Bile detection of squamous cell carcinoma antigen (SCCA) in extrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a rare biliary tract tumor with poor prognosis that often is challenging to diagnose and the majority of patients present with advanced stage. Squamous cell carcinoma antigen 1 (SCCA1) overexpression has been found in different tumors associated with poor prognosis and chemoresistance. AIMS: To assess the presence and possible prognostic role of SCCA1/2 isoforms in bile and serum of patients with CCA. METHODS: Forty seven surgical patients (36 with CCA and 11 with benign diseases) were prospectively included in the study. Serum and bile specimens were collected at the time of surgery and free and IgM-complexed SCCA was quantified by ELISA (Xeptagen, srl). RESULTS: Free or IgM linked SCCA was rarely found in serum, while SCCA was detectable in bile samples of patients with CCA, especially in those with extrahepatic form (43% vs 17%, p = 0.008), but not in controls. Despite similar tumor stage, these positive patients presented a trend toward a higher percentage of portal invasion (27% vs 15%) and of tumor recurrence than negative cases (62% vs 40%), although the difference was not statistically significant. CONCLUSION: These preliminary results indicate that bile testing for SCCA is a specific marker of extrahepatic CCA, with potential prognostic value.

Click chemistry, a potent tool in medicinal sciences.

This review focuses on the application of click chemistry in medicinal sciences, and particularly on its role in drug discovery. Because of its high modularity, click chemistry helps to accelerate the current drug discovery process, which relies on massive screening of chemical libraries. This article describes examples of click chemistry applications that are aimed at finding new lead candidates against pathologies such as cancer, AIDS and Alzheimer's disease, and explores the impact that the technique could have in therapy and prevention in the near future, through application in drug delivery systems, bioconjugation and diagnostic. An introduction, addressed to researchers who intend to use this methodology, examines the opportunities to perform click reactions according to the most common and best studied techniques, such as synthesis in water, on solid phase, and under microwave or ultrasound irradiation. Every topic is furnished with examples which have appeared in the literature in the last five years and is clarified by schemes and figures.

Inhibition of a protein-protein interaction between INI1 and c-Myc by small peptidomimetic molecules inspired by Helix-1 of c-Myc: identification of a new target of potential antineoplastic interest.

c-Myc is a transcription modulator proto-oncogene. When overexpressed, it becomes an important contributor to the multi-hit process of malignant transformation. In two earlier papers in this journal (see refs. 19 , 20) we reported that retro-inverso peptidomimetic molecules inspired by the Helix-1 of c-Myc motif could be sequence-specific antiproliferative agents active in the low micromolar range. We also found that our peptides were not opening the four-alpha-helix Myc:Max bundle. Their antiproliferative activity in cancer cell lines needs the presence of side chains projecting outside of the bundle in the corresponding native H1 motif. This observation suggested interference with an external partner. In this study we investigated the INI1:Myc interaction. INI1 is a subunit of the SWI/SNF complex (component of the enhanceosome surrounding Myc:Max heterodimer). The INI1:Myc interaction was confirmed via pull down, ELISA, and fluorescence anisotropy assays. According to the length of INI1 fragments used, we calculated Kds ranging between 1.3x10(-6) and 4.8x10(-7) M. The three different techniques applied showed that the INI1:Myc interaction was also the target of our retro-inverso peptidomimetic molecules, which seem to bind specifically at INI1. A Myc binding, 21aa INI1 fragment (minimum interacting sequence), could inspire the synthesis of a new class of more selective c-Myc inhibitors.

Synthesis of 3,3'-(1-piperidino)substituted methylene-bis-isoxazoles preventing stimulus-induced leukocytes activation.

Some 3,3'-(1-piperidino)substituted methylene-bis-isoxazoles were prepared via Mannich base and tested to verify their antiinflammatory-related activity. Human neutrophils stimulated with either PMA and f-MLP were used as the cellular model. The efficiency of eight differently substituted compounds (2-9) was established on their capacity to reduce the O(2)(-) production by activated human neutrophils. The rising hydrophobicity in the side-chain of methylene-bis-isoxazoles leads to a distinction in the neutrophil response against the two stimuli, favoring the inhibition of the PMA elicited cell activation and leaving inaffected the f-MLP induced cell responses. Compounds 8 and 9 are particularly active and abolish almost completely the neutrophil activation in the presence of PMA stimulus.

Unsymmetrical methylene derivatives of indoles as antiproliferative agents.

Indole-3-carbinol is a natural product which has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumours in animals. Eighteen unsymmetrical methylene derivatives of indoles were prepared by reaction of Mannich bases of 7-hydroxycoumarins with substituted indoles in acetic or propionic anhydride. The synthesised molecules were tested in vitro against the MCF7 and MDA-MB-231 breast cancer cell lines by MTT and cell count assays. Results from 16 tested compounds showed that 60% of them exerted some effects against the MDA-MB-231 compared to about 30% towards the MCF7. Among all, the 3-(7'-acetoxy-4-methylcoumarin-8'-yl)methyl-2-methylindole resulted the most effective in both cell lines, compared to indole-3-carbinol. In conclusion, these preliminary results report that some of these compounds might be promising potential antiproliferative agents.