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Biomedical subjects

T L Dao

Publications and source records attributed to T L Dao.

At least 37 records · Page 2Linked to original sources
PubMed1983

Is medullary carcinoma of the breast hormone dependent?

From 1951 to 1981, 22 patients with metastatic medullary carcinoma of the breast were treated with hormonal therapies at Roswell Park Memorial Institute. Bilateral oophorectomy was performed in 6 premenopausal patients, and none had objective response, although one patient did have stable disease for 7 months. Three of these patients subsequently underwent bilateral adrenalectomy and none responded. Thirteen of 16 postmenopausal patients underwent bilateral adrenalectomy and only one had an objective response of 4 months. Eight of 22 patients received additive hormones, and one patient was treated with Tamoxifen. There was no objective response to these therapies. From this study, it appears that medullary carcinoma of the breast is less often responsive to endocrine therapy, and this finding correlates well with the recent data showing lower frequency of estrogen receptor-positive tumors in these patients.

Adrenalectomy↗
PubMed1983

Effects of dietary fat on age-dependent sensitivity to mammary carcinogenesis.

Two groups of female Fischer rats were fed either a high-fat, low-carbohydrate (HF) diet or a low-fat, high-carbohydrate (LF) diet throughout the experiments, beginning from weaning. Each group of rats was divided into 4 subgroups and given an i.v. dose (50 mg/kg body wt.) of N-methyl-nitrosourea (NMU) at 35, 50, 90 or 130 days of age, respectively. Mammary tumor yield showed an age-dependent response in both groups. Although mammary tumor incidence decreased in rats as their age increased, irrespective of whether they were fed a high- or low-fat diet, the tumor incidence was significantly higher in rats fed the high-fat diet at any age. Thus, the combined effect of dietary fat and age-dependent sensitivity on mammary carcinogenesis caused more than a 4-fold difference in mammary tumor incidence rates between the 2 groups of rats.

Age Factors↗
PubMed1983

Hormones and dietary fat as promoters in mammary carcinogenesis.

Hormones, particularly ovarian steroids and pituitary prolactin, promote mammary carcinogenesis in rats treated with a carcinogen. Hormones also play a critical role during the initiation process as demonstrated by mammary carcinogenesis in ovariectomized rats. A diet high in fat content, especially polyunsaturated fat, promotes mammary tumorigenesis when it is fed to carcinogen-treated rats for a prolonged period of time. Although a high fat diet is not essential for neoplastic transformation of the mammary cells, its effect on initiation is demonstrated when it is fed to rats for a long duration. Thus, both hormones and high dietary fat play a dual function in mammary carcinogenesis. There are indications that dietary fat may modulate endocrine activities, but a relationship between dietary fat and endocrine function remains to be conclusively demonstrated.

Animals↗
PubMed1983

Effect of duration of high fat intake on enhancement of mammary carcinogenesis in rats.

The relationship between dietary fat and mammary carcinogenesis was studied in weanling female inbred Fischer rats fed a purified, high-fat, low-carbohydrate (HF) or a purified, low-fat, high-carbohydrate (LF) diet and given N-nitroso-N-methylurea (NMU) at 50, 90, or 133 days of age. By a change in the diet at different times after NMU treatment (50 mg/kg body wt), it was found that mammary tumor incidence was positively correlated with the time period that the rats were fed an HF diet. A dose-response effect of NMU at 10, 20, 30, 40, and 50 mg/kg body weight was also studied in groups of rats fed an HF or an LF diet. The results show an optimal carcinogenic dose of 50 mg NMU/kg body weight and a threshold dose of 27 mg NMU/kg body weight. The data conclusively demonstrated that the HF diet enhanced mammary carcinogenesis at every dose level of NMU, except 10 mg/kg. Further, the experiments also showed that an HF diet failed to promote mammary carcinogenesis in rats receiving a subthreshold dose (20 mg/kg body wt) of NMU. Altogether, the data demonstrate that an HF diet is not just a promoter but is in fact co-carcinogenic in mammary tumor induction by a chemical carcinogen.

Animals↗
PubMed1983

Effects of different dietary fats on mammary carcinogenesis.

Mammary tumor induction was examined in female Fischer rats fed a low-corn oil, a high-corn oil, a high-lard, a high-beef tallow, or a high-coconut oil diet since weaning. The diets were prepared by adding the experimental fat to a basal diet containing sufficient essential fatty acids for growth. These diets differed only in the concentration or type of dietary fat. The rats were given a single i.v. dose (50 mg/kg body weight) of N-nitrosomethylurea at 50 days of age. Mammary tumor incidences 28 weeks after N-nitrosomethylurea treatment in rats on low-corn oil, high-corn oil, high-lard, high-beef tallow, and high-coconut oil diets were 33, 85, 65, 50, and 43%, respectively. The data show that an increase in fat intake enhances mammary carcinogenesis, but the magnitude of the increase depends on the type of fat. Further analyses showed that the total oleic and linoleic acid intake in the five groups of rats correlated positively (r = 0.95) with mammary tumor incidence, whereas the composition of the mammary tissue neutral lipids and phospholipids did not. Our data suggest that the total oleate and linoleate intake in the high-fat diet is the major factor influencing the incidence of tumors by N-nitrosomethylurea.

Animals↗
PubMed1982

Comparison of four-combination chemotherapy programs in metastatic breast cancer: comparison of multiple drug therapy with cytoxan, 5-FU and prednisone versus cytoxan and adriamycin, versus cytoxan, 5-FU and adriamycin, versus cytoxan, 5-FU and prednisone alternating with cytoxan and adriamycin.

In 126 postmenopausal women with metastatic breast cancer, four chemotherapeutic combination programs were tested. Patients were stratified and randomized to one of the four programs: (1) fluorouracil, cytoxan and prednisone (CFP): (2) fluorouracil, cytoxan and Adriamycin (CAF); (3) cytoxan and Adriamycin (CA); or (4) alternating combinations of CFP-CA. Objective response rates were 17% for 18 patients on CFP, 25% for 40 patients on CAF, 42% for 41 patients on CA and 63% for 19 patients on CFP-CA. CFP-CA provided a significantly higher response rate than either CFP or CAF. The response rate of CA was intermediate. The duration of remission and survival were similar for all four groups. When progression or relapse following remission was demonstrated, patients were rerandomized to either adrenalectomy or tamoxifen. There were no responders either in the 15 patients undergoing adrenalectomy or the 11 patients receiving tamoxifen. In a crossover study, nine adrenalectomized patients received tamoxifen and four tamoxifen-treated patients underwent adrenalectomy. None responded. It appears that response rates to hormonal modalities are reduced in patients previously treated by combination chemotherapy.

Adrenalectomy↗
PubMed1982

Leukocyte-derived interferon (alpha) in human breast carcinoma. The American Cancer Society phase II trial.

A multi-institutional trials program was initiated to define the effects of interferons in disseminated human breast carcinoma. Interferon alpha, prepared from buffy coats, was administered intramuscularly at 3 x 10(6) U daily for an initial period of 28 days. Of 23 patients who entered the program, five had an objective partial response of 92 days mean duration at diverse sites of involvement. Patients who responded were significantly older (p = 0.05) than nonresponders. Dose escalation in eight patients did not result in any clear evidence of additional responses. Major toxicities were fatigue, anorexia with weight loss, and reversible leukopenia (less than 3.5 x 10(9) leukocytes/L in 16 patients). Natural killer cell and antibody-dependent cell-mediated cytotoxicity were significantly (p less than 0.05) enhanced 48 hours after interferon administration began but subsequently declined despite continued therapy. Serum beta 2-microglobulin concentration increased on day 15 (p less than 0.05) and remained significantly elevated on day 22 (p less than 0.005). Peak interferon titers (mean, 62 U) occurred 6 hours after interferon was started, varied widely between patients, and were higher and more persistent with dose escalation. Once an optimal dose is defined, prospectively randomized trials will define what role interferons may have in systemic therapy of breast carcinoma.

Adult↗
PubMed1982

Effect of estrogen and progesterone on cellular replication of human breast tumors.

A total of 54 infiltrating carcinomas of the breast were studied for estrogen receptor concentration in the tumor cytosol and thymidine-labeling indexes. The results showed that there was no significant difference in the level of thymidine-labeling index between 22 primary and 32 metastatic breast cancers. No significant association between the levels of thymidine-labeling index and the presence or absence of estrogen receptors was observed. The effect of "physiological" doses of estrogen and progesterone on cell proliferative activity was studied by the level of thymidine-labeling indexes in the tumor cells in 10 patients with multiple skin and s.c. metastases. Tumor biopsies were performed for labeling indexes both before and after hormonal treatment. The results showed that physiological doses of estrogen and progesterone induced a significant rise in thymidine-labeling index within 3 days after hormonal treatment in seven of the 10 tumors. Of the seven tumors that showed a rise in thymidine-labeling index, three were estrogen receptor positive and four were estrogen receptor negative. Of the three nonresponsive tumors, one was estrogen receptor positive and two were estrogen receptor negative. The study suggests that estrogen and progesterone can induce cell replication in both estrogen receptor-positive and -negative tumors.

Adult↗
PubMed1982

Estrogen synthesis in human breast tumor and its inhibition by testololactone and bromoandrostenedione.

A total of 53 tumors have been examined for estrogen synthesis from androstenedione and assayed for estradiol receptors. It was found that of the 40 tumors that metabolized androstenedione to estrogens, 17 tumors were estradiol receptor negative and 23 tumors were estradiol receptor positive. Of the 13 tumors that did not synthesize estrogens, 7 tumors were receptor negative and 6 tumors were receptor positive. No correlation was found between the ability of the tumor to synthesize estrogens and the presence or absence of estradiol receptors. The inhibition of aromatase enzyme in human breast tumors by delta 1-testololactone, testololactone, and 6 alpha- and 6 beta-bromoandrostenedione was investigated. Estrone and estradiol synthesis from androstenedione was reduced in five tumor incubations by the presence of 0.2 mM delta 1-testololactone and testololactone, 6 alpha- and 6 beta-bromoandrostenedione (2.0 microM) were also shown to block estrogen synthesis in 5 tumors. Furthermore, Lineweaver-Burk plots revealed that all four compounds were competitive inhibitors of androstenedione aromatization. An apparent Km of the aromatase enzyme for androstenedione of 0.08 microM and a Vmax of 23 pmol of estrone synthesized per g tumor per hr were determined for one human breast tumor specimen. The use of an aromatase inhibitor such as delta 1-testololactone in the treatment of breast cancer should be reconsidered. Data from one patient with advanced cancer of the breast, responding to previous oophorectomy and adrenalectomy and treated with large doses of delta 1-testololactone, are presented to illustrate the significance of successful treatment by scientific approaches.

Adrenalectomy↗
PubMed1981

Axillary lymph node metastasis from an occult breast cancer.

Twenty-nine cases were reviewed in which carcinoma manifested first as the enlargement of an axillary node from an occult breast carcinoma. A small hidden breast cancer was identified in 16 patients. In the remaining 13, the breast tumor was never discovered. Regardless of whether the primary tumors were discovered, the metastasis-free survival rates were comparable to those of patients with breast carcinoma with axillary nodal metastasis. The authors recommend that carcinoma found in an axillary node should be treated as a breast cancer, even in the absence of the breast tumor. Extensive investigative procedures in an attempt to uncover an extramammary primary site were largely unproductive and should either be omitted or performed selectively. Mammography, if positive or suspicious, can lead to the primary tumor in 75% of the patients, but, when negative, it does not necessarily exclude the breast as the source of the carcinoma. A carcinoma of the breast was found by pathologic examination in 44% of the patients with negative mammograms.

Adenocarcinoma↗
PubMed1981

Prolactin binding by human mammary carcinoma: relationship to estrogen receptor protein concentration and patient age.

Biopsy specimens of 55 human mammary carcinomas (38 primary and 17 metastatic) were assayed for prolactin receptors (PrlR). Prolactin bound specifically to 32 (58%) of the tumor biopsy specimens. The apparent Kd for PrlR in individual tumors ranged from 15 pM to 2.3 nM (mean 600 pM, n = 5) and the concentration of PrlR ranged from 0 to 44.5 fmoles/mg protein. Estrogen receptors (ERP) were also detected in 28 of the 32 tumors which had PrlR. Overall, there was no correlation between PrlR and ERP. However, the mean concentration of PrlR was significantly higher (p less than 0.01) in tumors with 6-100 fmoles/mg protein ERP (approximately 13 fmoles PrlR) than in tumors with either less than 6 or greater than 250 fmoles ERP (4.0 +/- 0.4 and 6.5 +/- 1.8 respectively fmoles PrlR). Analysis of PrlR concentration as a function of patient age also showed no overall correlation, but the mean PrlR in tumors from women aged 60-70 was significantly higher (p less than 0.01) than in those from either younger or older women. A higher concentration of PrlR was observed in tumors which were classified histologically as medium or well differentiated (6.1 +/- 1.2 and 11.1 +/- 2.1, respectively) than in those classified as poorly differentiated (3.3 +/- 1.2) (p less than 0.03). There was a negative correlation between PrlR concentration and membrane yield from the tumors (r = 0.43, p less than 0.02). The membrane yield correlated with the ratio of tumor cells to stroma (histologically) (r = 0.63, p less than 0.001). In tumors from 12 patients with metastatic disease on whom follow up after endocrine-related therapy was available, the mean PrlR concentration was significantly higher in the non-responding group (8.2 +/- 3.0) than in the responding group (3.4 +/- 4.2, p = 0.05).

Adult↗
PubMed1981

Enhancement of mammary carcinogenesis by a high-fat diet in Fischer, Long-Evans, and Sprague-Dawley rats.

The relationship between dietary fat and mammary carcinogenesis was examined by feeding a high-fat or a low-fat purified diet, differing only in fat and carbohydrate content, to Fischer, Long-Evans, and Sprague-Dawley rats. An additional group of rats from each strain was fed a nonpurified laboratory diet for comparison. The rats were given an i.v. dose of N-nitrosomethylurea (50 mg/kg body weight) at 50 days of age. The results showed that (a) a high-fat purified diet significantly enhanced mammary carcinogenesis; (b) a nonpurified laboratory diet retarded mammary carcinogenesis compared to a low-fat purified diet; (c) rats on three different diets had a similar body weight gain; (d) the susceptibility of N-nitrosomethylurea-induced mammary carcinogenesis in the three strains of rats was in the order of Sprague-Dawley > Fischer > Long-Evans; and (e) Fischer rats appeared to be better suited for further systematic studies of dietary fat and mammary carcinogenesis.

Animals↗
PubMed1980

Steroid receptors and response to endocrine ablations in women with metastatic cancer of the breast.

Estrogen receptors in breast tumors were assayed in 55 premenopausal women undergoing bilateral oophorectomy and in 120 postmenopausal women undergoing bilateral adrenalectomy for treatment of metastatic breast cancer. The data show that 20 (60%) of the 32 patients with estrogen receptor-positive (ER+) tumors had objective remission after oophorectomy, and 44 (51%) of the 87 patients with ER+ tumors responded to adrenalectomy. In contrast, of those patients with estrogen receptor-negative (ER-) tumors, only 3% had an objective remission following oophorectomy and 9% following adrenalectomy. It is concluded that major endocrine ablative procedures are not justified in patients with ER- tumors. The data also conclusively demonstrate the significance of 4S receptors in predicting the response to endocrine therapy. In this study, it was found that although the response rate to endocrine ablation was substantially higher (71-83%) in patients whose tumors contained both estradiol and progesterone receptors, between 50 and 60% of ER+ tumors lacking progesterone receptors had objective remission after endocrine ablative therapy.

Adrenalectomy↗
PubMed1980

Regulation of cyclic adenosine 3',5'-monophosphate in relation to growth of dimethylbenz[a]anthracene-induced mammary tumors in rats.

In this study, adenylate cyclase, phosphodiesterase and cyclic adenosine 3',5'-monophosphate (cAMP) levels were measured in 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors with different growth characteristics in both intact and ovariectomized rats. Tumors were classified as growing, stable, or regressing over a 10-14-day period before excision. Regressing or static tumors had a higher cAMP concentration relative to tumors that were growing actively. This was due to high adenylate cyclase activity and low phosphodiesterase (both high and low Km) activities. Although estrogen deprivation resulted in a much greater rate of tumor regression than would occur spontaneously under normal conditions, the levels of adenylate cyclase, phosphodiesterases and cAMP were the same in tumors obtained from either intact or ovariectomized rats, when comparisons were made within the same category of tumor. These observations suggest that cAMP metabolism is independent of estrogen, since it is related to enhancement or retardation of growth rather than to the presence of absence of estrogen.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Inhibition of estrogen synthesis in human breast tumors by testololactone and bromoandrostenedione.

The inhibition of aromatase enzyme in human breast tumors by delta 1-testololactone, testololactone, 6 alpha-bromoandrostenedione, and 6 beta-bromoandrostenedione was investigated. Estrone and estradiol synthesis from androstenedione was reduced in 3 tumor incubations by the presence of 0.13 mM delta 1-testololactone and testololactone. 6 alpha- and 6 beta-bromoandrostenedione (2.0 microM) were also shown to block estrogen synthesis in 2 tumors. Furthermore, Lineweaver-Burk plots revealed that all 4 compounds are competitive inhibitors of androstenedione aromatization. An apparent Km of the aromatase enzyme for androstenedione of 0.08 microM and a Vmax of 23 pmol of estrone synthesized/g tumor/hr were determined for one human breast tumor specimen. These results demonstrate that these aromatase inhibitors may be useful for the treatment of breast cancer.

Androstenedione↗
PubMed1980

Serum sialyltransferase and 5'-nucleotidase as reliable biomarkers in women with breast cancer.

Sialyltransferase and 5'-nucleotidase were measured in the sera of 135 women with breast cancer: 53 undergoing mastectomy for primary cancer and 83 receiving different modalities of palliative therapy for metastatic disease. The objective of this study was to determine whether these enzyme levels were associated with the extent of the disease and whether changes in these enzyme levels could be correlated with success or failure of treatment. Mastectomy caused a rapid fall of elevated enzyme levels to within the normal range in all patients with stage I breast cancer but not in those with stage II or III disease. In women with metastatic disease, elevated enzyme levels fell only in patients responding to treatment. Thus serum sialyltransferase and 5'-nucleotidase activities are reliable biomarkers of breast cancer activity, and serial measurement of these enzyme activities provides a useful tool for the monitoring of disease activity and success or failure of the treatment.

Adolescent↗
PubMed1980

Induction of mammary tumors in aging rats by 7,12-dimethylbenz[a]anthracene: role of DNA synthesis during carcinogenesis.

Two routes of administration were used to test the susceptibility of the mammary gland of the rat to 7,12-dimethylbenz[a]anthracene (DMBA) carcinogenesis in relation to age of the tissue. In one series of experiments, 60-, 70-, 90-, 120-, 150-, and 200-day-old female noninbred Sprague-Dawley rats were given DMBA iv. In parallel experiments, rats of the same ages as those above were given DMBA by local application. Mammary tumors developed in 80-90% of the 60- and 70-day-old rats and in 40% of the 90-day-old rats. Rats 120 days old and older were completely "refractory" to DMBA. In contrast, all rats, irrespective of their ages, developed tumors when DMBA was applied locally. The DNA synthesis labeling index (LI) of mammary glands of rats in two series of experiments was examined by [3H]thymidine incorporation and autoradiography at 24, 48, and 72 hours after DMBA treatment. DMBA, given iv significantly inhibited DNA synthesis in mammary glands, but DMBA applied locally significantly increased the LI of the mammary glands. Thus the LI of the mammary glands in 60-day-old rats increased from 8% (control, untreated) to 16% (rats receiving local applications of DMBA), whereas the LI of the mammary glands in 150-day-old rats increased from 1.15% (control, untreated) to 8% (rats receiving local application of DMBA).

9,10-Dimethyl-1,2-benzanthracene↗