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PubMed1983

[Sex hormone dependency and endocrine therapy in diffuse carcinoma of the stomach].

In order to investigate the hormone dependency of gastric cancer, the presence of estrogen receptor (E.R.) in surgically resected carcinomatous tissues was studied. E.R. assay was performed by dextran coated charcoal method. We have found 10% E.R. positive cases in gastric cancer (4/40). These 4 patients were all female, and showed Borrmann 3 or 4 type macroscopically. The histological types of these cases were signet-ring cell carcinoma or poorly differentiated adenocarcinoma. Furthermore, experimental studies suggest that the growth of signet-ring cell carcinoma transplanted on nude mice depends on sex hormone. Based on these observations, the clinical trial of chemo-endocrine therapy after gastrectomy for female patients with diffuse carcinoma of the stomach has been performed in our hospital since 1980. The therapy consists of Mitomycin-C plus subsequent Tegafur, with or without Tamoxifen 20 mg/day given orally, twice a day starting 2 weeks after surgery. The results are as follows: The cumulative 3-year survival rate in 21 cases receiving chemo-endocrine therapy (TAM+) after gastrectomy revealed higher (43.3%) than that (5.6%) in 23 cases receiving chemotherapy alone (TAM-). Furthermore, 2 and 3 years survival rates of TAM + in curatively resected cases (8 cases) were both 100% including 2 recurrent cases. In TAM- 10 cases, 2 and 3 years survival rate showed 68.4% and 16.3% respectively with statistically significance (p less than 0.01). Chemo-endocrine therapy for non-curatively resected and recurrent cases were also effective. This result suggests that the chemo-endocrine therapy after gastrectomy may be a new hopeful adjuvant in female patients with diffuse carcinoma of the stomach.

Adenocarcinoma↗
PubMed1983

Differential response of an ovarian-responsive mouse mammary tumor to androgenic and estrogenic agents.

An ovarian-responsive mammary tumor subline, T4-OR26, was isolated from an outgrowth of a progressed TPDMT-4 pregnancy-dependent mammary tumor in a virgin DDD mouse. T4-OR26 tumors were characterized by significantly faster growth in virgin mice than in ovariectomized mice. Both estrogen and progesterone were important for growth of the subline, as they were for that of the parent. Tamoxifen (TAM), with estrogenic activity, and epithiostanol (EPI) and testosterone propionate, with androgenic activity, which all caused TPDMT-4 tumors to regress, were compared for antitumor potency against the new subline by 3 s.c. injections weekly in virgins. EPI at 300 micrograms and testosterone propionate at 1000 micrograms elicited immediate tumor growth suppression with subsequent slight regression as did ovariectomy. TAM at 1000 micrograms caused tumor growth suppression after 2 weeks without subsequent regression. At 600 micrograms, EPI but not TAM significantly inhibited 17 beta-estradiol plus progesterone-induced tumor growth; at 400 micrograms, neither had any significant effect on the tumor growth induced by 17 beta-estradiol alone. With regard to their effect on hormone receptors, it was noted that EPI and testosterone propionate treatments with tumor regression caused significant reduction in cytoplasmic progesterone receptor, but TAM treatment, which does not influence tumor growth, did not cause such reduction. The results provide evidence that hormone-dependent mammary tumors may acquire greater resistance to estrogenic than to androgenic therapeutics with progression.

Androstanols↗
PubMed1982

An evaluation of tamoxifen dose escalation in advanced breast cancer.

We escalated the dose of tamoxifen (TAM) to 30 or 40 mg daily in 23 patients who had experienced remission or stable disease (NC) under prior treatment with TAM 20 mg daily. One patient, whose bone and soft tissue disease had previously been stabilized under TAM 20 mg daily for 13 months, showed a partial remission (PR) lasting for 6 months. In 14 patients (64%) the disease remained stable for a median duration of 6 months (1.5-18+ mos.). Subjective improvement was noted in nine patients (39%), including the patient with PR and another one with progressive disease (PD). We conclude that dose escalation has no relevant activity in patients failing prior treatment with conventional doses of TAM.

Adult↗
PubMed1995

[Is breast cancer prevention by tamoxifen possible?].

Breast cancer is a frequent disease especially in the Western world with an incidence that increases by 1% each year. Distressingly, even nowadays, 40% of patients with breast cancer will die of their disease. Postoperative adjuvant therapy and detection of non-palpable cancers by mass screening of women have improved patient survival but have not impinged upon the steady increase in incidence. Treatment before radiological detection could improve the chances of survival and even prevent the full-blown expression of the disease. The probability that a woman will develop breast cancer during her life-time is high but not evenly distributed. Knowledge of predisposing factors can help to identify those women subject to greater risk than the general population. The most important known risk factors are age, family history, factors related to ob-gyn antecedents, lifestyle, benign hyperplastic breast disease with or without atypia. These various risks, are often associated and cumulative. A woman who has already had breast cancer has a 3 to 5 times greater probability of developing cancer of the contralateral breast than the average woman. The second breast is therefore at risk in the same way as are the women with predisposing factors. Many clinical studies have demonstrated the benefits of postoperative adjuvant tamoxifen (TAM) in improving the disease-free interval and survival of patients. An analysis of the site of relapse has interestingly brought to light a marked decrease in the percentage of cancers of the contralateral breast. In order to establish whether TAM could prevent or delay the onset of high-risk women without detectable signs of illness into groups receiving either TAM or placebo. Is this ethically acceptable? The answer to this question rests heavily on an objective evaluation of the unwanted and beneficial side-effects of TAM in order to weigh up all pros and cons before initiating a trial.

Adult↗
PubMedDate not supplied

Growth inhibitory effect of estrogen conjugated drugs against primary cultured breast cancer cells.

An in vitro assay method for predicting the hormonal response of primary cultured cells was used in 38 women with breast carcinoma. The response to 17 beta-estradiol (E2) was compared with other hormone treatments, such as tamoxifen (TAM), estracyt (EC) and bestrabucil (BB). The response to the E2-conjugated drugs (EC and BB) and TAM showed a good correlation with the response to E2 (p < 0.01). Coincidental rates of EC and BB response (stimulatory, insensitive, and inhibitory) with E2 response were 47% (16/34) and 53% (16/30) of cases, respectively. Cells showing an inhibitory response to E2 were also inhibited by EC and BB in 60% (6/10) and 100% (8/8) of cases, respectively. In premenopausal women, 28% (5/18) and 43% (6/14) of cases were inhibited by EC and BB, respectively, whereas in postmenopausal women 44% (7/16) and 56% (9/16) of cases showed inhibition with EC and BB, respectively. The inhibitory response to the E2-conjugated drugs was not significantly different between pre- and post-menopausal women. Cells resistant to inhibition by TAM were inhibited by EC and BB, respectively, in 17% (4/24) and 30% (6/20) of cases. These results indicate that E2-conjugated drugs may inhibit the growth of breast cancer cells and that their inhibitory actions might be different from those of TAM.

Adult↗
PubMed1994

Fluorimetric studies of calmodulin interactions with antiestrogens.

Recent cumulative data have shown that tamoxifen and its metabolites inhibit the activation of cAMP phosphodiesterase by calmodulin (CaM). In this study, the interaction of antiestrogens with CaM was investigated using a hydrophobic fluorescent probe, 2-p-toluidinylnaphthalene-6-sulfonate (TNS). Tamoxifen (TAM) enhanced the fluorescence of TNS bound to CaM and shifted the emission maximum to lower wavelengths. These effects were concentration-dependent. No change in the apparent affinity of TNS for CaM was noted in the presence of TAM. These results suggest that TAM bound to CaM at sites distinct from those of TNS and induced a change in TNS environment. Interaction of TAM metabolites with CaM depended on the degree of alteration of the dimethylaminoethoxy side-chain. Thus, N-desmethylation or N-di-desmethylation notably reduced the interaction of the drug with the macromolecule by 24 and 77% respectively. Side-chain deamination to the primary alcohol (metabolite Y) totally suppressed the interaction. The ability of these different metabolites to interact with CaM correlates with their efficiency to inhibit CaM-dependent cAMP phosphodiesterase and their growth inhibitory potency reported previously.

Calmodulin↗
PubMed1993

Effects of tamoxifen and CV 205502 on the morphology and the evolution of the noncancerous mouse mammary gland.

Tamoxifen (TAM, 0.01 mg/animal, three times a week) and the experimental prolactin-lowering CV 205502 (CV, 1 microgram/animal, daily) were administered prophylactically, alone or combined, to virgin C3H/Sy mice during the early period of promotion in this spontaneous mammary carcinogenesis system (end of 2nd-5th month of age), in order to study their influence on the morphology and evolution of the noncancerous mammary gland during therapy and after treatment cessation. During TAM administration the epithelial cells of the growing part of the gland exhibited myoepithelial- and, late in the treatment period, apoptotic-like features instead of the secretory ones expected, accompanied by intense basement membrane alterations, thickening of the surrounding connective tissue and arrested adipocyte maturation. These effects reversed progressively after drug withdrawal. The epithelial alterations were more intense and longer lasting in the TAM+CV-group, while growth arrest of the glands was observed in both groups parallel to the degree and the duration of these morphological changes. In these groups, tumor incidence was diminished, as expected, but the tumors that developed late after treatment cessation were of low histological differentiation. The above morphological observations show that TAM inhibits noncancerous mammary gland growth during the reproductive period by altering stromal and epithelial differentiation, effects that reverse progressively after treatment discontinuation and are potentiated by a prolactin-lowering agent in this animal study.

Adipocytes↗
PubMed1994

[Experimental chemoendocrine therapy of human breast carcinoma xenograft serially transplanted into nude mice].

The antitumor effect of combined chemoendocrine therapy with tamoxifen (TAM) and 5-fluorouracil (5-FU) on breast carcinoma xenograft (R-27), serially transplanted into the nude mice, was examined from the aspect of estrogen receptors (ER) and cytological features. The mice were given 6 intramuscular injections of TAM (5mg/kg) at 3-day intervals (TAM group), 3 intraperitoneal injections of 5-FU (60 mg/kg) at 4-day intervals ((5-FU group), or a combination of the two drugs (combined group). When the tumor was resected on 21 days after the initial treatment, the ER were assayed and %S was determined by flowcytometry. Furthermore, proliferative cell nuclear antigen (PCNA) was stained, and the stained cells were counted. A synergistic antitumor effect of TAN and 5-FU was found in mice given combined therapy. Reduction in the ER level was more marked in this group than in the others, but there were no significant differences in the %S value or the ratio of PCNA positive cells among the three treated groups. These results suggest that the combined effect of TAM and 5-FU has no relation to the inhibition of DNA synthesis.

Animals↗
PubMed1994

Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen.

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.

Animals↗
PubMed1994

Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen.

We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mammary carcinogenesis induced by N-nitroso-N-methylurea in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methylurea (50 mg/kg body weight) and then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor incidence, average number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low levels of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was particularly effective; addition of 9cRA to a TAM regimen doubled the number of animals that were tumor-free at autopsy and significantly diminished tumor number and tumor burden. For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induce the expression of the adhesion molecule, E-cadherin, in the SK-BR-3 cell line. We suggest that clinical evaluation of the combination of 9cRA and TAM, either for chemoprevention or for adjuvant therapy, should be considered.

Animals↗
PubMedDate not supplied

A possible direct action of a gonadotropin-releasing hormone agonist, goserelin, on the clonogenic growth of human breast cancer.

Direct inhibitory effects of a gonadotropin-releasing hormone agonist (GhRh agonist, goserelin, GOS) were studied on the in vitro clonogenic growth of human breast cancer, in comparison with estradiol-17 beta (E2) and tamoxifen (TAM). Estrogen (ER) and progesterone receptors (PgR) were asseyed in the adjacent cancer tissues using the DDC method. In 19% or 12 out of 64 cancers, E2, 10(-8) M, was shown to be effective in increasing the number of colonies per dish to 150% or more of the control. On the other hand, 16% (10/64) responded to TAM or GOS, respectively, i.e. the plating efficiency decreased to 50% or less of the control. While E2 and TAM had a tendency to have better effects in ER-positive tumors than ER-negative ones, the inhibitory effect of GOS was not dependent on the presence or absence of ER or PgR in the tumor. The GOS sensitivity did not correlate with the E2 dependence or the TAM sensitivity. These results suggest that a possible direct action of GOS may not be mediated by the ER system.

Adult↗
PubMed1995

Tamoxifen increases the proliferation of human endometrial stromal cells in in vitro. A model for evaluation of endometrial hyperplasia.

Tamoxifen given for breast cancer therapy, has a complex and an unclear action on the endometrium. A large number of literatures has attributed the proliferous changes in the endometrium caused by tamoxifen (Tam). No report has appeared on the endometrial cellular changes induced by Tam. The present study shows a significant (P < 0.001) increase in the proliferative activity due to Tam in endometrial stromal cells over control and estradiol (E2). This in vitro model is useful for the study of the hyperplasic effect of Tam at the cellular level.

Cell Division↗
PubMed1996

A permanently charged tamoxifen derivative displays anticancer activity and improved tissue selectivity in rodents.

A quaternized form of tamoxifen (TAM), tamoxifen methiodide (TMI), was shown to demonstrate very low brain uptake compared to TAM and, unexpectedly, was considerably less estrogenic than TAM in the uterus. The agonist activity of TMI in the bone was similar to that of TAM. TMI manifested significant dose-dependent tumoricidal activity with a rapid onset of action against MCF-7 human breast cancer implants in nude mice and a mean reduction in tumor size of 60% over six weeks.

Adenocarcinoma↗
PubMed1997

[Mechanism of acquired antiestrogen resistance and its management in breast cancer].

Although non-steroidal antiestrogen, tamoxifen(TAM), has been known to be useful for estrogen receptor(ER)-positive breast cancer, acquired tamoxifen resistance frequently occurs during the treatment. Several factors seem to be responsible for the resistance; decreased level of ER, mutation of ER, agonistic effect of TAM, ovarian steroidogenesis, altered metabolism of TAM, and increased expression level of antiestrogen binding sites. Withdrawal of TAM and second-line endocrine therapy might be effective on the tamoxifen resistant breast cancer which retains estrogen dependency. Otherwise, chemotherapy should be chosen for estrogen-independent breast cancer which has lost ER and fails to respond to other endocrine therapy. In this context, the menstrual status, serum level of estradiol, and steroid receptor status should be considered for the management of acquired antiestrogen resistance in breast cancer.

Animals↗
PubMed1997

Involvement of activator protein-1 (AP-1) in induction of apoptosis by vitamin E succinate in human breast cancer cells.

The purpose of this study was to document induction of apoptosis by vitamin E succinate (VES; RRR-alpha-tocopheryl succinate) in human breast cancer cells in culture and to characterize potential c-jun involvement. VES at 18.8 microM (10 micrograms/mL) induced DNA synthesis arrest, reduced total cell numbers, and induced apoptosis in estrogen receptor-positive and estrogen-responsive MCF-7 human breast cancer cells. VES at 10 micrograms/mL induced apoptosis in greater than 60% of cells within 3 d of treatment. Apoptosis was documented by detection of fragmented or condensed nuclei in 4',6-diamindino-2-phenylindole-stained cells, detection of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeled DNA, and DNA laddering. Analyses of mRNA and protein levels of candidate molecules involved in apoptosis showed that MCF-7 cells treated with VES exhibited elevated and persistent expression of c-jun. MCF-7 cells stably transfected with a dominant-negative interfering mutant c-jun, TAM-67, and expressing high levels of mutant jun exhibited approximately 50% blockage of VES-mediated apoptosis. In addition to increased c-jun expression after VES treatment, VES-treated MCF-7 cells exhibited elevated activator protein-1 (AP-1) binding activity. Comparisons of AP-1 binding factors by super-shift analyses with jun-specific antibodies in cells sensitive to VES-induced apoptosis (empty-vector control 7-1 cells) and cells resistant to VES-induced apoptosis (TAM-67-containing TAM-9 cells) showed that the sensitive cells expressed c-jun and jun D and the resistant cells TAM-67 AP-1 binding proteins after VES treatment. These studies suggested that c-jun may be involved in the apoptotic process initiated by VES treatment of human MCF-7 breast cancer cells.

Apoptosis↗
PubMed1997

Changes in the phosphorylation status of the 27 kDa heat shock protein (HSP27) associated with the modulation of growth and/or differentiation in MCF-7 cells.

We have used human mammary cells of the MCF-7 strain, which constitutively express high levels of the small heat shock protein HSP27 and we have compared the changes in the phosphorylation status of this protein together with changes in cell growth and/or morphology induced by the action of one of the following agents: (1) TPA (12-O-tetradecanoylphorbol-13-acetate), known as a differentiation inducer in MCF-7 cells; (2) OH-TAM (hydroxytamoxifen), which exerts a cytostatic and cytotoxic action; or (3) TNF alpha (tumour necrosis factor), which induces apoptotic cell death in this cell line. Our data show that TPA and TNF stimulate an immediate and massive phosphorylation of HSP27, whereas OH-TAM affect the phosphorylation status of the protein only after a 3 day delay. In the case of TPA, high levels of HSP27 phosphorylation were maintained for at least 4 days, along with growth inhibition and acquisition by the cells of a secretory phenotype. TPA and OH-TAM exerted similar immediated effects on cell growth, despite the different time course of their action on HSP27 phosphorylation. This excludes the possibility that the latter is a necessary consequence of, or an absolute requisite to, growth inhibition. With OH-TAM and TNF the increase in HSP27 phosphorylation was concomitant with the appearance of apoptosis, not observed with TPA. This indicates that increased phosphorylation of HSP27 is not specifically associated with the triggering or the execution of apoptosis in these cells. Altogether, our data support the concept that phosphorylated HSP27 is involved (and might then be rate limiting in some instances) in the execution of vital cell programmes (including resistance to stress, proliferation and differentiation), as well as in that of cell death. This is consistent with its role in actin polymerization and its position downstream of the p38/RK-type MAPkinase, itself a point of convergence for diverse signal transduction pathways.

Antineoplastic Agents↗
PubMed1998

Alpha-hydroxytamoxifen is a substrate of hydroxysteroid (alcohol) sulfotransferase, resulting in tamoxifen DNA adducts.

When alpha-hydroxytamoxifen (alpha-OHTAM) was incubated with rat liver hydroxysteroid (alcohol) sulfotransferase a (STa) and 3'-phosphoadenosine 5'-phosphosulfate, (E)-alpha-OHTAM was found to be a better substrate for STa than (Z)-alpha-OHTAM. To explore the formation of tamoxifen (TAM)-derived DNA adducts, DNA was incubated with STa and either (E)-alpha-OHTAM or (Z)-alpha-OHTAM in the presence of 3'-phosphoadenosine 5'-phosphosulfate. Using 32P-postlabeling analysis, the amount of TAM-DNA adducts resulting from (E)-alpha-OHTAM was 29 times higher than that observed with (E)-alpha-OHTAM alone. Using (Z)-alpha-OHTAM and STa, some TAM-DNA adducts were also detected but at levels 6.5 times lower than that observed with (E)-alpha-OHTAM and STa. When compared with standards of stereoisomers of 2'-deoxyguanosine 3'-monophosphate-N2-tamoxifen, the major tamoxifen adduct was identified chromatographically as an epimer of the trans form of alpha-(N2-deoxyguanosinyl)tamoxifen, and the minor adduct was identified as an epimer of the cis form. In the reaction mixture, a conversion from (E)-alpha-OHTAM to (Z)-alpha-OHTAM through the carbocation intermediate was also detected. These results show that sulfation of alpha-OHTAM catalyzed by STa results in the formation of TAM-DNA adducts.

Animals↗
PubMed1998

[Treatment strategy for recurrent breast cancer].

In recent years, many kinds of efficacious modalities have been available for the treatment of recurrent breast cancer. Endocrine therapy is essentially the treatment of choice for both premenopausal and postmenopausal patients. The recommended sequence of endocrine therapies is described as follows: In premenopausal women, ovarian ablation (LH-RH agonists) is considered the first-line therapy, with tamoxifen (TAM) and aromatase inhibitors (AI) as the second-line alternatives. In postmenopausal women, the recommended first and second-line therapy is TAM and AI, respectively. Medroxyprogesterone acetate (MPA) should be used as the third-line agent, irrespective of menopausal status. However, efficacy of combinations such as LH-RH agonist plus TAM for premenopausal women and TAM plus AI for the postmenopausals is still uncertain. Patients with rapidly progressing and/or endocrine-resistant tumor should be treated with anthracycline containing regimen such as CAF (cyclophosphamide, adriamycin, 5-fluorouracil). As for the palliative modality, chemotherapy (CAF, doxifluidine) combined with MPA has resulted in improved QOL.

Antineoplastic Combined Chemotherapy Protocols↗