Abstract. Both de novo and acquired endocrine resistance constitute a major therapeutic problem for treatment of hormone-positive breast cancer. Multiple explanatory mechanisms have been proposed through the study of cellular models which focus principally on receptor tyrosine kinase mediated signalling pathways utilizing sRC, PI3K, MAPK and sMAds. Many of the transducing molecules, particularly nuclear transcription factors such as sNAIL, TwIsT, sNAIL2, ZEB, FOXC2, TCF/LEF and GOOsECOId are participants in proliferation as well as invasion and metastasis, involving a process of orchestrated cellular remodeling which is being likened to the process of epithelial to mesenchymal transition that takes place during embryonic development. we review the accumulating evidence that points towards the occurrence of this phenomenon as a consequence of the loss of endocrine control, with both processes being similarly characterized by depletion of cell adhesion proteins, E-cadherin, catenins and cytokeratins, increased association with the extracellular matrix through induction of metalloproteinases, fibronectin and collagen, and a switch to a mobile vimentin-based cytoskeletal structure with loss of apical basal polarity. IntroductionEndocrine therapy represents the most effective form of treatment for the majority of breast cancer patients whose tumours over-express the estrogen receptor (ER). In addition to ablative procedures (ovariectomy) and administration of antiendocrine agents to inhibit ovarian function, treatment is reliant predominantly upon anti-hormonal agents termed selective estrogen modulators (sERMs). Until recent introduction of agents such as toremifene and raloxifene, tamoxifen has been the mainstay of treatment (1) inducing objective response or disease stabilization in over half of previously untreated metastatic breast cancer patients with ER + tumours (2). Further options include the use of pure anti-estrogens such as fulvestrant (Faslodex) which achieves its effects through receptor degradation, and application of aromatase inhibitors that reduce extra-gonadal peripheral estrogen synthesis from the adrenals and adipose tissue, including the breast. Both types of agents improve relapse-free survival and reduce incidence of contralateral breast cancers in women with early-stage cancer and increase overall survival in patients with advanced disease (3,4). Unfortunately, following initial response to sERMs and second line therapy with aromatase inhibitors, most patients subsequently develop resistance to both classes of drugs and become refractive to further attempts at endocrine manipulation. Added to the de novo resistance in patients whose tumours express levels of ER <10 fmol/mg protein, this presents a serious therapeutic problem, particularly in view of the increased aggressiveness of hormone insensitive breast cancers. Estrogen receptor actionThe classical mode of action of ER is related to the regulation of expression of genes with estrogen response elements (ERE) in their promoters through t...

Overall, there is limited in vivo data to support the potential clinical advancement of the currently reported novel derivatives.

No abstract

No abstract

No abstract

Objectives: To evaluate the stability of 12 triazolyl oxazolidinone (TOZ) derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 ± 1°C. Materials and Methods: A stability-indicating high-performance liquid chromatography (HPLC) procedure with a C₈ column (250 × 40 mm, 5 µm particle size) and a mobile phase of acetonitrile/H₂O (50/50 v/v) at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 ± 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution (pH about 7.4) as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 ± 1°C was evaluated as well. Results: The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-(4-((R)-5-((1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate] and 1b [tert-butyl 4-(2-fluoro-4-((R)-5-((4-methyl-1H-1,2,3-triazol- 1-yl)methyl)-2-oxooxazolidin-3-yl)phenyl) piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters (k_deg, t_1/2, t₉₀) of 0.180 h^–1, 3.85 h, and 0.58 h for 1a and of 0.184 h^–1, 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. Conclusion: With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms.

Triorganotins belong to toxic components present predominantly in antifouling paints for marine vessels. Tributyltin/triphenyltin at pico- or nanomolar concentrations in sea water are known to induce an irreversible sexual abnormality in females of over 190 marine species, an "imposex" phenomenon - the superimposition of male genitalia on a female. Moreover, trialkyltins and triaryltins function as potent nuclear retinoid X receptors (RXR) agonists. In mammals, triorganotin compounds induce immunosuppressive, metabolic, reproductive or developmental effects. Toxic effects of triorganotins warrant the need for monitoring of their long-lasting presence in the environment. This study brings novel data on the stability of two triorganotin compounds in artificial sea water model obtained by applying ultra-pressure liquid chromatography (UPLC) and gas chromatography-mass spectrometry (GC-MS) methods. Stability of tributyltin and triphenyltin chlorides was studied for 180 days and the degradation kinetic parameters were obtained. Tributyltin chloride was the less stable with the degradation kinetic parameters Kdeg = 0.00014 day-1 and t1/2 = 4950 days (13.6 years). Kdeg of the more stable triphenyltin chloride was determined to be Kdeg = 0.00006 day-1 with t1/2 = 11550 days (31.6 years). Since similar stability data of triorganotin compounds were not published previously, we report high stability for both tested compounds, which indicates a significant environmental problem when these substances enter sea water and later coastal sediments.

No abstract