Tamoxifen-induced hypercalcemia in metastatic breast cancer.
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Biomedical subjects
Publications and source records attributed to T L Dao.
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The daily excretion of estrone, estradiol, and estriol was determined for 22 normal women and 35 women with primary breast cancer. The excretion of the hormones (measured in microgram/24 hr) in the breast cancer group was elevated and showed a statistical significance of P less than 0.001. The same wide difference between the 2 groups was also noted when excretion was expressed in terms of the body area of the individuals and when women of similar ages were compared.
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Carcinogen-induced hyperplastic alveolar nodules failed to form tumors after transplantation into isologous female rats; instead they developed ductal or ductal-alveolar outgrowths. Mammary glands from mid-pregnant female rats showed similar outgrowths following transplantation to the isologous hosts. In vitro and in vivo studies failed to demonstrate that subcarcinogenic doses of 7,12-dimethylbenz(a)anthracene can induce mammary tumorigenesis in the hyperplastic alveolar nodules. Our observations suggest that carcinogen-induced hyperplastic alveolar nodules are not 'preneoplastic' lesions in mammary carcinogenesis in the rat.
The chromosome constituents of 101 normal mammary gland cells, 122 hyperplastic alveolar nodule (HAN) cells, and 360 cells from eleven 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in the WF rat were examined. Both mammary gland and HAN had normal diploid karyotype patterns, whereas mammary tumors showed frequent (approximately 30%) abnormalities, e.g., aneuploidy, pseudodiploidy, polyploidy, and structural aberrations such as breakage and translocation. These results suggested that chromosome constituents of HAN cells are essentially the same as those of the normal mammary epithelial cells.
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After incubation with [3H]estradiol low-salt sucrose gradient centrifugation of 250 human breast tumor cytosis demonstrated receptor-bound steroid in both 4 S and 8 S forms. Cytosols prepared from 24 of these receptor-positive tumors were examined in the presence of KCl, Ca2+ and the serine protease inhibitor, phenylmethylsulfonyl fluoride. After incubation with KCl (0.4 M), interconversion of 8 S and 4 S forms was found in one-half of the 24 cytosols examined whose original low-salt patterns contained well-defined 4 S and 8 S peaks. When cytosols were made 4 mM in Ca2+ 15 to 30 min before the addition of KCl, an additional 4.5 S form was observed in low-salt gradients in 18 tumors, and, in 6 tumors, inactivation of receptor occurred. The effects were not produced when Ca2+ and salt were added simultaneously. After 2 to 24 hr of preincubation with Ca2+ of the same cytosols under the same conditions, an increased recovery of the approximately 4 S receptor complex was observed in low-salt gradient. These Ca2+ effects were inhibited if phenyl-methylsulfonyl fluoride and Ca2+ were added simultaneously to cytosols prior to the addition of salt. The data suggest that human mammary tumor cytosols may contain proteolytic activities that can be activated by Ca2+ and that can effect irreversible changes in the salt-dissociated steroid receptor proteins which can be detected in sucrose density gradients.
Seventy-two women with metastatic breast cancer were treated with multiple-agent chemotherapy. Fifty women were treated with 5 drugs in combination: 5-FU, methotrexate, vincristine, cytoxan, and prednisone; 22 were treated with the combination of 3 drugs: 5-fu, cytoxan, and prednisone. In 14 patients receiving 5 drugs and in 22 receiving 3 drugs, the multiple chemotherapy was the primary palliative treatment of extensive visceral metastases unsuitable for adrenalectomy. Results were similar with 6 responders in 14 (0.43) receiving 5 drugs, and 10 responders in 22 (0.45) receiving 3 drugs. The remaining 36 patients who were given 5-drug therapy all had previous adrenalectomy, and there were 16 responders (0.44). Toxicities from 3-drug treatment were substantially less severe than those from the 5-drug combination therapy. Whereas treatment-related death occurred in 6 of 50 patients receiving the 5-drug combination, no such incidence occurred in those receiving 3-drug combination therapy.
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Effects of neonatal androgenization or neonatal ovariectomy in female rats on endocrine functions and mammary tumourigenesis are examined. Pituitary gonadotrophin contents (both LH and FSH) are significantly lower in neonatally androgenized rats (TT) and significantly increased in neonatally ovariectomized rats (NO) when compared with controls of the same age. Plasma and pituitary prolactin levels are higher in TT rats than in the control rats of the same age, but the difference is not significant. Mammary tumours developing in TT rats after DMBA treatment are predominantly fibroadenomata, and lactogenesis in TT rats occurs almost entirely in those receiving DMBA treatment. Neonatal ovariectomy in female rats protects against subsequent induction of mammary cnacer by DMBA. The relationship between neonatal modification of endocrine functions and mammary tumourigenesis is discussed.
The estrogen receptor binding properties of 3,9-dihydroxybenz[a]anthracene (3,9-diOHBA) were determined in uterine cytosol of immature Sprague-Dawley rats by competitive binding experiments with [3H]estradiol and sucrose density centrifugation. 3,9-DiOHBA inhibited estradiol binding to the 8S binding protein at a concentration (1.2 X 10(-5) M) approximately equal to that of nafoxidine-HCl (3 X 10(-5) M) required to inhibit estradiol-specific binding, and bioassay for estrogenic activity substantiated this finding.
Bilateral adrenalectomy with radical mastectomy has been performed in a series of 17 postmenopausal women with breast cancer having metastasis in four or more axillary lymph nodes. Results to date show that both the recurrence and mortality rates are significantly lowered in this group of "high-risk" breast cancer patients by the combined treatment. Of these 17 patients, 14 are living and well with no evidence of disease. Six are surviving without recurrence 5 or more years since their primary treatment. The study also demonstrated that adrenalectomy patients on hormone replacement therapy are able to lead full and active lives for a long time without complications. This pilot study should be considered as a guide to future clinical trials rather than as an immediate recommendation for general therapy.
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The effectiveness of axillary dissection by modified radical mastectomy was assessed by a comparison of the total axillary nodes removed by this operation to that by radical mastectomy. In a series of 121 consecutive radical mastectomies performed during the period of 1964 to 1969, we found that the number of axillary nodes removed ranged from 3 to 63 with a median of 22 and a mean of 23.4 per patient. In a subsequent series of 111 consecutive modified radical mastectomies performed between 1969 and 1973, the total axillary nodes removed ranged from 6 to 77 with a median of 24 and mean of 25.7 nodes in each mastectomy specimen. These results strongly suggest that axillary dissection in modified radical mastectomy is as complete as that in the Halsted radical mastectomy.