toremifene and Fibroma

Desmoids are uncommon mesenchymal tumours that occur at single or multiple anatomical sites, occasionally in association with polyposis coli. This paper describes the use of the triphenylethylene tamoxifen, and a new chlorinated analogue, toremifene, in 20 patients with progressive desmoid disease. Clinical responses ranging from stabilisation of disease to complete resolution were observed in 65% of cases. The antitumour activity of this group of drugs has been attributed to their anti-oestrogenic behaviour. However, desmoids provide a clinical model of a purely mesenchymal tumour which appears to respond despite having generally low levels of hormone receptor. This emphasises the significance of stroma within breast (and other) tumours, in particular how the stroma may regulate the response to these drugs regardless of receptor status.

Topics: Adult; Antineoplastic Agents; Clomiphene; Female; Fibroma; Humans; Male; Middle Aged; Tamoxifen; Toremifene

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 3H-glucosamine and 3H-proline incorporation, TGFbeta1 activity with the ELISA method, TGFbeta1 receptor affinity with 125I-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.

Topics: Blotting, Northern; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Collagen; Fibroblasts; Fibroma; Fibromatosis, Aggressive; Fibronectins; Glycosaminoglycans; Humans; Proline; Protein Serine-Threonine Kinases; Proteoglycans; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA; Selective Estrogen Receptor Modulators; Toremifene; Transforming Growth Factor beta1

Desmoid tumors are uncommon, benign, fibrous lesions occurring sporadically and in association with familial adenomatous polyposis. Typical clinical features include a locally aggressive behavior, an unpredictable course, and a high propensity for recurrence after surgical resection. There are no standard medical or surgical approaches, and no markers for monitoring medical therapy of desmoid tumors.. We report two cases of mesenteric desmoid tumors treated with interferon alfa-2b and toremifene, a novel regimen devised to block angiogenesis. Pre- and posttreatment desmoid tumor tissues were obtained in one patient during a repeat resection for recurrent stenosing Crohn's disease and examined for mean vessel count and cellular proliferation levels by immunostaining for the endothelial surface antigen CD31 and the proliferation associated nuclear antigen, Ki-67, respectively. We assessed plasma D-dimers, a potential marker of angiogenic activity, and followed this throughout the course of antiangiogenic therapy in our two patients.. Examination of posttreatment tissue revealed a significant decrease in microvessel density (P<0.02) and Ki-67-positive nuclei (P<0.0001) compared with pretreatment tissue. Both patients demonstrated a prompt and sustained drop in previously elevated plasma D-dimer levels, which correlated clinically with lesion regression and sustained remission.. Treatment with toremifene and interferon alfa-2b was successful and well tolerated in our two patients. Our data suggest a combined antiangiogenic and antiproliferative mechanism of action. Furthermore, normalization of previously elevated plasma D-dimers may emerge as a strategy to monitor treatment efficacy in mesenteric desmoid tumors.

Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Female; Fibroma; Humans; Interferon alpha-2; Interferon-alpha; Male; Mesentery; Peritoneal Neoplasms; Recombinant Proteins; 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

Topics: Adult; Estrogen Antagonists; Female; Fibroma; Humans; Mesenchymoma; Neoplasms, Multiple Primary; Tamoxifen; Toremifene