Original article: Immuno-chemotherapy of advanced colorectal cancer with alpha-2a interferon and 5-Fluorouracil immunopharmacological studies

Summary: Twelve patients with metastatic colorectal cancer received alternating cycles of low immunomodulat-ing doses of alpha-IFN + 5-Fluorouracil (5-FU) or 5-FU alone. Hematological, biochemical and physical evaluation showed that both treatment cycles were well tolerated. However, transient fever and moderate flu-like symptoms were observed following alpha-IFN administration. Treatment with 5-FU alone produced long-lasting inhibition of CD8+ T lymphocytes, but did not depress NK activity (NKA). Combined treatment with alpha-IFN produced a short-term increase of NKA and antagonized the effect of 5-FU on CD8+ cells on day 5 of the cycle. Parallel studies on in vitro models showed antiproliferative effects of 5-FU on PHA-stimulated MNC and confirmed the preferential inhibition of CD8+ cells. Pretreatment with alpha-IFN did not reverse the effect of 5-FU on CD8+ lymphocytes, but partially protected MNC from the toxic effects of the drug. This was presumably due to the cytostatic effects induced by alpha-IFN on MNC before exposure to the cycle-specific antineoplastic agent. This investigation suggests that alpha-IFN could play a positive role in immuno-chemotherapy of colorectal cancer through multiple mechanisms not entirely related to direct antitumor effects of the agent. © 1991 Kluwer Academic Publishers

Combined effects of 5-Fluorouracil, Folinic acid and Oxaliplatin on the expression of carcinoembryonic antigen in human colon cancer cells: pharmacological basis to develop an active antitumor immunochemotherapy

<p>Abstract</p> <p>Background</p> <p>Five-fluorouracil (FU), mainly associated with leucovorin (L), plays an essential role in chemotherapy of colorectal carcinoma. Moreover, FU ± L has been found to increase the expression of tumor-associated carcinoembryonic antigen (CEA), that may be an important target in therapeutic protocols of active specific immunotherapy. FU + L (FUL) are frequently combined with oxaliplatin (OXA) in advanced colon cancer patients. Thus, we investigated whether FUL in combination with OXA according to 2 different schedules may influence CEA expression in human colon cancer cells in vitro.</p> <p>Methods</p> <p>CEA protein expression was evaluated by cytofluorimetric and western blot analysis. Relative quantification of CEA mRNA was assessed by real time RT-PCR analysis.</p> <p>Results</p> <p>Levels of CEA protein and transcript were found to be higher in FUL-treated cells than in controls. However, when target cells were exposed to OXA before but not after FUL treatment, the up-regulation of CEA was partially inhibited.</p> <p>Conclusion</p> <p>These results suggest that target cells must be exposed to OXA after but not before treatment with the fluoropyrimidine in order to exploit drug-induced up-regulation of CEA. This finding appears to provide useful information to design chemo-immunotherapy protocols based on FUL + OXA, combined with host's immunity against CEA directed cancer vaccines.</p

Effect of the combined treatment with 5-fluorouracil, γ-interferon or folinic acid on carcinoembryonic antigen expression in colon cancer cells

5-Fluorouracil (5-FU) and human recombinant γ-interferon (γ-IFN) were found to increase the expression of carcinoembryonic antigen (CEA) in human cancer cells in vitro. In the present study, the antimetabolite was associated with γ-IFN or folinic acid (FA), a biochemical modulator of cellular metabolism of 5.FU, able to increase its antineoplastic activity. Treatment of two human colon cancer cell lines (HT-29 and WiDr) with 5-FU + γ-IFN resulted in an increase of CEA expression higher than that obtainable with both agents alone, although no synergistic effects were obtained. This was demonstrated in terms of: (a) mRNA transcripts (HT-29); (b) cytoplasm and membrane CEA protein levels detected by Western blot analysis (HT-29); and (c) plasma membrane reactivity determined by flow cytometry analysis (HT-29 and WiDr). Moreover, 5-FU + γ-IFN increased HLA class I molecules in the HT- 29 cell membrane over that obtainable with γ-IFN alone. In contrast, both agents did not induce the expression of the costimulatory molecule B7-1. Treatment with FA enhanced the antitumor effect of 5-FU but not its ability to augment CEA expression. This suggests that the FA-sensitive biochemical mechanism of action of 5-FU is not involved in its effect on CEA expression. In vivo studies showed, for the first time, that 5-FU, alone or combined with γ-IFN, increases the amount of CEA protein over controls, either in cancer cells or in peripheral blood of nude mice bearing HT-29 cells. These results could be of potential diagnostic and/or therapeutic value when CEA protein is the target of humoral or cell-mediated immunity

Computer Simulations Provide Guidance for Molecular Medicine through Insights on Dynamics and Mechanisms at the Atomic Scale

International audienceComputer simulations provide crucial insights and rationales for the design of molecular approaches in medicine. Several case studies illustrate how molecular model building and molecular dynamics simulations of complex molecular assemblies such as membrane proteins help in that process. Important aspects relate to build relevant molecular models with and without a crystal structure, to model membrane aggregates, then to link (dynamic) models to function, and finally to understand key disease-triggering phenomena such as aggregation. Through selected examples-including key signaling pathways in neurotransmission-the links between a molecular-level understanding of biological mechanisms and original approaches to treat disease conditions will be illuminated. Such treatments may be symptomatic, e.g. by better understanding the function and pharmacology of macromolecular key players, or curative, e.g. through molecular inhibition of disease-inducing molecular processes

Parole al muro e sull’asfalto per le vie di Roma. Epigrafi, targhe d’inciampo, scritte spontanee e murales

Il lavoro raccoglie e commenta ottanta scritture esposte collocate nel panorama metropolitano di Roma a partire dagli anni Duemila. Tra le tipologie scelte sono oggetto di studio le epigrafi commemorative, le “targhe d’inciampo”, le scritture spontanee, i murales, i graffiti e i poster. L’analisi condotta, che si articola per ciascuna scrittura in trascrizione integrale, indicazione del luogo, datazione, descrizione del supporto materiale e dell’aspetto grafico e commento linguistico, da una parte mette in luce come l’epigrafia romana oggi abbia sviluppato elementi d’innovazione (e di trascuratezza) rispetto alla tradizione precedente, dall’altra evidenzia e presenta un nutrito e variegato panorama di scritture spontanee e murales, che non si limitano più a supporti materiali tradizionali e che soprattutto hanno una veste linguistica variegata (dal dialetto alla lingua, dal latino all’inglese)

Ma che ce stanno a fa? Le parole di Roma nella lessicografia italiana

Il volume prende in considerazione le voci che tre dizionari contemporanei (il GRADIT 2007, lo Zingarelli 2022 e il Devoto-Oli 2022) indicano come regionalismi romani o come dialettismi di origine romanesca o come parole italiane usate a Roma con specifici significati. Si tratta in tutto di circa 500 parole, ben poche delle quali, tuttavia, sono registrate in tutti e tre i dizionari e con le stesse marche: infatti, in corrispondenza dell’etichetta roman[esco] presente in un dizionario negli altri si trovano indicazioni geografiche più estese (centr[ale], centromerid[ionale], ecc.) oppure marche come gerg[ale], volg[are], pop[olare]. L’analisi, che si svolge in quattro capitoli, analizza le parole raccolte per gruppi omogenei, spiega le ragioni di alcune incoerenze lessicografiche, mostrando come i dizionari accolgano non di rado romaneschismi ormai desueti e voci che hanno avuto limitata circolazione nella stessa Roma. Si segnalano, infine, alcune parole che da Roma si sono diffuse in italiano ma che i dizionari o non registrano o non consentono di riconoscere come tali