The effects of tamoxifen treatment on the endometrium

OBJECTIVE: To investigate the association between tamoxifen and endometrial cancer. BACKGROUND: Tamoxifen is a nonsteroidal antiestrogenic drug that has been used successfully for 15 years in the treatment of all stages of breast carcinoma. In light of the positive results, several studies are now being conducted to test prolonged tamoxifen treatment as a prophylaxis against breast cancer in high-risk women. Although tamoxifen was thought to have only a few side effects, reports indicate that it is associated with an increased incidence of proliferative and neoplastic changes in the endometrium. As the current trend is to administer tamoxifen for prolonged periods and for more indications, the detrimental effects on the endometrium have vast implications. METHODS: Review of the current literature. RESULTS: Tamoxifen treatment is associated with an increased incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS: The results of tamoxifen treatment in breast carcinoma override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with tamoxifen should be investigated carefully and promptly. In the future it may be necessary to advise these women to undergo routine uterine cavity examination.     

A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery. Stockholm Breast Cancer Study Group

BACKGROUND: The use of adjuvant tamoxifen to treat postmenopausal breast carcinoma patients as an adjunct to primary surgery is well established. The current study reports the long term results for a low risk stratum in a randomized trial of adjuvant tamoxifen. The main focus of this analysis was to determine whether tamoxifen would result in a reduced local failure rate for lymph node negative, postmenopausal patients treated with breast-conserving surgery and postoperative radiotherapy. METHODS: The study population included 432 lymph node negative, postmenopausal patients with invasive breast carcinoma (classified as T1-T2) who underwent breast-conserving surgery followed by radiotherapy in Stockholm during the period 1976-1990. The patients constituted a separate stratum of the Stockholm Adjuvant Tamoxifen Trial, which included a total of 2729 patients. Of 432 patients, 213 received 40 mg of tamoxifen daily for either 2 or 5 years. The median follow-up time was 8 years (range, 5-19 years). RESULTS: At 10 years, the overall survival was 90% for the tamoxifen group and 88% for the control group. The event free survival at 10 years was 80% for the tamoxifen group and 70% for the control group (P=0.03). Tamoxifen reduced the overall rate of ipsilateral (hazard ratio=0.4, 95% confidence interval [CI]=0.2-0.9, P=0.02) and contralateral breast tumor recurrences (hazard ratio=0.4, 95% CI=0.1-1.1, P=0.06). Trends toward a reduced number of distant metastases (hazard ratio=0.6, 95% CI=0.3-1.2, P=0.1) and deaths due to breast carcinoma (hazard ratio=0.5, 95% CI=0.2-1.2, P=0.1) also were observed. CONCLUSIONS. The addition of tamoxifen to radiotherapy for postmenopausal, lymph node negative breast carcinoma patients treated with breast-conserving surgery resulted in a reduced rate of ipsilateral and contralateral breast tumor recurrences. The avoidance of salvage mastectomies, reexcisions, and new contralateral malignancies justifies the use of tamoxifen even in the treatment of patients with a 10-year survival rate of 90%.     

Effects of tamoxifen and interferon-beta or the combination on tumor-induced angiogenesis

Inhibition of angiogenesis by anti-tumor agents may play a role in tumor growth arrest. Tamoxifen and interferon-alpha/beta (IFN-alpha/beta) exhibit potentiated anti-proliferative activity against tumor cells. However, additional host-mediated effects such as modulation of angiogenesis may also inhibit tumor growth in vivo. The effect of tamoxifen and IFN-beta on angiogenesis induced by 2 human tumors, MCF-7 breast carcinoma (estradiol dependent) and NIH-OVCAR-3 ovarian carcinoma (estradiol independent), was assessed. Treatment of nude mice bearing MCF-7 tumors with tamoxifen resulted in a 68% decrease in the number of vessels at the tumor periphery. Treatment with IFN-beta yielded a 33% reduction. Treatment of nude mice bearing NIH-OVCAR-3 tumors with tamoxifen resulted in a 73% decrease in the number of vessels. Treatment with IFN-beta yielded a 57% reduction. Combination treatment resulted in augmented anti-angiogenic effects. As single agents, both tamoxifen and IFN-beta inhibited xenograft tumor growth. Ten weeks of tamoxifen treatment resulted in growth inhibition of MCF-7 and NIH-OVCAR-3 carcinomas by 85% and 66%, respectively. Ten weeks of IFN-beta treatment resulted in inhibition of growth of MCF-7 and NIH-OVCAR-3 carcinomas by 67% and 88%, respectively. The combination of tamoxifen and IFN-beta completely prevented growth of MCF-7 and NIH-OVCAR-3 carcinomas. The anti-angiogenic effects of tamoxifen and IFN-beta were additive. Inhibition of angiogenesis was detectable before measurable effects on tumor volume in both MCF-7 and NIH-OVCAR-3 tumors. Potentiation of anti-angiogenic effects by tamoxifen and IFN-beta, possibly resulting from enhanced IFN-induced gene expression, may contribute to anti-tumor activity in both estradiol-dependent and estradiol-independent tumors in vivo.     

Adenoid cystic carcinoma of the submandibular gland with symptomatic ovarian metastases

We report the clinical and pathologic features of an adenoid cystic carcinoma of the submandibular gland that metastasized to the ovaries 10 years after initial presentation. A 30-year-old woman underwent excision of a right submandibular adenoid cystic carcinoma followed by regional external beam radiation therapy. Three years later, she underwent extended hepatic resection and localized radiotherapy to the hepatic region for metastatic disease. The patient was without evidence of disease for 7 years when she developed pelvic pain and a pelvic mass was found. A solid and cystic 10-cm left ovarian mass and a single metastatic tumor nodule involving the right ovary were excised via the laparoscope. Histologically, the tumor was identical to the patient's initial salivary gland neoplasm. The neoplastic cells were CAM 5.2 positive, S100 positive, muscle-specific actin positive, and smooth muscle actin positive. Ultrastructurally, characteristic pseudocysts (pseudolumina) with abundant basal lamina and true glandular lumina lined by short microvilli were present. Other than a single anecdotal account of a parotid gland adenoid cystic carcinoma, this case represents the first documented report of an adenoid cystic carcinoma of salivary gland origin that was associated with symptomatic ovarian metastases. This case demonstrates that the ovary is a potential site for metastatic disease many years following the diagnosis and treatment for a primary neoplasm however uncommon or remote the site of origin. Since metastatic adenoid cystic carcinoma can rarely present as an ovarian mass, a clinical history of this neoplasm should be heavily weighed in the differential diagnosis of any unusual ovarian tumor with a predominant cribriform, trabecular, or tubular pattern.     

Regulation of parathyroid hormone-related protein expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens

Expression of parathyroid hormone-related protein (PTHrP) in breast carcinoma is a frequent cause of the paraneoplastic syndrome of hypercalcemia. In response to treatment with estrogen or tamoxifen, some breast cancer patients also develop a transient hypercalcemia. Therefore, the effect of 17beta-estradiol (E2), tamoxifen, or its more potent metabolite, 4-hydroxytamoxifen (OH-tamoxifen), on PTHrP expression in an estrogen receptor (ER)-positive breast carcinoma cell line (MCF-7) was evaluated. E2 increased PTHrP mRNA levels in MCF-7 cells and stimulated PTHrP(1-86) release in a dose-dependent fashion (10(-10)-10(-6) M). Tamoxifen and OH-tamoxifen also stimulated PTHrP release in a concentration-dependent fashion that paralleled their relative ER binding affinities (10(-6) or 10(-8)-10(-6) M, respectively). Combined treatment with the partial estrogen agonist, OH-tamoxifen, and E2 decreased E2-stimulated PTHrP secretion in MCF-7 cells to the levels seen with OH-tamoxifen treatment alone. These results suggest that transient estrogen- or tamoxifen-induced hypercalcemia in patients with breast carcinoma may be a PTHrP-mediated effect that is a marker of ER positivity.     

Parameters of estrogen expression in patients with endometrial tumors as prognostic signs of the effectiveness of neoadjuvant antitumor hormone therapy

Comparison was made of changes in such morphological characteristics of tumor as cell differentiation and mitotic activity in 142 patients with endometrial carcinoma in the course of treatment, using tamoxifen or oxyprogesterone capronate or both, and those of estrogen background (karyopicnotic, eosinophilic and maturity indices, numerical index of maturity and blood-estradiol level). Three levels of estrogen background-low, medium and high-were identified by assay of the colpocytological indices in postmenopausal patients with endometrial carcinoma. Levels of the colpocytological indices observed at high indices of estrogen background proved a reliable numerical criterion for evaluating the sensitivity of the patients to neoadjuvant hormone therapy. A significant correlation was established between high estrogen background, pathogenetic variant I and high differentiation of tumor cells. The high incidence of hormonal pathology in tumor tissue was registered when the colpocytological indices dropped by half after oxyprogesterone capronate treatment, and by third-after combined therapy (tamoxifen + oxyprogesterone capronate). In cases free from pronounced pathomorphism, said indices dropped by not more than 20%.     

Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.     

Effect of tamoxifen on serum lipid metabolism

The effect of tamoxifen, an antiestrogenic agent, on lipid metabolism was studied in postmenopausal patients with breast cancer who received the drug for postoperative adjuvant treatment following mastectomy. To measure total cholesterol and triglyceride concentrations, fasting blood samples were collected before and 2 months after the initiation of tamoxifen therapy from 16 patients who satisfied the study criteria. All patients were normolipidemic before tamoxifen was administered. Control samples were obtained from hypertriglyceridemia patients who were free from breast cancer. Marked hypertriglyceridemia was observed in 3 of 16 patients after tamoxifen treatment. The activity of lipoprotein lipase and hepatic triglyceride lipase, the key enzymes of triglyceride metabolism, decreased significantly in all of 16 patients as a result of tamoxifen treatment (P = 0.008 and P = 0.007, respectively). However, the mean mass of lipoprotein lipase significantly increased (P = 0.011) after tamoxifen treatment. We therefore conclude that tamoxifen might increase inactive lipoprotein lipase. Because marked hyperlipidemia is a potent risk factor for life-threatening acute pancreatitis and arteriosclerosis, plasma lipid levels should be tested periodically during tamoxifen treatment, even if the patients are normolipidemic during the pretreatment stage.     

Gynecologic effects of tamoxifen and the association with endometrial carcinoma

Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty cases of endometrial carcinoma are reported, but only one case is identified in a premenopausal woman. When documented, 77% (n=127) of the cases are good-grade (grade 1 or 2) and 80% (n=125) are stage-I disease. Since the distribution of good grade (79%) and stage I (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressive or late-stage disease appear to be unwarranted. The modest increase in the incidence of early-stage, good-grade endometrial carcinoma described during tamoxifen therapy suggests that it would be unreasonable to institute an aggressive detection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination.     

The effects of postradiation treatment with tamoxifen on local control and cosmetic outcome in the conservatively treated breast

BACKGROUND: The aim of this study was to evaluate the impact on disease recurrence and cosmetic outcome of tamoxifen treatment initiated after breast-conserving therapy (BCT). METHODS: Between 1982 and 1994, 498 women (509 breasts) were treated with BCT in accordance with a highly standardized institutional protocol. Adjuvant tamoxifen was administered to 130 patients (134 breasts), beginning 1-6 weeks after irradiation. The median ages and duration of follow-up for groups who received tamoxifen (TAM+) and no tamoxifen (TAM-) were 62.5 years/56 months and 53 years/60 months, respectively. The members of the TAM+ group were significantly older (P = 0.0001) and had increased incidences of positive axillary lymph nodes or undissected axilla (P = 0.001). There was a significant (P = 0.001) difference between the TAM+ and TAM- groups in the distribution of histopathologic subtypes; this reflected an increased proportion of associated ductal carcinoma in situ in the TAM- group. More extensive regional lymphatic irradiation was administered to the TAM+ group. Chemotherapy was administered to 15% of TAM+ and 28% (P = 0.003) of TAM- patients. There were no significant differences between the groups with respect to tumor size, reexcision, total excised tissue volume, final margin status, total radiation dose, or use of interstitial implant boost. RESULTS: There was no significant difference between the TAM+ and TAM- groups in the overall distribution of cosmetic scores (P = 0.18). The 5-, 7-, and 10-year actuarial local failure rates for TAM+ versus TAM- patients were 0% versus 3.1%, 1.9% versus 5.4%, and 1.9% versus 8.4%, respectively. Multivariate regression analyses of potentially confounding variables revealed no significant associations between tamoxifen and either cosmetic outcome or local failure. CONCLUSIONS: Radiotherapy followed by tamoxifen has no adverse interactive effect on cosmesis, and tamoxifen is associated with a trend toward enhanced 5-year local control probability.     

Morbidity pattern, health care utilization and per capita health expenditure in a rural population of Tamil Nadu

This retrospective analysis intends to evaluate by histeroscopy the endometrial findings in a group of 63 patients in post-menopausal treated with tamoxifen for breast cancer. Our patients assumed tamoxifen for a different period between 6 and 120 months. Patients have been divided in two groups: I) patients undergoing hysteroscopy because of some clinical symptoms; II) patients who undergoing hysteroscopy as a routine examination. The most important observation of this work is the correlation between the presence of negative endometrium and low risk hyperplasia (LRH) associated to: symptomatology and duration of therapy. In the group of asymptomatic patients the LRH is found only after 3 years of treatment, while in the group of symptomatic patients, LRH is present within the first two years of treatment; beyond this period high risk hyperplasia (HRH) and endometrial carcinoma have been diagnosed. We also observed a higher incidence of endometrial polyps in this population than among the non treated group and among the symptomatic patients. From these data we conclude that hysteroscopy follow-up has to be performed in the group of patients treated with tamoxifen and that it would be necessary to have a hysteroscopy before the beginning of therapy and that this one has to be repeated once a year through the treatment. Obviously the symptomatic patients have to undergo hysteroscopy as soon as possible as a higher incidence of HRH and endometrial carcinoma has been detected in this group of patients.     

Mullerian adenosarcoma of the uterine corpus associated with tamoxifen therapy: a report of six cases and a review of tamoxifen-associated endometrial lesions

Six consultation cases of mullerian adenosarcoma of the uterus were encountered in women who were receiving adjuvant tamoxifen therapy for carcinoma of the breast. To our knowledge, only one previous similar case has been reported. The women, who were 48-76 years of age, had received tamoxifen for periods of 6 months to 4 years (mean 2.7 years) in five of the cases; the duration of tamoxifen therapy in the sixth case is unknown. All of the tumors were polypoid endometrial masses that superficially invaded the myometrium in two cases. The microscopic appearance of the tumors was similar to that of previously described uterine mullerian adenosarcomas. These and other recent observations indicate that tamoxifen treatment may be complicated by uterine neoplasms other than endometrial adenocarcinoma. These findings also support previous observations that prolonged exogenous or endogenous hyperestrinism may lead to the development of mesenchymal and mixed epithelial-mesenchymal tumors of the uterus.     

Studies of tamoxifen as a promoter of hepatocarcinogenesis in female Fischer F344 rats

Tamoxifen, an antiestrogen used in the treatment of breast cancer, was assessed for carcinogenic potential in the two-stage model of experimental hepatocarcinogenesis. Groups of female Fisher F344 rats were initiated with a non-necrogenic, subcarcinogenic dose of diethylnitrosamine (DEN; 10 mg/kg, po) and fed tamoxifen at a concentration of 250 mg per kg of AIN-76A diet for 6 or 15 months. The livers of these animals exhibited an increase in size and number of altered hepatic foci compared with those animals which were initiated with DEN but not exposed to tamoxifen. This finding indicates that tamoxifen may have a carcinogenic potential in the rat liver. After 6 months of treatment, neoplastic nodules were observed in 3/8 rats in the DEN-initiated, tamoxifen-treated group. In the initiated group provided with tamoxifen for 15 months, neoplastic nodules were observed in 7/8 rats and hepatocellular carcinomas in 3/8 rats. The serum level of tamoxifen in these rats was 200-300 ng/ml. The ratio of tamoxifen, 4-hydroxy tamoxifen, and N-desmethyl tamoxifen was 1:0.1:0.5-1 in the serum. When adjusted for age-related weight increases, the serum and liver levels of tamoxifen and its N-desmethyl metabolite did not change over the 15 months. In the rat liver, the level of tamoxifen and its N-desmethyl metabolite was 10-29 micrograms/g liver after 6 or 15 months of chronic dietary administration. The ratio of tamoxifen:4-hydroxy tamoxifen:N-desmethyl tamoxifen was 1:0.1.3-3.3 in the liver. Therefore, the liver had 20- to 30-fold more tamoxifen and 4-hydroxy tamoxifen and at least 100-fold more N-desmethyl tamoxifen than the serum (assuming 1 gram of tissue is equivalent to 1 ml of serum). These results indicate that tamoxifen is a promoting agent for the rat liver at serum levels found in patients given the usual therapeutic course of tamoxifen. The high concentrations of tamoxifen attained in the rat liver indicate that actions other than its known estrogenicity for liver could contribute to its promoting action. In addition, these results indicate that the pharmacodynamic differences in tamoxifen metabolism in rats and humans and at low versus high doses should be determined. Thus, the therapeutic indications for tamoxifen should be balanced by the potential risk it may present as a promoting agent in mammalian liver.     

Cell cycle regulation of human pancreatic cancer by tamoxifen

BACKGROUND: Clinical trials have suggested a survival advantage for selected patients with metastatic pancreatic cancer treated with tamoxifen. We sought to identify the molecular mechanism by which tamoxifen inhibits human pancreatic cancer cell (HPCC) growth. METHODS: HPCCs were grown in tamoxifen and growth inhibition was determined by 3H-thymidine uptake and by the MTT assay; changes in cell viability were determined by cell counts. Cell cycle alterations were evaluated by FACS, and the induction of apoptosis was evaluated using the TUNEL assay. Total cellular RNA was isolated after tamoxifen treatment, and Northern blot analysis was performed for p21waf1. RESULTS: Tamoxifen inhibited HPCC growth as measured by inhibition of 3H-thymidine incorporation and by the MTT assay. However, there was no decrease in the total number of viable cells after 6 days of treatment with 10 microM of tamoxifen and no evident apoptosis, confirming the absence of a cytotoxic effect. Cell cycle analysis revealed cellular arrest in the G0/G1 phase, which correlated with p21waf1 mRNA upregulation in response to tamoxifen treatment. CONCLUSIONS: Tamoxifen inhibits HPCC growth by inducing G0/G1 arrest with an associated increase in p21waf1 mRNA expression. Tamoxifen is an effective inhibitor of HPCC growth in vitro and warrants further in vivo study.     

Chemo- and endocrino-therapy of breast carcinoma xenografts in the dormant or exponential growth phase

In case of concerning about recurrence case after operative treatment of breast cancer, we must suppose existence of dormant breast cancer cell. To elucidate a rational treatment of the breast cancer in the dormant stage, we have developed a new treatment model using human breast carcinoma xenografts (MCF-7, R-27 and Br-10) in nude mice. After the sc inoculation of the tumors, the treatment was initiated with or without the previous estradiol (E2) stimulation. While MCF-7 was sensitive to mitomycin C (6 mg/kg i.p.) and and tamoxifen pellet (2.5 mg/mouse s.c.) in the dormant and exponential growth phase, R-27 and Br-10 were sensitive to the drugs only in the exponential growth phase but not in the dormant stage. These results suggested that the sensitivity of human breast carcinoma cells in the dormant stage is rather low, however some strain would be also sensitive to the treatment. This model seems to be useful in evaluating the adjuvant therapy of breast carcinoma after surgery.     

Asymptomatic intrahepatic choledochal cyst associated with chronic active hepatitis C

A rare case of asymptomatic congenital choledochal cyst (Todani Type V) associated with chronic active hepatitis C is reported. A 45 year-old man was admitted for work-up of localized cystic dilatation of the intrahepatic bile ducts after effective interferon treatment for chronic active hepatitis C. Radiologic examination revealed localized cystic dilatation of the intrahepatic bile ducts in the atrophic left lobe. A left hepatic lobectomy was performed because malignancy had not been excluded. Macroscopic examination of the resected specimen revealed cystic dilatation of the intrahepatic bile ducts. Histologically, there was no evidence of malignancy. Hepatic lobectomy is the treatment of choice for Type V cysts if the disease is confined to a single lobe. Choledochal cysts should be excised to eliminate the potential for cholangitis, lithiasis, and carcinoma.     

Intestinal obstruction caused by peritoneal carcinomatosis due to signet ring cell carcinoma of the breast

The signet ring variant of lobular mammary carcinoma is aggressive and metastasis to serosal surfaces. We report a 46 years old woman presenting with an intestinal obstruction due to a peritoneal carcinomatosis secondary to a signet ring cell carcinoma of the breast. After surgery, the patient received chemotherapy (5-fluorouracil, adriamycin, cyclophosphamide and tamoxifen). A satisfactory response, with regression of peritoneal carcinomatosis and a good quality of life, was achieved. The patient is alive after 2 years of diagnosis.     

Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype

Tamoxifen is an antiestrogen used in adjuvant therapy of breast carcinoma and could potentially prevent the development of mammary cancer. While it is widely clinically used, its exact mechanisms of action are not yet fully elucidated. MCF-7/6 cells are estrogen receptor-positive invasive human breast cancer cells with a functionally inactive cell surface E-cadherin. In this study, we report that tamoxifen, and to a lesser extent its metabolites 4-OH-tamoxifen and N-desmethyltamoxifen, restore the function of E-cadherin in MCF-7/6 cells. In an aggregation assay, 10(-6) M tamoxifen significantly increases the aggregation of MCF-7/6 cells. This effect is abrogated by a monoclonal antibody against E-cadherin (HECD-1), is fast (within 30 min), and does not require de novo protein synthesis. Tamoxifen was also found to inhibit the invasion of MCF-7/6 cells in organ culture. Our data is the first demonstration that tamoxifen can activate the function of an invasion suppressor molecule and suggest that the restoration of E-cadherin function may contribute to the therapeutic benefit of tamoxifen in breast cancer patients.     

Failure in self care and heart failure, thiamine deficiency in geriatric patients

The ultrasonographic findings of 25 lesions in 23 patients with surgically proven ovarian masses were reviewed. There were 10 cystic teratomas, two simple cysts, two follicular cysts, two mucinous cystadenomas, two NHL, one corpus luteum cyst, one hydrosalpinx, one serous cystadenoma, one yolk sac carcinoma, one dysgerminoma, one embryonal carcinoma, and one mixed form (yolk sac carcinoma, choriocarcinoma). All patients were less than 15 years old. We classified all cases into four patterns: cystic, cystic with mural nodule, mixed, and solid. Eight lesions of the cystic pattern included two simple cysts, two follicular, cysts and one corpus luteum cyst. The other lesions were benign, too. Nine lesions with the cystic with mural nodule pattern consisted of eight cystic teratomas and one mucinous cystadenoma. All lesions were benign. The mixed pattern was seen in four lesions, half of which were malignant, i. e., one embryonal carcinoma and one yolk sac carcinoma. Four lesions with the solid pattern were all malignant masses: one dysgerminoma, two NHL and one mixed form. In this classification, the cystic and cystic with mural nodule patterns are benign, while mixed and solid patterns are highly suggestive of malignancy.     

Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines. A comparison between staurosporine and tamoxifen

We have previously demonstrated that the proliferation of established human glioma cell lines correlated with protein kinase C (PKC) activity and that a relatively selective PKC inhibitor, staurosporine, inhibits glioma cell proliferation. The purpose of this study was to determine whether low-passage glioma cell lines were also sensitive to staurosporine and to compare the antimitotic effects of staurosporine with tamoxifen, an antiestrogen with a known PKC inhibitory effect presently being investigated in the treatment of recurrent glioma. We measured the effects of treatment with staurosporine or tamoxifen on the proliferation rate of five established glioma cell lines (A172, U251, U87, U373, U563) and four low-passage glioma cell lines. The proliferation of all cell lines was inhibited by staurosporine, at an IC50 value (concentration at which activity is 50% inhibited) of approximately 2 nmol/L. All established lines, but only one low-passage line, were susceptible to tamoxifen, with an IC50 value of 10 mumol/L. Three of the four low-passage lines were poorly inhibited by tamoxifen. The IC50 values for the inhibition of cellular proliferation by staurosporine and tamoxifen closely corresponds to the IC50 data for the inhibition of particulate PKC activity in gliomas. We conclude that staurosporine is more effective in the inhibition of glioma proliferation than tamoxifen and that staurosporine is potentially useful in the adjuvant treatment of gliomas. The correspondence in IC50 results for proliferation and PKC activity further strengthens the hypothesis that an aberrant PKC system in gliomas drives their hyperproliferative state.