Genotoxicity and epigenotoxicity of carbazole-derived molecules on mcf-7 breast cancer cells

The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damageinducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with PK9320 and PK9323 being eligible candidates as “anticancer compounds” and “anticancer epi-compounds” and PK083 a “damage-corrective” compound on human breast adenocarcinoma cells. Such different properties may be exploited for their use as anticancer agents and chemical probes

Tumor targeting by intra-arterial infusion of 5-[123I]iodo-2'-deoxyuridine in patients with liver metastases from colorectal cancer

We previously showed the tumor-targeting potential of the 125I-labeled thymidine analog 5-iodo-2′-deoxyuridine (IUdR) injected intratumorally in patients with high tumor-cell kinetics. In this study, we evaluated the tumor incorporation of [ 123I]IUdR infused intra-arterially in patients with liver metastases from colorectal cancer. Methods: Iodine-123-IUdR (110-300 MBq, 3-8 mCi, specific activity, 150-200 Ci/μmole) was infused into the hepatic artery of 16 patients with inoperable liver metastases over 30-45 min through a permanent intra-arterial catheter. A dynamic sequence during infusion, spot images, whole-body scans and SPECT acquisitions were recorded up to 42 hr. Blood and urine samples were obtained for biodistribution and HPLC analyses. Results: In the 14 patients with adequate tumor perfusion patterns, tumor uptake reached 2%-17.6% ID at the end of infusion. After a washout phase that lasted 18-20 hr, incorporated radioactivity remained steadily associated with the tumor lesions until at least 42 hr after infusion (about 1.4%-11.1% ID). HPLC analysis indicated a virtually 100% first-pass hepatic deiodination of unincorporated [ 123I]IUdR (about 80%-95% ID recovered in the 42-hr urine). No significant uptake was detected in the bone marrow or in other normal dividing tissues. Conclusion: These results encourage further studies to enable dosimetric estimates, optimization of dose regimens, and examination of the therapeutic potential of Auger-electron-emitter-labeled IUdR in cancer therapy utilizing this type of approach

Sicurezza collettiva e diritti fondamentali in tempo di terrorismo. Atti del workshop tenutosi a Ferrara il 26 settembre 2007

Il terrorismo internazionale ha catalizzato l’attenzione sulla necessità preminente di garantire la sicurezza collettiva, spingendo le organizzazioni internazionali ed i singoli stati ad adottare legislazioni preventive ed a potenziare le attività congiunte di intelligence internazionali. Ma le norme d’emergenza sono per loro natura inclini ad incidere sulle libertà fondamentali. Questo volume collettaneo, grazie alla poliedricità dei contributi pubblicati, offre alla curiosità del lettore innumerevoli spunti ed osservazioni che, sotto più profili, tendono alla ricerca di un possibile bilanciamento tra l’esigenza di sicurezza ed il rispetto dei diritti inviolabili della persona. Qui trovano, dunque, ampio spazio riflessioni riguardanti la tutela dei diritti dei migranti e degli stranieri, i limiti all’attività di intelligence, la prassi del black-listing e la tutela giurisdizionale delle libertà fondamentali offerta dai giudici interni, comunitari ed internazionali