toremifene and Neoplasms

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed.

Topics: Antineoplastic Agents; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship; Triazoles

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antithrombin III; Drug Evaluation; Estrogen Antagonists; Female; Gonadotropins; Humans; Middle Aged; Neoplasms; Sex Hormone-Binding Globulin; Tamoxifen; Toremifene

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Climacteric; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Estrogens; Female; Gonadotropins; Humans; Middle Aged; Nausea; Neoplasms; Remission Induction; Sex Hormone-Binding Globulin; Tamoxifen; Toremifene; United States

A Phase I study of the new antiestrogenic drug toremifene was carried out in 27 Japanese women, using oral doses of 10-480 mg per day for one or five days. Serum concentrations reached a dose-dependent maximum 2-6 hours after each oral administration. Side effects were generally mild.

Topics: Administration, Oral; Adult; Aged; Anorexia; Antineoplastic Agents; Drug Evaluation; Estrogen Antagonists; Female; Humans; Japan; Middle Aged; Nausea; Neoplasms; Tamoxifen; Toremifene

Cancer-induced skeletal muscle defects show sex-specific differences in severity with men performing poorly compared to women. Hormones and sex chromosomal differences are suggested to mediate these differences, but the functional skeletal muscle markers to document these differences are unknown. We show that the myogenic microRNA miR-486 is a marker of sex-specific differences in cancer-induced skeletal muscle defects. Cancer-induced loss of circulating miR-486 was more severe in men with bladder, lung, and pancreatic cancers compared to women with the same cancer types. In a syngeneic model of pancreatic cancer, circulating and skeletal muscle loss of miR-486 was more severe in male mice compared to female mice. Estradiol (E2) and the clinically used selective estrogen receptor modulator toremifene increased miR-486 in undifferentiated and differentiated myoblast cell line C2C12 and E2-inducible expression correlated with direct binding of estrogen receptor alpha (ERα) to the regulatory region of the miR-486 gene. E2 and toremifene reduced the actions of cytokines such as myostatin, transforming growth factor β, and tumor necrosis factor α, which mediate cancer-induced skeletal muscle wasting. E2- and toremifene-treated C2C12 myoblast/myotube cells contained elevated levels of active protein kinase B (AKT) with a corresponding decrease in the levels of its negative regulator PTEN, which is a target of miR-486. We propose an ERα:E2-miR-486-AKT signaling axis, which reduces the deleterious effects of cancer-induced cytokines/chemokines on skeletal muscle mass and/or function.

Topics: Animals; Cell Differentiation; Cell Line, Tumor; Estradiol; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Muscle, Skeletal; Muscular Diseases; Myostatin; Neoplasms; Sex Factors; Signal Transduction; Toremifene; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Estrogen Antagonists; Female; Humans; Lavandula; Male; Neoplasms; Oils, Volatile; Ovarian Neoplasms; Piperidines; Plant Oils; Plants, Medicinal; Prostatic Neoplasms; Raloxifene Hydrochloride; Retinoids; Tamoxifen; Toremifene

The carcinogenic potential of the nonsteroidal triphenylethylene antiestrogen toremifene (Fareston) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 and 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study weeks 1-16) or once every four weeks thereafter (study weeks 17-104). Blood samples were taken at weeks 34, 52 and 104 and the plasma concentrations of toremifene, as well as the two main metabolites (deaminohydroxy)toremifene and N-demethyltoremifene, were measured. All doses of toremifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced incidences of pituitary tumors. This was evident in all dose groups. Drug-related decrease of mammary tumors in females (at all doses) and testicular tumors in male rats (doses > or = 1.2 mg/kg/day) were also evident. The incidence of the preneoplastic foci of basophilic hepatocytes were significantly decreased in treated female groups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-related changes were observed in the genital organs, thyroid, spleen, mammary gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or reduced incidences of pituitary, mammary or testicular tumors. This study indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.

Topics: Aging; Animals; Antineoplastic Agents, Hormonal; Body Weight; Carcinogenicity Tests; Eating; Female; Gonads; Liver; Male; Neoplasms; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Survival Rate; Toremifene