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PubMed1999

Thirteen-week oral toxicity study of difluoromethylornithine in combination with tamoxifen citrate in female dogs.

PURPOSE: Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM), a nonsteroidal antiestrogen, is approved for use in the treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of TAM with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma. METHODS: The toxicity of DFMO in combination with TAM was evaluated in female Beagle dogs following 13 weeks of daily oral administration by capsule. Dose levels in milligrams per kilogram body weight per day were: 0 (vehicle control), 100 DFMO, 0.1 TAM, 1.0 TAM, 0.1 TAM + 100 DFMO and 1.0 TAM + 100 DFMO. RESULTS: No mortalities occurred. Diarrhea was produced by TAM and vaginal discharge, due to reproductive tract lesions, was produced by both DFMO and TAM, either alone or in combination. DFMO decreased reticulocyte counts and TAM increased counts of mature neutrophils. DFMO alone resulted in lesions to the intestines and ovaries, and cornified epithelium of vagina and cervix. TAM produced cornified epithelium of vagina and cervix, and numerous lesions in the ovaries, fallopian tube, uterus, cervix and vagina which were likely due to an estrogen agonist effect. Coadministration of DFMO increased the incidence and/or severity of these reproductive tract lesions. Each compound alone produced ovarian atrophy, and antral follicles and corpora lutea were completely absent in the 1.0 TAM + 100 DFMO group. CONCLUSIONS: Coadministration of DFMO and TAM resulted in additive toxicity involving the female reproductive system.

Animals↗
PubMed2005

Role of mitochondria in tamoxifen-induced rapid death of MCF-7 breast cancer cells.

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.

Antineoplastic Agents, Hormonal↗
PubMed2002

Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases.

The phenolic active metabolites, cis-4-hydroxytamoxifen (cis-HO-TAM) and trans-4-hydroxytamoxifen (trans-HO-TAM), of the anti-breast-cancer drug, trans-tamoxifen (TAM), were geometrically selectively glucuronidated in the manner of cis>>trans by microsomes and sulfated in the manner of trans>>cis by cytosol from the liver of 10 human subjects (7 females and 3 males). There was a large individual difference in the microsomal glucuronidation of cis-HO-TAM, which correlated well with glucuronidation of 4-hydroxybiphenyl by human liver microsomes. However, there was only a slight correlation between the glucuronidation of cis-HO-TAM and trans-HO-TAM or 4-nitrophenol (NP). A small individual difference was observed for the human liver cytosolic sulfation of trans-HO-TAM, which correlated well with the sulfation of NP. Recombinant human UDP-glucuronosyltransferase (UGT)2B15 catalyzed the cis-selective glucuronidation of geometrical isomers of HO-TAM. UGTs1A1, 1A4, 1A9 and 2B7 had weak activity toward HO-TAMs with a much smaller cis-selectivity than did UGT2B15. UGTs1A3 and 1A6 had no detectable activity toward these substrates. Among the four known major sulfotransferases (SULTs) occurring in the human liver, SULT1A1 was strongly suggested to play the most important role in the hepatic cytosolic trans-selective sulfation of HO-TAM isomers. A good correlation was observed between the hepatic cytosolic sulfation of trans-HO-TAM and NP, a standard substrate for SULT1A1. SULT1E1 had slight activity toward the HO-TAMs. SULTs1A3 and 2A1 had no detectable activity toward HO-TAMs.

Adult↗
PubMed1999

A toxicity study of simultaneous administration of Tamoxifen and Diazepam to female Wistar rats.

Tamoxifen (TAM) is used in the treatment of breast cancer and decreases the incidence of breast cancer when given to healthy women for different therapeutic purposes. This expansion of its use calls for further studies of its own potential side effects and those in combination with other prescription drugs. Diazepam (DP) is one such drug normally administered to patients who are under cancer treatment and those who suffer from insomnia. The present study examines the effect of individual and simultaneous administration of TAM and DP at therapeutic dose level of 0.8 mg/Kg/day of TAM and 0.3 mg/Kg/day of DP to normal female Wistar rats for a period of 12 weeks. The drugs were administered orally by mixing it in pellet made by wheat dough. There was no significant change in the terminal body weight and liver weights of animals. The ovary weights in TAM + DP treated animals were significantly decreased. The serum succinate dehydrogenase (SDH) levels were significantly lower in TAM, DP and TAM + DP treated rats and comparatively were lowest in TAM and TAM + DP treated animal groups. Serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT), acid and alkaline phosphatase (ACP & ALP) levels were significantly higher in the three treated groups, but comparatively lower in TAM + DP treated animals when compared to TAM or DP alone treated rats. There was marked increase in liver triglyceride and cholesterol levels in the three treated groups but remarkable decrease in liver glycogen. Total serum cholesterol levels were significantly high in DP and TAM + DP treated rats and total serum triglyceride levels were significantly high only in TAM treated rats. As a whole it can be concluded that DP does not enhance TAM toxicity on simultaneous administration, but on its own when administered individually brings about perturbation in lipid storage and metabolism.

Administration, Oral↗
PubMed2001

Identification and quantification of tamoxifen-DNA adducts in the liver of rats and mice.

A new HPLC gradient system was developed for (32)P-postlabeling analysis to identify and quantify hepatic tamoxifen-DNA adducts of rats and mice treated with tamoxifen. Four stereoisomers of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG(3')(P)-N(2)-TAM), alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen (dG(3')(P)-N(2)-N-desmethyl-TAM), and alpha-(N(2)-deoxyguanosinyl)tamoxifen N-oxide (dG(3')(P)-N(2)-TAM N-oxide) were prepared by reacting either alpha-acetoxytamoxifen, alpha-acetoxy-N-desmethyltamoxifen or alpha-acetoxytamoxifen N-oxide with 2'-deoxyguanosine 3'-monophosphate, and used as standard markers for (32)P-postlabeling/HPLC analysis. Our HPLC gradient system can separate the above 12 nucleotide isomers as nine peaks; six peaks representing two each trans epimers (fr-1 and fr-2) of dG(3')(P)-N(2)-TAM, dG(3')(P)-N(2)-N-desmethyl-TAM and dG(3')(P)-N(2)-TAM N-oxide, and three peaks representing a mixture of two cis epimers (fr-3 and fr-4) of nucleotides. Tamoxifen was given to female F344 rats and DBA/2 mice by gavage at doses of 45 mg/kg/day and 120 mg/kg/day, respectively, for 7 days. Totally 15 and 17 tamoxifen-DNA adducts were detected in rats and mice, respectively; among them 13 adducts were observed in both rats and mice. trans-dG-N(2)-TAM (fr-2) and trans-dG(3')(P)-N(2)-N-desmethyl-TAM (fr-2) were two major adducts in both animals. Except for these two adducts, trans-dG-N(2)-TAM N-oxide (fr-2) was the third abundant adduct that accounted for 6.4% of the total adducts in mice, while this accounted for only 0.3% in rats. A trans-isomer (fr-1) and cis-isomers (fr-3 and -4) of dG(3')(P)-N(2)-TAM, dG(3')(P)-N(2)-N-desmethyl-TAM and dG(3')(P)-N(2)-TAM N-oxide were also detected as minor adducts in both animals except for cis-form of dG-N(2)-TAM N-oxide in rats. Although the administered dose for rats was 2.7-fold less than that for mice, the total adduct level of rats (216 adducts/10(8) nucleotides) were 3.8-fold higher than mice (56.2 adducts/10(8) nucleotides). Thus, these three types of tamoxifen adducts accounted for 95.0 and 92.5% of the total DNA adducts of the rats and mice, respectively. The formation of tamoxifen adducts primarily resulted from alpha-hydroxylation of tamoxifen.

Animals↗
PubMed2002

Preparation of oligodeoxynucleotides containing a diastereoisomer of alpha-(N(2)-2'-deoxyguanosinyl)tamoxifen by phosphoramidite chemical synthesis.

Women treated with an antiestrogen tamoxifen (TAM) for endocrine therapy or prevention of breast cancer show an increased risk of developing endometrial cancer. TAM-DNA adducts have been detected in the liver of rodents treated with TAM and in the endometrium of women taking TAM. The major TAM adducts have been identified as diastereoisomers of trans- and cis-forms of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG-N(2)-TAM) and alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen. In the study presented here, we prepared oligodeoxynucleotides containing a diastereoisomer of dG-N(2)-TAM by phosphoramidite chemical synthesis. Initially, the trans- and cis-forms of alpha-aminotamoxifen (alpha-NH(2)-TAM) were synthesized from alpha-hydroxytamoxifen using the Mitsunobu reaction followed by hydrolysis. Thereafter by coupling the trans- and cis-form of alpha-NH(2)-TAM with the DMT-derivative of 2-fluoro-(O(6)-2-(trimethylsilyl)ethyl)-2'-deoxyinosine, the trans- and cis-forms of DMT-dG-N(2)-TAM, respectively, were prepared in high yield and used in the preparation of the phosphoramidite precursors. Large quantities of oligodeoxynucleotides containing a trans- or a cis-form of dG-N(2)-TAM were prepared efficiently by automated DNA synthesizer. The incorporation of dG-N(2)-TAM adduct into the oligodeoxynucleotides was confirmed using (32)P-postlabeling/polyacrylamide gel electrophoresis analysis. These site-specifically modified oligodeoxynucleotides will be used for exploring biological properties and three-dimensional structure of TAM-DNA adducts.

DNA Adducts↗
PubMed1998

Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status.

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX +/- TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX + TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p = 0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.

Adult↗
PubMed2000

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age.

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.

Aged↗
PubMed1999

Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells.

Tamoxifen (Tam), besides its action as an anti-estrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cancer cells by an unknown mechanism. In this study, we used ER-negative lung cancer cells to clarify such ER-independent inhibitory effect of Tam. We found that Tam induced G1 growth arrest in these cells. However, our results indicated that the expression of G1 cyclins (including D1, 2, 3 and E) was not regulated by Tam in these lung cancer cells. Additionally, the protein levels of G1 acting cyclin-dependent kinases (CDKs), CDK2, 4 and 6, was unaltered in Tam-treated lung cancer cells with the exception of CDK2 expression in H322 cells which was attenuated by Tam in a cell line-specific manner. We next examined the effect of Tam on the expression of cyclin-dependent kinase inhibitors (CDKIs) and our results demonstrated that the expression of p21WAF1 and p27KIP1, but not p57KIP2, was strongly activated by Tam in these cells. The amounts of p21WAF1 and p27KIP1 co-immunoprecipitated with cyclin E were obviously increased after Tam treatment and reduced activity of cyclin E-associated kinases and accumulation of hypo-phosphorylated retinoblastoma (Rb) protein were clearly detected in Tam-incubated cells. No consentaneous induction of CDKIs was found when ER-negative lung cancer cells were incubated with cytotoxic drugs, cisplatin and etoposide, this indicates that enhancement of CDKI expression is not a non-specific effect of Tam. We also found that Tam may up-regulate p21WAF1 expression via transcription activation. Considered together, these results suggest that Tam-induced growth inhibition in ER-negative lung cancer cells is associated with induction of p21WAF1 and p27KIP1.

Antineoplastic Agents, Hormonal↗
PubMed2004

Prognostic significance of endothelial Per-Arnt-sim domain protein 1/hypoxia-inducible factor-2alpha expression in a subset of tumor associated macrophages in invasive bladder cancer.

PURPOSE: Endothelial Per-Arnt-Sim domain protein 1 (EPAS1) is induced under hypoxia and it transactivates a series of genes involved in angiogenesis and energy metabolism. Recent studies showed that EPAS1 is expressed in tumor associated macrophages (TAMs), which have multifaceted roles in tumor progression. We hypothesized that EPAS1 expressed in TAMs may contribute to bladder cancer progression. MATERIALS AND METHODS: Clinicopathological and followup data on 69 patients undergoing radical cystectomy for T1-4N0-2M0 high grade bladder urothelial carcinoma were reviewed. Quantitative immunohistochemical analysis of TAMs and EPAS1 was performed separately in invasive front and in other superficial parts of carcinoma tissues. TAM counts and EPAS1 positive cell counts were compared with pathological variables and cancer specific survival (CSS). RESULTS: The 5-year CSS rate in the 69 patients was 69% at a median followup of 58 months (range 2 to 196). EPAS1 expression was restricted to a small subset of TAMs. Although TAM counts were not associated with T stage or lymph node metastasis, EPAS1 expressing TAM counts were significantly associated with higher T stage. On univariate and multivariate analyses higher EPAS1 expressing TAM counts in invasive front along with higher T stage and positive lymph node metastasis were significantly associated with shorter CSS, while total TAM counts or EPAS1 expressing TAM counts in other superficial parts did not. CONCLUSIONS: Despite limited prognostic effects of total TAMs EPAS1 expressing TAMs were associated with a poor prognosis of invasive bladder cancer, suggesting that EPAS1 expressed in a subset of TAMs mediates bladder cancer progression.

Adult↗
PubMed1998

Chemoprevention of N-nitroso-N-methylurea-induced rat mammary cancer by miso and tamoxifen, alone and in combination.

We examined the effects of a Japanese fermented soybean product, miso, and tamoxifen (TAM), alone and in combination, on N-nitroso-N-methylurea (MNU)-induced rat mammary cancer. Seven-week-old female CD/Crj rats received a single i.v. dose (50 mg/kg body weight) of MNU. After administration of MNU, the rats were divided into 4 groups: regular diet (control), 10% miso diet, regular diet + TAM, and 10% miso diet + TAM. TAM was implanted s.c. in the form of pellets containing 2.5 mg at the same time as MNU was administered. All rats were observed for 18 weeks after MNU administration. Incidence (percentage of rats with tumors) and multiplicity (mean tumors/rat) of mammary tumors were 91% and 4.5 in the control, 77% and 2.4 (P < 0.05) in the 10% miso group, 68% and 1.4 (P <0.01) in the TAM group, and 10% (P < 0.0001 or less) and 0.2 (P < 0.0001) in the 10% miso + TAM group. In the second experiment, the effect of the combination of miso and TAM on established rat mammary tumors was investigated. When the mammary tumors induced by MNU reached 10 to 25 mm, the rats were divided into 3 treatment groups: regular diet, regular diet + TAM, and 10% miso diet + TAM. At 6 weeks after the start of treatment, the mean tumor size in the control and TAM groups was 160% and 141% of the pretreatment value, but a decrease of 85% of the pretreatment value was produced by the combination of miso and TAM, and this was significantly different from both the control and TAM groups (P < 0.01) and P < 0.05, respectively). These results indicate that miso is useful in protecting against mammary cancer and it can be expected to have a potent antitumor effect, especially when used in combination with TAM.

Animals↗
PubMed2004

Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.

We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include alpha -, 3-, and 4'-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to alpha-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

Biotransformation↗
PubMed1997

High frequency of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen.

Pathologic evaluation for adenomyosis in uterine specimens as well as demographic characteristics, health habits and risk factors for endometrial cancer were compared in 28 postmenopausal breast cancer patients with tamoxifen (TAM) treatment and in 11 similar patients without TAM treatment in order to determine the association between postmenopausal TAM exposure and the frequency of adenomyosis. The same comparison was also made between TAM-treated patients with adenomyosis and TAM-treated patients without adenomyosis. Adenomyosis was histologically diagnosed in 53.6% TAM-treated patients and in 18.2% non-TAM patients. Overall, there were no significant statistical differences in all parameters tested between the 2 groups, as well as between the TAM-treated patients with adenomyosis and the TAM-treated patients without adenomyosis. It can be concluded that adenomyosis was significantly more common among postmenopausal breast cancer patients who were treated with TAM as compared to similar patients without TAM treatment (p = 0.0186). This significant high rate of adenomyosis may be attributed to the continuous and unopposed exposure to TAM. It is, however, impossible to predict which postmenopausal breast cancer patient will develop adenomyosis after treatment with TAM.

Aged↗
PubMed1990

Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a randomized clinical trial to determine whether tamoxifen (TAM) plus chemotherapy is more effective than TAM alone in improving disease-free survival (DFS), distant disease-free survival (DDFS), and survival (S) of positive-node, TAM-responsive patients aged greater than or equal to 50 years. Women were randomized among three treatment groups: (1) TAM alone, (2) Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), cyclophosphamide, and TAM (ACT), or (3) melphalan (L-PAM), fluorouracil (5-FU), and TAM (PFT). The PFT arm was later modified so that new patients also received Adriamycin (PAFT). Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone (84% v 67%; P = .0004). An advantage in DDFS and S was also observed after ACT therapy (83% v 73% [P = .04 in the former] and 93% v 85% [P = .04 in the latter]). Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone (83% v 66%, P = .0002 and 85% v 73%, P = .003). PFT patients also fared better in DFS and DDFS than TAM patients (81% v 72%, P = .07 and 85% v 74%, P = .02). Odds ratios consistently favored the three TAM-plus-chemotherapy groups. No significant S advantage is as yet evident in favor of the PAFT or PFT groups. Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM, which was administered simultaneously. The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer. The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy (completed in 63 days) than from prolonged TAM therapy alone.

Aged↗
PubMed1986

Oestrogen agonistic effects of tamoxifen in the uterus of newborn guinea pigs after short and long treatment. Biological and histological studies.

Tamoxifen (TAM) alone or combined with oestradiol (E2) or progesterone (P) was administered to newborn guinea pigs (2 days old) for short (2 days) or a long (12 days) treatment period. TAM alone provoked a great stimulatory effect on uterine growth and DNA content and the effect was particularly intense after the long treatment. These actions were markedly enhanced when TAM was administered together with E2. Following short treatment, the values of the uterine wet weights (mg +/- SD) were as follows: control animals, 142 +/- 15; animals treated with TAM, 298 +/- 53; E2, 335 +/- 15; (TAM + E2), 362 +/- 16. The values after the long treatment were 177 +/- 30, 555 +/- 93, 709 +/- 117 and 1263 +/- 222, respectively. Histological studies showed that TAM provoked morphological changes in both the endometrium and the myometrium. The effects were particularly great on the height of the luminal epithelial cells and on the uterine glands. After 2 days of treatment with E2, TAM and P, the thickness of the luminal epithelium, which was 13.5 micron +/- 1.5 in the control animals, increased as follows: TAM, 19 microns +/- 1.7; E2, 20.3 microns +/- 3.3; (TAM + E2), 30.5 microns +/- 5; P, 12 microns +/- 0.9 and (P + TAM), 19.7 microns +/- 1.2. The values after the 12 day treatment were: controls, 20.8 microns +/- 1.8; TAM, 27.4 microns +/- 2.1; E2, 32 +/- 3; (TAM + E2), 43 microns +/- 5; P, 17.8 microns +/- 1.2 and (P + TAM), 23.6 microns +/- 1.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance.

Human breast tumors that are initially responsive to tamoxifen (TAM) eventually relapse during treatment. Estrogen receptor (ER) expression and function are often preserved in these tumors, and clinical evidence suggests that this relapse may be related to TAM's known agonistic properties. ER can interact with the activator protein-1 (AP-1) transcription factor complex through protein-protein interactions that are independent of ER DNA binding and, in certain ER-positive cells, this may allow TAM to exert an agonist response on AP-1-regulated genes. We, therefore, assessed both AP-1 DNA binding and the known AP-1 activating enzyme, c-Jun NH2-terminal kinase (JNK), in a panel of 30 ER-positive primary human breast tumors with acquired TAM resistance, as compared to a matched panel of 27 untreated control ER-positive breast tumors and a separate control set of 14 primary tumors, which included 7 ER-positive tumors that were growth-arrested by 3 months of preoperative TAM. AP-1 DNA binding activity was measured from cryopreserved tumor extracts using a labeled oligonucleotide probe containing a consensus AP-1 response element by electrophoretic mobility shift assay. JNK was first extracted from the tumor lysates by incubation over a Sepharose-bound c-Jun(1-89) fusion protein, and its activity was then measured by chemiluminescent Western blot by detection of the phosphorylated product using a phospho-Jun(Ser-63)-specific primary antibody. The set of control ER-positive breast tumors growth arrested by TAM showed no significant difference from untreated control tumors in their AP-1 DNA binding and JNK activities. In contrast, there was a significant (P < 0.001) increase in mean AP-1 DNA binding activity for the panel of ER-positive TAM-resistant (TAM-R) tumors as compared to its matched control panel of untreated tumors. Mean JNK activity in the TAM-R tumors was also significantly higher than that found in the untreated tumors (P = 0.038). Overall, there was no significant correlation between JNK activity and AP-1 DNA binding; however, regression analysis showed that, for any given level of JNK activity, the TAM-R tumors possessed a 3.5-fold increase in AP-1 DNA binding activity as compared to the untreated tumors. These findings indicate that, when compared to untreated ER-positive primary breast tumors, TAM-R tumors demonstrate significantly increased levels of AP-1 DNA binding and JNK activity, consistent with experimental models suggesting that TAM-stimulated ER-positive tumor growth may be mediated by enhanced AP-1 transcriptional activity. These observations support the need for further evaluation of these markers in breast tumors as predictors of TAM resistance.

Aged↗
PubMedDate not supplied

Relationships between tumor-associated macrophages and clinicopathological factors in patients with colorectal cancer.

BACKGROUND: As macrophages have both tumor promoting and inhibiting effects, tumor-associated macrophages (TAM) play a complex role in the regulation of cancer progression and tumor growth. The clinicopathological significance of TAMs in human colorectal cancer remains unclear. MATERIALS AND METHODS: We investigated the relationships between TAM IF (invasive front), TAM TS (tumor stroma), prognosis and clinicopathological factors in 30 patients with colorectal cancer. Moreover, MVD (microvessel density) was examined for correlation with these factors. TAMs were detected by immunohistochemistry using the anti-CD68 antigen, KP1 mouse monoclonal antibody. MVD was determined by counting the number of CD34-positive vessels. RESULTS: Low TAM IF and TAM TS tended to occur with more advanced colorectal cancer, although this finding was not statistically significant. High TAM IF tended to be found in patients with a good prognosis or those with less recurrence or worsening of their condition. MVD was significantly higher in patients with lymph node metastasis, lymphatic invasion or more advanced tumors than stage III (TNM). Although the correlation between TAM IF, TAM TS and MVD was not statistically significant, the correlation between TAM IF and TAM TS was statistically significant. CONCLUSION: These results suggest that TAMs may act as one line of defence against malignant cells in patients with colorectal cancer.

Adult↗
PubMed1982

Tamoxifen and oophorectomy in the treatment of recurrent breast cancer: a Southwest Oncology Group Study.

The relatively short survival following chemotherapy in patients with metastatic carcinoma of the breast and the introduction of antiestrogens has led to renewed interest in the hormonal therapy of breast cancer. Pritchard et al. (Cancer Treat. Rep., 64: 787-796, 1980) have recently stated that response to the antiestrogen tamoxifen (TAM) strongly predicts a subsequent response to oophorectomy in premenopausal patients. The Southwest Oncology Group administered TAM to pre- and postmenopausal women with first recurrence of breast cancer. Following response and subsequent relapse, or after no response, patients underwent an oophorectomy while continuing on TAM. None of 14 premenopausal patients who responded to TAM had a response to oophorectomy plus TAM, while 5 of 22 had a remission with oophorectomy plus TAM after initially failing with TAM alone. The reverse was seen in postmenopausal women; 4 of 18 responders to TAM subsequently responded to oophorectomy plus TAM, but none of 18 TAM failures responded to oophorectomy plus TAM. These results suggest that in the premenopausal women the TAM dose may be insufficient to block all estrogen action and that oophorectomy, by removing the major source of estrogen, can result in a more effective antiestrogen action of TAM leading to a response. No explanation is readily available for the results in postmenopausal patients.

Breast Neoplasms↗