toremifene and Skin-Neoplasms

The EORTC Melanoma Cooperative Group conducted a phase II trial (study number 18891) to study the effect of Toremifene in 45 patients with advanced, metastatic melanoma. Male and female patients, median age 61 (range 23-88) years received a mean total dose of 11 g (4.3-62.6) orally for at least 6 weeks. No objective remissions were seen. Four patients (3 women and 1 man; 9%) experienced 3-6 months' disease stabilization. The toxicity of the drug, given at a dose of 240 mg daily, was negligible. Because of the minimal side-effects, Toremifene may be recommended for patients who have only a small number of slowly growing metastases, in particular to soft tissue and lung.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Menopause; Middle Aged; Sex Factors; Skin Neoplasms; Soft Tissue Neoplasms; Toremifene

We report a case of recurrence of skin and lymph nodes from asynchronous breast cancer achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 49-year-old woman who received both sides of muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) had a skin redness of her left breast. Aspiration biopsy cytology for the skin led to a diagnosis of Class V. Skin biopsy for the part of the redness was performed. The pathological diagnosis was an invasive ductal carcinoma, negative for estrogen receptor and positive for progesteron receptor, and negative for HER2/neu protein expression. Ultrasonography showed the subpectral and the inflaclavicular lymph nodes swelling and the skin metastasis. Enhancement CT showed no metastasis of brain, lung, liver, and other organs. Although she had already received 6 cycles of tri-weekly FEC (C: 500 mg, E 60 mg, F: 500 mg/m2) after previous operation, we performed 7 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The response for the lesion of lymph nodes metastasis after paclitaxel and toremifene therapy was evaluated as a complete response. The subpectoral and the inflaclavicular lymph nodes metastasis disappeared. However, the skin redness of her left breast was still remained. She had received a radiation therapy (30 Gy) for skin metastasis. After radiation therapy, we performed a skin biopsy for the part of the redness. The pathological diagnosis was no carcinoma of skin. She had no recurrence during the two years after the treatment. Paclitaxel and toremifene therapy was effective for a recurrent breast tumor and could improve patient's QOL and the clinical outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lymphatic Metastasis; Mastectomy, Radical; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Skin Neoplasms; Toremifene; Ultrasonography

High-dose toremifene therapy (120 mg/day) is useful for the recurrence of receptor-positive breast cancer. However, some reports show that combination therapy of high-dose toremifene and chemotherapy exhibits additive effects. Twelve patients were given oral chemotherapy (capecitabine, 5'-DFUR+CPA, S-1) with high-dose toremifene. The overall response rate was 41.7%, in addition to 58.3% with no change beyond three months. Adverse events were restricted to headache, stomatitis and nausea. Average time to progressive (TTP) was 5.8 months. It was shown that high-dose toremifene and oral chemotherapy were useful for breast cancer recurrence without severe side effects.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Quality of Life; Skin Neoplasms; Tegafur; Toremifene

To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-beta1 and TNF-alpha in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardner's syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF-beta1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF-beta1 secretion into the medium was associated with a parallel increase in TGF-beta1 gene expression and receptor number. Receptor cross-linking studies using radiolabelled TGF-beta1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF-alpha, but they had TNF-alpha membrane receptors, as shown by TNF-alpha assay. TNF-alpha secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF-beta1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF-beta1 secretion by fibroma fibroblasts and TNF-alpha secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF-beta1 gene expression and TGF-beta1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-alpha production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.

Topics: Animals; Antineoplastic Agents, Hormonal; Blotting, Northern; Cells, Cultured; Chickens; Collagen; Fibroblasts; Fibroma; Gardner Syndrome; Glycosaminoglycans; Humans; Receptors, Estrogen; Receptors, Transforming Growth Factor beta; RNA, Messenger; RNA, Neoplasm; Skin Neoplasms; Toremifene; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The distribution of topically applied toremifene (0.5-1 mg/day for 5 days) in the ultraviolet B (UVB)-induced Monodelphis domestica opossum melanoma model was examined. The mean concentration of toremifene measured in the skin was 1200 nmol/g, or > 500 times that detected in any other tissues (blood, brain, liver, testicles, heart, uterus, eyes). In plasma, toremifene could be detected in only one animal of six (0.04 nmol/ml). Intraperitoneal administration of 0.5 mg toremifene daily for 5 days in three female animals resulted in a mean uterus concentration of 22.9 nmol/g, or 400-fold that achieved by topical administration of 0.5 mg/day in three other female Monodelphis (0.05 nmol/g). The cytostatic effect of toremifene was studied in three human melanoma cell lines and three experimental cell lines derived from UVB-induced melanocytic nevi in M. domestica. Toremifene had a cytostatic effect on all cell lines (50% growth-inhibitory concentrations, 5.8-9.6 microM). Topical toremifene administration yields high local concentration with minimal systemic distribution. In addition, toremifene has a cytostatic effect at achievable concentrations in a variety of melanomatous cell lines.

Topics: Administration, Topical; Animals; Drug Screening Assays, Antitumor; Female; Humans; Injections, Intraperitoneal; Male; Melanoma; Melanoma, Experimental; Neoplasms, Radiation-Induced; Opossums; Skin; Skin Neoplasms; Tissue Distribution; Toremifene; Tumor Cells, Cultured; Ultraviolet Rays