Effect of Concomitant Administration of Clodronate and Estramustine Phosphate on their Bioavaibility in Patients with Metastasized Prostate Cancer

Abstract: Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.     

The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent

Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Fridén B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic.     

Diverging effects of 5-HT3 receptor antagonists ondansetron and granisetron on estramustine-inhibited cellular potassium transport

We used 86Rb+ (K+ analogue) to study potassium influx during the interaction of highly specific 5-HT3-receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 micromol/l) for 120 min. reduced 86Rb+ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 micromol/l), but augmented by granisetron (0.1 micromol/l). Serotonin (1.0 micromol/l) antagonized ondansetron inhibition and restored granisetron-augmented reduction of estramustine phosphate-induced 86Rb+ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na+, K+, 2Cl- -cotransport activity whereas Na+, K+, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate-induced reduction of 86Rb+ influx was due to increased Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport whereas augmentation of estramustine phosphate-induced reduction of 86Rb+ influx by granisetron, or combination of 5-HT3 receptor antagonists with serotonin was due mainly to inhibition of cellular Na+, K+, ATPase activity Thus, ondansetron possesses a distinct ability to reverse K+ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport activity. Highly 5-HT3 receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.     

Pilot study on the growth inhibition by estramustine phosphate (Estracyt) of rat mammary tumours sensitive and insensitive of oestrogen.

Rat mammary tumours induced by 7,12-dimethylbenz(a)anthracene had a higher concentration of 3H and 14C than muscle after injection of estramustine phosphate labelled with 3H in the oestrogen moiety and 14C in the alkylating moiety. Thin-layer chromatography showed that dephosphorylated estramustine phosphate was present in the tumours but no free oestradiol-17beta. The uptake of the drug in the tumours was parallelled by a dose dependant retardation of tumour growth and a prevention of tumour number increase. Estramustine phosphate also retarded growth of mammary tumours resistant to treatment with oestradiol-17 beta. It is concluded that estramustine phosphate has a greater effect on tumour growth than oestrogen.     

Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells.

Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5-15 microM) and PSC 833 (5 microM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5-15 microM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.     

Inhibition of T lymphocyte activation by estramustine: dose-dependent interference with IL-2 production and later proliferation events

Estramustine, a nitrogen mustard derivative of estradiol-17 beta widely used for treatment of prostatic cancer, was found to inhibit the proliferative response of mouse lymphocytes to T (concanavalin A) and B (lipopolysaccharide) cell mitogens in vitro. Concanavalin A-induced lymphoproliferation was considerably more sensitive to the antiproliferative effect of estramustine than lipopolysaccharide-stimulated proliferation. The concentration of estramustine selectively inhibiting T lymphocyte proliferation was only active when present during the first 24 h of culture and could be overcome by exogenously added interleukin 2. Estramustine was shown to directly inhibit the production of interleukin 2 in concanavalin A-stimulated lymphocyte cultures without affecting the expression of interleukin 2 receptors. Thus the preferential inhibitory effect of estramustine on mitogen-induced T lymphocyte activation is apparently mediated by interference with the production or release of interleukin 2.     

Docetaxel in prostate cancer

In contrast to several other tumor types, there has been relatively little experience with docetaxel in hormone-refractory prostate cancer. However, two phase II trials investigated the combination of docetaxel with estramustine, and reported prostate-specific antigen response rates of 69 and 74% and objective responses in 23% and 57% of patients. This activity is comparable with that of other estramustine combinations. However, there is uncertainty about whether estramustine itself should be omitted from therapy because of its emetogenic and thromboembolic potential, and also over the optimal schedule of docetaxel to avoid neutropenia. Preliminary data suggest that weekly docetaxel, with or without limited exposure to estramustine, may provide the right balance between efficacy and tolerability. Phase III studies now in progress are comparing regimens containing docetaxel and estramustine with a recent standard therapy consisting of mitoxantrone plus prednisone. In the future, the efficacy of docetaxel plus estramustine may be enhanced by adding agents to this regimen.     

Pilot Study on the Growth Inhibition by Estramustine Phosphate (Estracyt®) of Rat Mammary Tumours Sensitive and Insensitive to Oestrogen

Abstract Rat mammary tumours induced by 7,12-dimethylbenz(a)anthracene had a higher concentration of ³H and ¹⁴C than muscle after injection of estramustine phosphate labelled with ³H in the oestrogen moiety and ¹⁴C in the alkylating moiety. Thin-layer chromatography showed that dephosphorylated estramustine phosphate was present in the tumours but no free oestradiol-17β. The uptake of the drug in the tumours was parallelled by a dose dependant retardation of tumour growth and a prevention of tumour number increase. Estramustine phosphate also retarded growth of mammary tumours resistant to treatment with oestradiol-17β. It is concluded that estramustine phosphate has a greater effect on tumour growth than oestrogen.     

Diverging Effects of 5‐HT3 Receptor Antagonists Ondansetron and Granisetron on Estramustine‐Inhibited Cellular Potassium Transport

Abstract: We used ⁸⁶Rb⁺ (K⁺ analogue) to study potassium influx during the interaction of highly specific 5‐HT₃‐receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 μmol/l) for 120 min. reduced ⁸⁶Rb⁺ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 μmol/l), but augmented by granisetron (0.1 μmol/l). Serotonin (1.0 μmol/l) antagonized ondansetron inhibition and restored granisetron‐augmented reduction of estramustine phosphate‐induced ⁸⁶Rb⁺ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na⁺, K⁺, 2Cl^? ‐cotransport activity whereas Na⁺, K⁺, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate‐induced reduction of ⁸⁶Rb⁺ influx was due to increased Na⁺, K⁺, ATPase and Na⁺, K⁺, 2Cl^?‐cotransport whereas augmentation of estramustine phosphate‐induced reduction of ⁸⁶Rb⁺ influx by granisetron, or combination of 5‐HT₃ receptor antagonists with serotonin was due mainly to inhibition of cellular Na⁺, K⁺, ATPase activity. Thus, ondansetron possesses a distinct ability to reverse K⁺ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na⁺, K⁺, ATPase and Na⁺, K⁺, 2Cl^? ‐cotransport activity. Highly 5‐HT₃ receptor‐specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.     

Drug treatment of breast cancer.

Breast cancer is the most common malignancy of women in the United States, affecting one out of every 13 women at some time in their lives. Although only 10% of patients have demonstrable distant metastases at the time of diagnosis, a majority will eventually die of disseminated disease. Chemotherapy was formerly considered to be the treatment of last resort in patients with breast cancer, reserved for those who had failed surgery, radiotherapy and hormonal manipulation. However, combination chemotherapy has now been shown to be highly effective. The most active drug combinations produce objective tumour regression in about 60% of patients with advanced disease. Parallel to the development of effective chemotherapy, there has been a renewal of interest in hormonal therapy. The ability to predict whether or not a patient will respond to hormonal therapy has been improved significantly by the clinical application of the oestrogen receptor assay. The selection of a specific treatment for the patients with advanced breast cancer must be individualised. It should take into account a number of prognostic variables, including: sites of metastatic involvement; total extent of disease; disease free interval; menopausal status; and the presence or absence of oestrogen receptor in tumour tissue. The final decision regarding treatment should then be based not only on the probability of response, but also on the anticipated degree of toxicity. Current efforts to improve the management of advanced breast cancer include the development of more effective drug regimens and the combination of chemotherapy with hormonal manipulation. For instance, it would appear that in premenopausal patients, the combination of chemotherapy with oophorectomy may yield results that are superior to those achieved with either treatment alone. The most promising development in the management of early breast cancer has been the use of chemotherapy as an adjuvant treatment in patients with operable disease.     

Administration of estramustine in response to changes in the prostate-specific antigen and Karnofsky index in the treatment of prostate cancer

Androgen ablation is palliative and does not cure advanced prostate cancer. The hormone-sensitive cells die and the hormone-resistant cells overgrow, resulting in disease progression. The drug of choice for secondary treatment is estramustine (Estracyt). The success of the therapy is followed by changes of the prostate-specific antigen level and Karnofsky scale. In the present study, the results of estramustine treatment of 79 patients with advanced prostate cancer in 12 hospitals were evaluated. The mean prostate-specific antigen level improved for 6 months, but rose from the ninth month on. The improvement in the subjective condition of the patients paralleled the change in the prostate-specific antigen level. The short time of improvement was a consequence of the very high prostate-specific antigen level and the poor general condition. Estramustine administration is recommended when the prostate-specific antigen level becomes more than doubled following primary treatment. At a starting prostate-specific antigen level of > 100 ng/ml, the treatment leads to total androgen blockade. If the prostate-specific antigen level has not decreased after treatment for 3 months, the secondary strategy is to apply chemotherapy.     

Treatment of prostate cancer

The epidemiology, histopathology, diagnosis and staging, and treatment of prostate cancer are reviewed. Prostate cancer, one of the most common malignancies occurring in men over age 50, will strike an estimated 103,000 men in the United States in 1989. More than 95% of prostatic tumors are adenocarcinomas. Tumors are graded on the basis of their degree of differentiation. Most afflicted men initially complain of difficulty in starting the urinary stream and of urinary bleeding, dribbling, and retention. Urinary obstruction may be present in advanced disease, and anemia, anorexia, and bone pain are common in metastatic disease. Prostatectomy and irradiation are used to treat disease localized to the prostate; the prognosis for such patients is good. Survival is diminished in cases of locally advanced and metastatic disease. Symptomatic metastatic disease is treated by hormonal manipulation through orchiectomy and administration of exogenous estrogens (diethylstilbestrol), luteinizing hormone-releasing hormone analogs (leuprolide and goserelin), and antiandrogens (cyproterone acetate, flutamide, and others). Some 70-80% of patients respond to hormonal therapy for periods of up to three years. After relapse occurs, salvage hormonal therapies (aminoglutethimide and ketoconazole) may be attempted to prolong survival. Fluorouracil, doxorubicin, mitomycin, cisplatin, cyclophosphamide, methotrexate, and estramustine have also been administered, with mixed results. Once relapse occurs in prostate cancer patients after initial hormonal therapy, the response to salvage hormonal or cytotoxic therapy is minimal; in the future, total androgen blockade and methods of decreasing drug resistance may be used to prolong survival.     

Exemestane: a review of its use in postmenopausal women with advanced breast cancer

Exemestane is an orally active irreversible steroidal aromatase inactivator that effectively suppresses in vivo aromatase activity and circulating estrogen levels in postmenopausal women with advanced breast cancer. In clinical trials, tumour responses were elicited by exemestane regardless of disease site, importantly, in patients with visceral disease. In patients with disease refractory to tamoxifen, once daily exemestane 25 mg produced objective response rates of 15 to 28% that were sustained for a median duration of 69 to 76 weeks. In a large comparative study, exemestane and megestrol showed similar clinical efficacy according to objective response and overall success rates. However, the duration of overall success and times to disease progression and treatment failure were significantly prolonged with exemestane compared with megestrol. Additionally, a significant survival advantage for exemestane over megestrol was reported. Exemestane retains efficacy in patients refractory to multiple hormonal therapies. In patients whose disease had progressed after tamoxifen and megestrol, objective response rates of 11 and 13% were reported, and responses were similar regardless of whether megestrol resistance was de novo or acquired. Objective responses also occurred in studies that explored sequential use of exemestane after failure of aminoglutethimide (26% with exemestane 200 mg/day) or other nonsteroidal aromatase inhibitors (6.6% with exemestane 25 mg/day). Additionally, tumour responses (objective response 6.1%, overall success rate 24.7%) were reported in patients who had not responded to their last hormonal treatment. As first-line treatment, once daily exemestane 25 mg elicited objective and overall success rates of 42 and 58%, compared with 16 and 31% for once daily tamoxifen 20 mg. Exemestane was generally well tolerated in clinical trials at once daily dosages up to 600 mg. At the 25 mg recommended once daily dosage, the most commonly occurring adverse events were nausea, hot flushes, fatigue, increased sweating and dizziness. Weight gain occurred in significantly more patients receiving megestrol than among those treated with exemestane. Androgenic events have been reported in a small number of patients receiving once daily exemestane 200 mg, but were rarely reported at the recommended dosage. Conclusions: Exemestane is effective in postmenopausal patients with tamoxifen-refractory advanced breast cancer, prolonging time to disease progression and treatment failure and improving survival compared with megestrol treatment. Moreover, exemestane has an acceptable tolerability profile and a convenient once daily oral dosage regimen. Available data indicate that exemestane maintains its efficacy in patients with visceral metastases and does not show cross-resistance with nonsteroidal aromatase inhibitors. Preliminary data indicate that exemestane is also effective as first-line therapy for advanced breast cancer.     

Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer

Flutamide is a non-steroidal antiandrogenic drug devoid of hormonal agonist activity. Flutamide appears to be a specific antiandrogen only at androgen-dependent accessory genital organs. Its pharmacological activity is due substantially to the principal metabolite, 2-hydroxyflutamide. In comparative trials involving small numbers of patients with previously untreated advanced prostatic cancer, flutamide 750mg daily is comparable with stilboestrol 1 or 3mg daily and with estramustine 560 or 840mg daily. Treatment of newly diagnosed advanced prostatic cancer with flutamide plus a luteinising hormone releasing hormone (LHRH) agonist has produced very promising results, and appears to prolong survival relative to that achieved with leuprolide alone. However, these results require confirmation in suitably designed prospective studies. In previously treated patients refractory to castration, flutamide 750mg daily appears comparable in efficacy to estramustine phosphate 600 mg/m2 daily. Apart from a high incidence (34 to 100%) of gynaecomastia flutamide monotherapy is usually well tolerated, and has the advantage of preserving libido and sexual potency in at least 80% of patients. Gynaecomastia is infrequent, however, when flutamide is used in conjunction with surgical castration or an LHRH agonist. Thus, flutamide is a suitable alternative to other systemic treatment in patients with advanced prostatic cancer who wish to preserve sexual potency. In combination with an LHRH agonist flutamide may become a first-line agent for previously untreated patients with cancer of the prostate.     

Genetic predictors of therapeutic response to clozapine: current status of research

Clozapine is one of the most clinically potent drugs currently available for treating the symptoms of schizophrenia. Compared with conventional antipsychotics it surpasses its predecessors in its ability to treat a wider range of symptoms in otherwise refractory patients, while possessing a low propensity to produce extrapyramidal symptoms. Despite its significant advantages, not all patients benefit from treatment. Some patients react adversely to therapy while others fail to respond adequately. If those most likely to benefit from clozapine could be identified prior to treatment, this would significantly improve the clinical management of these patients. Genetic alterations in drug-metabolising enzymes have previously been demonstrated to influence the efficacy of clinically relevant drugs. It is possible that similar alterations in these and other systems may influence the response variability of patients to clozapine. Pharmacogenetic studies are at present investigating genes encoding drug receptors, drug-metabolising enzymes and neurotransmitter transporters to identify genetic variants that may be important. To date polymorphisms within serotonergic and dopaminergic pathways have been implicated, though the involvement of similar variants in other candidate systems is also likely. This information will ultimately enable the genetic prediction of patients most likely to benefit from the drug, and in the process would alleviate the unnecessary exposure of predisposed individuals to potentially serious adverse effects.     

希罗达治疗老年晚期消化道肿瘤的临床观察

目的观察希罗达治疗老年晚期消化道肿瘤的疗效及安全性。方法对33例具有可测量指标的老年晚期？削七道肿瘤患者采用希罗达单药每天2000mg，分早晚2次口服，连续服用2周、休息1周为1个周期，每例患者至少进行2个周期的治疗，结束后进行评价。结果全组33例客观疗效为，CR0例，PR12例、NC11例、PD10例。（CR＋PR）12例。总有效率36．36％肿瘤控制率为（CR＋PR＋NC）69．70％；部分PD患者主观症状有减轻。主要毒副反应为手足综合征，皮肤色素沉着，恶心呕吐，厌食，腹泻，疲劳，口炎等，少数患者出现胆红素和丙氨酸转氨酶轻度升高及轻至中度贫血和白细胞及血小板减下降。结论对晚期老年消化道肿瘤患者来说，希罗达治疗有效并安全。     

Use of beta-adrenergic blocking agents in congestive heart failure

The use of beta-adrenergic blocking agents in patients with congestive heart failure (CHF) is reviewed. The sympathetic nervous system plays an important compensatory role in maintaining inotropic support of the failing heart; therefore, beta blockers have long been considered contraindicated in CHF patients. However, prolonged excessive activation of the sympathetic nervous system may be detrimental. Several clinical trials have shown improved functional status and hemodynamic indices in some patients with dilated cardiomyopathy who received beta blockers. The maximum effect required up to 12 months. Two studies also showed trends toward improved survival. Aspects of study design that appear to be associated with the observation of a favorable response to beta blockade in CHF patients are a low initial dosage, gradual adjustment of the dosage, and a sufficient duration of therapy. Trials with unfavorable results lacked one or more of those design characteristics. Mechanisms proposed to underlie the beneficial effects of beta blockers in CHF patients include up-regulation of beta-receptors, reduction in cardiac energy requirements, protection of the myocardium against norepinephrine toxicity, and anti-arrhythmic effects. Most studies were conducted in patients with idiopathic dilated cardiomyopathy; it is unknown whether beta-blocker therapy is equally beneficial in patients with CHF arising from other causes. Metoprolol is the agent for which there is the most experience; comparative efficacy trials have not been conducted. Beta-adrenergic blockers appear to be beneficial in some patients with CHF. Further trials are needed to identify the patients most likely to respond and the drugs most likely to work.     

Estramustine resistance.

Estramustine (EM), a conjugate of nornitrogen mustard and estradiol, is a antimicrotubule drug currently in use for the treatment of advanced prostatic carcinoma. Experimental data are accumulating concerning the antitumor effect of EM in other malignancies, and clinical studies in other malignancies are ongoing. This review summarizes the information available to date concerning the effects of EM and the development of drug resistance. EM depolymerizes microtubules by binding to microtubule-associated proteins (MAPs) as well as tubulin. Because of the radiosensitizing effect of this drug there has been a recent increase in interest concerning estramustine and its clinical use. Recently, it was proposed that EM induces an apoptotic cell death in glioma cells in vitro and in a rat model. EM resistance is distinct from MDR phenotype; it has been used in combination with antimitotic agents which are part of the MDR phenotype. Observations made with estramustine-resistant cell lines show the acquisition of estramustine resistance is a function of multiple adaptation by changes at tubulin expression pattern, and is also associated with changes in tau expression and phosphorylation.