The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer

The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.     

Influence of ACTH on aminoglutethimide induced reduction of plasma steroids in postmenopausal breast cancer

In postmenopausal women estrogens are mainly produced by aromatase mediated conversion of adrenal 4-ene-steroids in peripheral tissue, a process which is inhibited by aminoglutethimide (AG). To assess possible fluctuations in adrenocortical steroid secretion and the impact on plasma estrogen levels the effect of physiological ACTH doses was studied in 24 postmenopausal women with advanced breast cancer treated with AG 4 X 250 mg and hydrocortisone 2 X 10 + 1 X 20 mg daily. Synthetic 1-24 ACTH (Synacthen) 0.5 mg was injected i.m. at 8.30 a.m. (t0), 10 h after the last AG + hydrocortisone dose. A definite decrease of t0 levels of the 5-ene-steroids dehydroepiandrosterone and its sulphate, and androstenediol was found at 1 month, with no further decrease at 2 months. 5-Ene-steroids responded decreasingly to ACTH under treatment. The 4-ene-steroids progesterone, androstenedione and testosterone, before and after ACTH were not suppressed by 1 or 2 months of treatment. Basal (t0) cortisol remained normal. Cortisol response to ACTH (delta max) was drastically diminished, but still present. Plasma estrogens were decreased. Estradiol (E2) at t0, being low from the start, fell by 50%. Estrone (E1) at t0 dropped to 30%. ACTH had measurable influence on E2, but did cause a transient increase of E1 (mean delta max 40% of baseline value) under treatment. The following conclusions are drawn: Treatment with AG + hydrocortisone for postmenopausal breast cancer reduces plasma estrogens, particularly E1. Plasma E1 reduction is not stable as demonstrated by the response to a physiological ACTH dose. The responses of 4-ene-steroids to ACTH are not affected by treatment, except for the response of cortisol which is significantly diminished.     

Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--I. General findings

The influence of oral high dose progestin (medroxyprogesterone acetate, MPA and megestrol acetate, MA) treatment on serum hormone levels was studied in ten postmenopausal women with advanced breast cancer. The gonadotropins and ACTH were significantly reduced by greater than 50 and 23%, respectively. Serum cortisol, DHEAS, androstenedione and testosterone were all significantly reduced (mean reduction between 64 and 76%), while serum estrone, estradiol and estrone sulfate were significantly reduced by 20-30%. Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CGB) were reduced by 68 and 25%, respectively. Although the dose of MA used (160 mg/day) was only 1/6 of the MPA dose (1000 mg/day), the mean serum level of MA was 2-fold higher than the mean serum level of MPA. MPA treatment gave a more pronounced suppression of SHBG than MA treatment, while estrone sulfate levels were more suppressed by MA. These findings suggest a differential effect of MPA and MA on certain plasma hormones, possibly of importance for understanding the mechanism of action of the two drugs. The reduction of estrone sulfate may be beneficial for the action of MA against breast cancer.     

Effects of flutamide and aminoglutethimide on plasma 5 alpha-reduced steroid glucuronide concentrations in castrated patients with cancer of the prostate

Plasma levels of androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-diol-G) and androsterone glucuronide (ADT-G) have been found to be effective markers of C-19 steroid metabolism in periphery in man. The present study has been performed in order to study in castrated patients the effect of antiandrogen administered alone or in combination with aminoglutethimide (AG) on the metabolism of adrenal C-19 steroid. Ten castrated patients with prostatic cancer received flutamide (FLU) alone for 2 months and, afterwards, the combined therapy of FLU and AG for 2 months. Antiandrogen treatment alone reduces the levels of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone glucuronide (DHEA-G) and androstenedione (4-ene-dione) by 43, 34 and 38% (P less than or equal to 0.01) respectively while dehydroepiandrosterone (DHEA), androst-5-ene-3 beta,17 beta-diol (5-ene-diol) and androst-5-ene-3 beta,17 beta-diol-glucuronide (5-ene-diol-G) levels show a nonsignificant inhibition. In these patients, plasma 3 alpha-diol-G and ADT-G concentrations are nonsignificantly stimulated to 122 and 143%. Moreover, when patients were receiving the combined administration of FLU and AG, adrenal C-19 steroids were further inhibited while both 3 alpha-diol-G and ADT-G show a small but nonsignificant decrease. Our data indicate that the antiandrogen increases the formation and/or the metabolism of adrenal C-19 steroids into steroid glucuronides.     

ARIMIDEX: A new oral, once-a-day aromatase inhibitor

ARIMIDEX® is a potent and selective aromatase inhibitor undergoing evaluation as a treatment for postmenopausal women with advanced breast cancer. Studies examining the pharmacology of ARIMIDEX were conducted in both animals and humans. In animals, ARIMIDEX elicits maximal aromatase suppressive activity at a dose of approx. 0.1 mg/kg, does not alter adrenal steroid hormone biosynthesis, and at a dose of 1 mg/kg, has no other pharmacologic effects other than aromatase inhibition. In this overview, the pharmacodynamic, pharmacokinetic, and safety profiles of single and multiple daily doses of ARIMIDEX are reported in humans. Daily doses of 1–10 mg of ARIMIDEX suppressed estradiol levels to the maximum degree measurable using sensitive estrogen assays. ARIMIDEX had no clinically significant effects on the response of cortisol and aldosterone to ACTH stimulation. Absorption of ARIMIDEX was rapid, with maximum plasma concentrations occurring within 2 h after oral administration. Plasma concentrations of ARIMIDEX rose with increasing doses of the drug. The elimination half-life of ARIMIDEX in humans ranged from 30 to 60 h. Consistent with the long plasma half-life, steady state plasma concentrations were 3–4-fold higher than plasma concentrations observed after single administration of 1, 3, 5, or 10 mg doses. Long term treatment of breast cancer patients with 10 mg/day has continued in 17 patients without an escape of estradiol suppression. Previously, these patients had received on average 2.6 systemic treatments for breast cancer and had significant metastatic disease. Three of the 17 patients continued ARIMIDEX treatment for 20 months and beyond. Given the number of previous treatments and tumor burden at the start of treatment, the response to ARIMIDEX treatment is encouraging. Phase III studies are now underway to assess the efficacy and safety of ARIMIDEX in the treatment of advanced breast cancer.     

Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators

Despite the dramatic fall in plasma estrogen levels at menopause, only minor differences in breast tissue estrogen levels have been reported comparing pre- and postmenopausal women. Thus, postmenopausal breast tissue has the ability to maintain concentrations of estrone (E₁) and estradiol (E₂) that are 2–10- and 10–20-fold higher than the corresponding plasma estrogen levels. This finding may be explained by uptake of estrogens from the circulation and/or local estrogen production. Local aromatase activity in breast tissue seems to be of crucial importance for the local estrogen production in some patients while uptake from the circulation may be more important in other patients. Beside aromatase, breast tissue expresses estrogen sulfotransferase and sulfatase as well as dehydrogenase activity, allowing estrogen storage and release in the cells as well as conversions between estrone and estradiol. The activity of the enzyme network in breast cancer tissue is modified by a variety of factors like growth factors and cytokines. Aromatase inhibitors have been used for more than two decades in the treatment of postmenopausal metastatic breast cancer and are currently investigated in the adjuvant treatment and even prevention of breast cancer. Novel aromatase inhibitors and inactivators have been shown to suppress plasma estrogen levels effectively in postmenopausal breast cancer patients. However, knowledge about the influence of these drugs on estrogen levels in breast cancer tissue is limited. Using a novel HPLC-RIA method developed for the determination of breast tissue estrogen concentrations, we measured tissue E₁, E₂ and estrone sulfate (E₁S) levels in postmenopausal breast cancer patients before and during treatment with anastrozole. Our findings revealed high breast tumor tissue estrogen concentrations that were effectively decreased by anastrozole. While E₁S was the dominating estrogen fraction in the plasma, estradiol was the estrogen fraction with the highest concentration in tumor tissue. Moreover, plasma estrogen levels did not correlate with tissue estrogen concentrations. The overall experience with aromatase inhibitors and inactivators concerning their influences on breast tissue estrogen concentrations is summarized.     

Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--II. A differential effect of megestrol acetate and medroxyprogesterone acetate on serum estrone sulfate and sex hormone binding globulin

Serum estradiol, estrone, estrone sulfate and sex hormone binding globulin were measured in 10 postmenopausal patients with advanced breast cancer receiving sequential treatment with medroxyprogesterone acetate and megestrol acetate. Treatment with megestrol acetate caused a non-significant reduction in serum estradiol (mean reduction of 19%, 0.05 less than P less than 0.1) but significant reductions in serum estrone (mean reduction of 20%, P less than 0.02) and serum estrone sulfate (mean reduction of 54%, P less than 0.005) compared to treatment with medroxyprogesterone acetate. In contrast, treatment with medroxyprogesterone acetate reduced serum sex hormone binding globulin more compared to treatment with megestrol acetate (mean reduction of 69%, P less than 0.01). These findings suggest that the two progestins have differential effects on serum hormone levels. The finding that treatment with megestrol acetate causes a significant reduction in serum estrone sulfate level warrants further investigations of this potentially important mechanism of action of this drug in advanced breast cancer.     

Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels

The adipocytokine leptin has recently been shown to enhance the expression of aromatase via promoter II and I.3 using an AP-1 motif. Thus, we evaluated the correlation between plasma leptin concentrations and total body aromatization (TBA) as well as plasma levels of estrone (E(1)), estradiol (E(2)) and estrone sulfate (E(1)S) in postmenopausal breast cancer patients. Twenty-two postmenopausal women with metastatic breast cancer, participating in tracer studies for the measurement of total body aromatization (TBA) in vivo, were available. In addition, blood samples for plasma estrogens and leptin measurements were available from another 22 breast cancer patients and 114 healthy postmenopausal women participating in the mammography-screening program. Values for TBA varied from 1.46 to 4.72% while plasma leptin levels ranged from 1.83 to 95.51 ng/ml in the same group of patients. All plasma estrogen levels were in the normal range expected for postmenopausal women. We found a significant correlation between pretreatment leptin levels and TBA (r(s) 0.452, P=0.01). In contrast, basal levels of TBA did not correlate to body mass index (BMI) in the same group of patients. Plasma leptin levels correlated to plasma levels of estradiol (r(s) 0.659, P=0.007), and estrone sulfate (r(s) 0.562, P=0.01) in the group of breast cancer patients (n=44) as well as in the group of healthy postmenopausal women (estradiol, r(s) 0.363, P< or =0.001, estrone sulfate r(s) 0.353, P< or =0.001). In conclusion, we found plasma leptin levels to correlate to TBA in breast cancer patients and to plasma levels of estradiol and estrone sulfate in breast cancer patients as well as in healthy postmenopausal females. These findings suggest that leptin may influence on aromatase activity in vivo, providing a possible link between body weight and plasma estrogen levels as well as breast cancer risk.     

Steroidal oxathiazine inhibitors of estrone sulfatase

The presence of estrone sulfatase in breast tumors and the high levels of circulating estrone sulfate may contribute the major portion of estrogen synthesized locally in breast tissues through conversion of estrone sulfate to estrone by the enzyme. Using inhibitors of estrone sulfatase for the treatment of estrogen-dependent (estrogen receptor positive, ER(+)) breast cancer could be a very effective therapeutic strategy for the treatment of estrogen-dependent breast tumors in postmenopausal women. Therefore, we designed and synthesized several steroidal 2',3'-oxathiazines that inhibit estrone sulfatase and have greatly reduced estrogenic side effects. Our in vitro studies indicate that the oxathiazine compounds have inhibitory activity on estrone sulfatase in MCF-7 human breast cancer cells. These estrone sulfatase inhibitors (ESIs) also inhibit the growth of MCF-7 cells induced by estrone sulfate. In addition, our in vivo experiments demonstrate that our ESIs have moderate antitumor activity against MCF-7 breast cancer xenografts in Balb/c athymic nude mice. The synthesis and biological activity of a number of these unique steroidal ESIs are described.     

阿霉素与青蒿素半乳糖苷联合用药对乳腺癌细胞的体外抑制作用及机制

目的：青蒿素及其衍生物具有抗癌活性,本研究旨在探讨阿霉素（DOX）与青蒿素半乳糖苷（AG）联合用药对乳腺癌细胞的体外抑制作用及机制。方法：DOX与AG联合对乳腺癌MCF-7细胞株进行干预,MTT法评价二者对癌细胞增殖的影响;流式细胞计量术检测细胞凋亡;免疫印迹法检测凋亡相关蛋白表达情况。结果：DOX与AG联合作用对MCF-7细胞增殖抑制率最高可达91．6％,均显著高于同浓度DOX或AG抑制效果（P〈0．01）,且浓度分别为10IzM和20μM量效比最佳。10斗MDOX＋20μMAG联合干预纽癌细胞凋亡率为19．8％,显著高于对照组及单用10μMDOX或20／zMAG干预组。DOX与AG联合给药比单独应用其中一种均更加显著激活caspase级联信号通路,进而更加有效的促进癌细胞凋亡。结论：DOX和AG联合用药对人乳腺癌MCF-7细胞具有协同抑制效应,其机制可能与caspase家族介导的蛋白酶级联反应以及PARP裂解失活有关。这项研究为提高DoX治疗乳腺癌的有效性提供了新的思路。     

The pharmacology of letrozole

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.     

Lack of inhibition of placental estrone sulfatase and aromatase enzymes by vitamin D3 and its analogs

The aromatase and estrone sulfatase enzymes are important sources of biologically active estrogens in postmenopausal women with breast cancer. Promising initial results in the treatment of endocrine-responsive breast cancer have been exhibited by 125-dihydroxyvitamin D₃ and the synthetic vitamin D analogues MC903 and EB1089. However, these compounds together with vitamin D₃ and vitamin D₃ sulfate did not inhibit the human placental aromatase enzyme when assayed up to 20 μm. Only vitamin D₃ sulfate and 125-dihydroxyvitamin D inhibited the estrone sulfatase activity in human placental microsomes, albeit at high concentration (32 and 37% inhibition, respectively with 50 μm each inhibitor). It is unlikely that inhibition of aromatase or estrone sulfatase enzymes contribute to the inhibitory effect of this group of compounds on breast cancer cells in vivo.     

Aromatization inhibition alone or in combination with GnRH agonists for the treatment of premenopausal breast cancer patients.

Aromatase inhibition in postmenopausal women causes a marked fall in the plasma levels of oestrogens and is an effective treatment for breast cancer, however, trials with aminoglutethimide found that this aromatase inhibitor was ineffective in suppressing plasma oestrogen levels in premenopausal breast cancer patients. We found that the more potent inhibitor, 4-hydroxyandrostenedione (4-OHA), which can suppress oestrogen synthesis in rodents and non-human primates with intact ovarian function, was also unsuccessful as an oestrogen suppressant in premenopausal women at its maximum tolerated dose (500 mg/week i.m.). GnRH agonists are effective suppressants of ovarian oestrogen synthesis but oestrogen production from peripheral sites is unaffected. Our studies of a combination of the GnRH agonist goserelin and 4-OHA demonstrated that the combination caused greater oestrogen suppression than goserelin alone and led to objective clinical response in 4/6 breast cancer patients after their relapse from treatment with goserelin as a single agent. The combination of a GnRH agonist and an aromatase inhibitor should be subjected to clinical trials.     

Aminoglutethimide--a new endocrine therapy in breast cancer. A cancer research review

Aminoglutethimide is an effective treatment for advanced postmenopausal breast cancer, acting in a novel way. It inhibits peripheral and tumour aromatase, which converts androgens to oestrogens. Marked suppression of oestrone and oestradiol is produced. Aminoglutethimide was used as an inhibitor of adrenal steroid biosynthesis, but the concentrations required to inhibit aromatase in vitro are 10 times lower. This has led to its clinical evaluation in much lower doses. Doses of 125 mg twice daily produce oestrogen suppression equivalent to conventional doses of 1 g daily, and also similar tumour responses. Toxicity is much reduced by the lower dose.     

4-Hydroxyandrostenedione treatment for postmenopausal patients with breast cancer.

Patients (186) with locally advanced or metastatic breast cancer were treated with the aromatase inhibitor 4-hydroxyandrostenedione given parenterally at 3 different doses. 21% of patients responded to treatment, 93% of objective responders whose oestrogen receptor (ER) status was known had ER positive tumours. The drug was well-tolerated particularly at a dose of 250 mg i.m. every fortnight. At this dose, only 4/96 (4%) patients had to discontinue treatment. We conclude that 4-hydroxyandrostenedione is a well-tolerated form of endocrine treatment for postmenopausal patients with breast cancer.     

Beneficial role of aminoguanidine on acute cardiomyopathy related to doxorubicin-treatment

Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic that has cardiotoxicity as a major side effect. One mechanism of this toxicity is believed to involve the reactive oxygen radical species (ROS); these agents likely account for the pathophysiology of DOX-induced cardiomyopathy. Aminoguanidine (AG) is an effective antioxidant and free radical scavenger which has long been known to protect against ROS formation. We investigated the effects of AG on DOX-induced changes in thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content. The rats were divided into four groups:1) Control; 2) DOX group; injected intraperitoneally (i.p.) with DOX 20 mg/kg in a single dose 3) AG-treated group; injected i.p. in single dose of 20 mg/kg DOX plus 100 mg/kg AG 1 h before the DOX for 3 days, 4) AG group; injected i.p. with AG 100 mg/kg for 3 days. DOX administration to control rats increased TBARS and decreased GSH levels. AG administration before DOX injection caused significant decrease in TBARS and increase in GSH levels in the heart tissue when compared with DOX only. Morphological changes, including severe myocardial fibrosis and inflammatory cell infiltration were clearly observed in the DOX-treated heart. AG reversed the DOX-induced heart damage. Therefore AG could protect the heart tissue against free radical injury. The application of AG during cancer chemotherapy may attenuate tissue damage and improve the therapeutic index of DOX.     

Development of (p-O-sulfamoyl)-N-alkanoyl-phenylalkyl amines as non-steroidal estrone sulfatase inhibitors

Estrogen levels in breast tumors of postmenopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ formation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Thus, inhibitors of estrone sulfatase are potential agents for treatment of estrogen-dependent breast cancer. Several steroidal compounds have been developed that are potent estrone sulfatase inhibitors, most notably estrone-3-O-sulfamate. However, these compounds and their metabolites may have undesired effects, including estrogenicity. To avoid the problems associated with a potentially active steroid nucleus, we designed and synthesized a series of nonsteroidal estrone sulfatase inhibitors, the (p-O-sulfamoyl)-N-alkanoyl phenylalkyl amines. The compounds synthesized vary in the length of their alkanoyl chain and in the number of carbons separating the phenyl ring and the carbonyl carbon. The ability of these compounds to inhibit estrone sulfatase activity was tested using human placental microsomes and intact cultured human breast cancer cells. Estrogenicity was also evaluated, using growth of estrogen-dependent human breast cancer cells. All of the test compounds inhibited estrone sulfatase activity of human placental microsomes to some extent, with the most effective compound having an IC50 value of 72 nM. In general, compounds with longer alkanoyl chains (12-14 carbons) were more effective than those with shorter chains. The test compounds also inhibited estrone sulfatase activity in intact cultures of MDA-MB-231 human breast cancer cells. Again, the longer chain compounds were more effective. In both the placental and breast cancer cell sulfatase assays, the optimal distance between the phenyl ring and the carbonyl carbon was 1-2 carbons. The MCF-7 cell proliferation assay revealed that estrone and estrone-3-O-sulfamate were both estrogenic, but the (p-O-sulfamoyl)-N-alkanoyl phenylalkyl amines were not. Our data indicate the utility of (p-O-sulfamoyl)-N-alkanoyl phenyl alkylamines for inhibition of estrone sulfatase activity. Furthermore, our data support the concept that nonsteroidal estrone sulfatase inhibitors may be useful as therapeutic agents for estrogen-dependent breast cancers.     

Development of novel steroid sulfatase inhibitors; II. TZS-8478 potently inhibits the growth of breast tumors in postmenopausal breast cancer model rats

In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.     

The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer

Fadrozole hydrochloride at a dose of 2 mg b.i.d. has been shown to be an effective aromatase inhibitor in advanced stage breast cancer patients as determined by its ability to significantly suppress endogenous estrogen biosynthesis over a 12-week period. Continued suppression of circulating estrogen levels over a prolonged period has not yet been examined in published reports. In this study, we report the extended use of fadrozole hydrochloride at a maintenance dose of 2 mg b.i.d. in a cohort of 11 patients extending to 973 days of therapy. Results show that the degree of suppression of plasma and urinary estrogens was maintained in all patients throughout the extended period of drug use. Continued estradiol suppression of over 50% or greater from baseline was observed, as was continued suppression of estrone to over 80% from baseline. Cortisol determinations after 9 months of treatment showed no suppression from baseline. The aldosterone values and responses to cortrosyn stimulation continued to be suppressed as first noted following the initial 3 months of the core clinical trial. Objective tumor response noted in the core clinical trial did not change until disease progression. The findings suggest that fadrozole hydrochloride maintains its ability to suppress the aromatase enzyme during long term use. No observable escape from suppression of plasma and urinary estrogens occurred during prolonged treatment.