Toremifene in the treatment of breast cancer

Although more widespread screening and routine adjuvant therapy has improved the outcome for breast cancer patients in recent years, there remains considerable scope for improving the efficacy, safety and tolerability of adjuvant therapy in the early stage disease and the treatment of advanced disease. Toremifene is a selective estrogen receptor modifier (SERM) that has been widely used for decades in hormone receptor positive breast cancer both in early and late stage disease. Its efficacy has been well established in nine prospective randomized phase III trials compared to tamoxifen involving more than 5500 patients, as well as in several large uncontrolled and non-randomized studies. Although most studies show therapeutic equivalence between the two SERMs, some show an advantage for toremifene. Several meta-analyses have also confirmed that the efficacy of toremifene is at least as good as that of tamoxifen. In terms of safety and tolerability toremifene is broadly similar to tamoxifen although there is some evidence that toremifene is less likely to cause uterine neoplasms, serious vascular events and it has a more positive effect on serum lipids than does tamoxifen. Toremifene is therefore effective and safe in the treatment of breast cancer. It provides not only a useful therapeutic alternative to tamoxifen, but may bring specific benefits.     

托瑞米芬联合长春地辛和顺铂化疗方案治疗不能手术切除的非小细胞肺癌

目的 探讨托瑞米芬联合丝裂霉素、长春地辛和顺铂(MVP方案)对非小细胞肺癌(NSCLC)的治疗价值。方法 将A549细胞以10×104个/孔浓度接种到96孔培养板中,分别加入不同浓度的顺铂、长春地辛、丝裂霉素、托瑞米芬或托瑞米芬联合上述药物;72 h后用四甲基偶氮唑蓝法(MTT),检测上述药物对细胞的抑制作用。本研究包括63例初治。NSCLC和30例复治NSCLC(复治组)患者。初治患者经随机抽签分为对照组与治疗组。每例均进行MVP方案化疗,治疗组和复治组在化疗前5 d,开始口服托瑞米芬420 mg/d,共7 d。治疗2个周期后评价患者疗效,并随访不良反应与生存期。结果 托瑞米芬可降低化疗药物对A549细胞半数生长抑制的剂量,增强化疗药物的细胞毒性作用。初治患者治疗组有效率和中位生存期分别为47％(15/32)与11个月,较对照组的32％(10/31)和9个月略有增加;复治组有效率为17％,中位生存期为7个月,1年生存率为20％。3组不良反应无明显差异。结论 托瑞米芬能增强顺铂、丝裂霉素及长春地辛的抗肿瘤作用,联合MVP方案治疗NSClC安全有效。     

大剂量托瑞米芬联合NP方案治疗晚期非小细胞肺癌的近期疗效观察

目的探讨大剂量托瑞米芬增敏长春瑞滨和顺铂（NP方案）I治疗非小细胞肺癌（NSCLC）的近期疗效。方法人组患者随机分为两组。治疗组采用大剂量托瑞米芬＋NP方案治疗。对照组仅用NP方案治疗。治疗组的患者在口服托瑞米芬后第2天和第8天抽血测定托瑞米芬血清浓度。结果治疗组PR7例，SD13例，PD2例，有效率为31．8％。对照组PR1例，SD17例，PD3例，有效率为4．7％；治疗组与对照组相比，有效率差异有统计学意义（P〈0．05）。二组不良反应无明显差异。托瑞米芬血清浓度在第2天和第8天均超过5μmol／L。结论通过随机对照研究证实，大剂量托瑞米芬联合NP方案治疗晚期NSCLC安全有效。     

Circumvention of Daunorubicin Resistance by a New Tamoxifen Derivative, Toremifene, in Multidrug-resistant Cell Line

The reversing effect of toremifene, a new tamoxifen derivative, on multidrug resistance in a K562 subline and its mechanism were studied. K562 cells were cultured in serially increasing concentrations up to 1.0 μ M daunorubicin (DNR), and were found to be 28 times more resistant to DNR in comparison to the parent cells. In the resistant cell line (K562/D1-9), intracellular accumulation of DNR was less than that of the parent cell line, and P-glycoprotein was overexpressed. The resistance was reversed by addition of toremifene in a dose-dependent manner in K562/D1-9, while toremifene had no effect in K562. DNR accumulation was also reversed by toremifene in K562/D1-9, but not in K562. However, there was no significant difference of toremifene retention between K562/D1-9 and K562, and neither verapamil nor DNR increased toremifene accumulation in K562/D1-9. Moreover, toremifene and verapamil did not show an additive effect on intracellular DNR accumulation. These results suggested that the reversing mechanism of toremifene is different from that of verapamil, and this compound could be a good candidate for overcoming multidrug resistance.     

Inhibitory Effects of Toremifene on N-Methyl-N-nitrosourea and Estradiol-17β-induced Endometrial Carcinogenesis in Mice

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg/30 g body weight) decreased expression of c- fos , interleukin (IL)-1α, estrogen receptor (ER)-α mRNAs and corresponding proteins induced by estradiol-l7β (E₂), in the uteri of the ovariectomized mice. Expression of ER-β mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N -methyl N -nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E₂ diet (5 ppm) plus TOR (0.2 mg/30 g body weight, subcutaneously, every four weeks); group 2, E₂ diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E₂-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c- fos as well as IL-1α expression induced by E₂. Such suppressive effects of TOR may be related to the decreased ER-α and increased ER-β expressions.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999     

Anti-oestrogenic drugs and endometrial cancers

Tamoxifen is one of the most effective drugs to be used in the treatment of women with breast cancer and as a chemopreventive agent in women ‘at risk’ from this disease. Tamoxifen can be regarded as a paradigm for a new range of selective oestrogen receptor modulators that include toremifene, used in the treatment of metastatic breast cancer and raloxifene, presently approved for use in postmenopausal women for the treatment of osteoporosis. Tamoxifen treatment of women leads to a small increase in the incidence of endometrial cancers. It is important to understand the mechanism for this side effect in order to predict the likely human risk for other drugs of this class. Two such mechanisms have been proposed: (1) conversion of the drug to electrophilic metabolites that damage cellular DNA; and (2) an oestrogen agonist action on the uterus, promoting endogenous lesions. In rats, long-term tamoxifen treatment results in liver cancer via a genotoxic mechanism. However, it seems most likely that, in women treated with tamoxifen, endometrial cancer is related to an oestrogen agonist effect of this drug, promoting uterine cell proliferation.     

法乐通治疗晚期乳腺癌临床总结

目的 考察法乐通治疗晚期绝经后乳腺癌的放疗及其不良反应。方法：法乐通一线治疗每日一次６０ｍｇ口服,二线治疗每日一次１２０ｍｇ口服。结果：共６０例,有效率１８．３％,一线治疗１８例,有效率３３．３％,二线治疗４２例,有效率１１．９％,淋巴结和骨转移疗效较好,肝转移,肺转移及胸壁转移也有一定疗效。一线治疗较二线治疗,未用内分泌治疗较曾用内分泌治疗,绝经时间长（≥１０年）较经时间短（〈１０年）以及疗后无     

Toremifene decreases type I, type II and increases type III receptors in desmoid and fibroma and inhibits TGFbeta1 binding in desmoid fibroblasts.

Tissue infiltration is different in desmoid and fibroma tumours. Both produce high levels of transforming growth factor beta1 (TGFbeta1), which is related to extracellular matrix (ECM) accumulation which in turn regulates cell function and cell migration. Interactions between collagen, proteoglycans and cell surface fibronectin are involved in the assembly and functions of the ECM. As toremifene inhibits collagen and TGFbeta1 synthesis, we tested it in normal, desmoid and fibroma fibroblasts. We will report the changes in glycosaminoglycan (GAG) and collagen synthesis, TGFbeta1 activity, fibronectin mRNA expression and TGFbeta1 receptors after toremifene treatment in normal, fibroma and desmoid fibroblasts. We evaluated GAG and collagen synthesis with (3)H-glucosamine and (3)H-proline incorporation, TGFbeta1 activity with the ELISA method, TGFbeta1 receptor affinity with (125)I-TGFbeta1 binding and total RNA with Northern blot analysis. GAG and collagen synthesis, TGFbeta1 activity and fibronectin levels were higher in fibroma and desmoid than normal fibroblasts. The increase was greater in desmoid than fibroma tumour cells. Toremifene treatment reduced GAG and collagen synthesis, TGFbeta1 activity and fibronectin levels in all cell cultures. The percentage reduction in GAG was similar in all cultures; the reduction in collagen synthesis and TGFbeta1 activity was the highest in desmoid fibroblasts. TGFbeta1 receptors were higher in fibroma and desmoid cells than controls. Toremifene reduced TGFbeta1 receptors only in desmoid fibroblasts, with no effect on the changes in type I, II, and III receptors. Our data show that toremifene modifies the ECM components that regulate cytokine activity and cell migration. The reduction in receptor number only in desmoid cells suggests that toremifene may reduce TGFbeta1's affinity for its receptors. Synthesis of a substance regulating protein kinase activity, which is directly involved in the link between TGFbeta1 and its receptors, cannot be excluded.     

In vitro Sensitivity Test of Breast Cancer Cells to Hormonal Agents in a Radionucleotide-incorporation Assay

Breast cancer cell lines (MCF-7, T47D, BT-20 and STT-11) and fresh cells from malignant effusions of eight breast cancer patients were examined for their in vitro sensitivity to 17β-estradiol (E₂), tamoxifen and toremifene in a miniaturized, improved nucleic acid precursor incorporation assay (MINI assay). Seven of the eight patients received either tamoxifen or toremifene following a MINI assay and the correlation was examined between in vitro sensitivity and clinical responses to the hormonal agents. In cell lines, E₂ stimulated thymidine incorporation by estrogen receptor (ER)-rich cells, MCF-7 and T47D, but not by ER-poor cells, BT-20 and STT-11. Tamoxifen induced both ER-mediated and -unmediated effects in ER-rich cells. The latter effect was also observed in ER-poor cells. Toremifene had less ER-unmediated effect in all of the cells tested than tamoxifen did. The ER-mediated effect of toremifene was weaker than that of tamoxifen in cell lines but was equipotent to tamoxifen in fresh cells. E₂ affected thymidine incorporation by cells withdrawn from patients who showed a partial response to the anti-estrogens. No clear correlation was demonstrated between in vitro sensitivity to anti-estrogens of fresh cells and clinical response to these agents. The present results suggest that 1) the MINI assay is a useful system to investigate hormonal effects on breast cancer cell lines; 2) clinical responses to anti-estrogens are not predicted by in vitro response to the agents but might be predicted by the in vitro response to E₂; and 3) toremifene has a smaller non-specific effect on breast cancer cells than tamoxifen and is equipotent to tamoxifen in the ER-mediated effect in vitro .