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

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

Image-clustering analysis of the wave-structure interaction processes under breaking and non-breaking waves

This contribution presents the effectiveness and the potentialities of a consolidated technique—the video-cluster analysis—to the study of turbulent flow and breaking waves, in order to demonstrate its suitability as a low-cost, non-intrusive method to derive quantitative key parameters describing the wave-structure interaction processes at coastal defense structures. For this purpose, a new methodology, consisting of a series of pre- and post-processing techniques developed to optimize the automatic detection of clusters in video imagery, was designed to process the video-records of experiments of wave run-up and wave overtopping at sea-dikes subjected to irregular waves. The results of the cluster analysis were elaborated to reconstruct the instantaneous profiles of the free-surface elevations across the structure crest and derive simultaneous information on overtopping volumes, discharges, depths, and velocities and to get spatial-time maps of the concentration of the air entrapped in the liquid phase. The accuracy of the methodology is demonstrated by comparing the quantities derived from the cluster analysis to laboratory measurements performed with resistive gauges and acoustic Doppler profilers. The novelty of the work is either represented by the results of the application of the cluster-analysis and by the procedures of optimizations, whose ensemble may establish a best practice and represent a guideline for other applications

Comparative studies between in vitro and in vivo effects of human beta-interferon on natural killer activity and its relevance to immunochemotherapy

A good correlation was found between in vivo and in vitro responses of peripheral MNC from breast cancer patients and the NK boosting effect of human beta IFN. In vitro immunochemistry studies showed that marked antitumor effects were obtained against cultured cancer cells when a widely used chemotherapeutic agent such as 5-FU was combined with nonsensitized spontaneously cytolytic MNC, preactivated in vitro with beta IFN. These results suggest that the in vitro susceptibility assay of MNC to IFNs could be used for predicting favorable responses to immunochemotherapy regimens employing IFNs as immunomodulating agents