferative effect of the antiestrogen tamoxifen by polyamines in breast cancer cells. , 1984, Endocrinology.

[14]  A. Manni,et al.  Effect of tamoxifen and alpha-difluoromethylornithine on clones of nitrosomethylurea-induced rat mammary tumor cells grown in soft agar culture. , 1983, Cancer research.

[15]  A. Manni,et al.  Hormone Dependency in iV-Nitrosomethylurea-Induced Rat Mammary Tumors* , 1982 .

[16]  N. Seiler,et al.  High-performance liquid chromatographic procedure for the simultaneous determination of the natural polyamines and their monoacetyl derivatives. , 1980, Journal of chromatography.

[17]  J. Fozard,et al.  Ovarian function in the rat following irreversible inhibition of L-ornithine decarboxylase. , 1980, Life sciences.

[18]  J. Jänne,et al.  Polyamines in rapid growth and cancer. , 1978, Biochimica et biophysica acta.

[19]  B. Metcalf,et al.  Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogs , 1978 .

[20]  W. McGuire,et al.  A Role for Progesterone in Breast Cancer * , 1977, Annals of the New York Academy of Sciences.

[21]  M. DeLaGarza,et al.  Evaluation of estrogen receptor assays in human breast cancer tissue. , 1977 .

[22]  A. Pegg,et al.  Concentrations of putrescine and polyamines and their enzymic synthesis during androgen-induced prostatic growth. , 1970, The Biochemical journal.

[23]  D. Morris,et al.  Regulation of amino acid decarboxylation. , 1974, Annual Review of Biochemistry.