Cetuximab concomitant with gemcitabine and radiotherapy in advanced squamous cell carcinomas of upper aerodigestive tract: a pilot study

PURPOSE: To explore the response and toxicity of advanced non-metastatic squamous cell carcinomas of upper aerodigestive tract (SCC-UADT) to a combination of cetuximab concomitant with gemcitabine and radiotherapy. METHODS: We managed patients with concomitant treatment of cetuximab (400 mg/m(2) as uploading dose, then 250 mg/m(2), IV) concomitant with gemcitabine (50 mg/m(2)) weekly for seven courses, and radiotherapy in classical fractionation until completion of 70 Gy. Primary endpoints were complete response (CR) to treatment and toxicity. We evaluated patients for toxicity on a weekly basis; evaluation of response included physical examination, endoscopy, computed tomography (CT) scan and biopsy when indicated, and was performed 6 weeks after completion of radiotherapy. Additional evaluations were done every 3 months to document disease status. Between November 2004 and November 2005, 20 patients were included. RESULTS: CR was 82.4%, overall response was 100%. Neck disease reached CR in 61.5% and partial in 38.5% of patients. The main toxicities were nausea, lymphopenia, neutropenia and mucositis. Grade 3 and 4 side effects were presented in 70.6% of patients, but mucositis, and lymphopenia without clinical repercussions, occurred in 88.2% of patients. Gastrostomy was required in 11.8% of patients to maintain nutrition. Radioepithelitis developed in 76.5%, but only three of these (23.1%) were grade III. Median overall survival was 53 months (range 6-55 months) and median progression-free survival has not yet been reached at the time of evaluation. CONCLUSIONS: Although toxicity is important, this approach has interesting activity and deserves further investigation (AU)

Stable expression of antisense RNAs targeted to the 5' non-coding region confers heterotypic inhibition to foot-and-mouth disease virus infection.

The antiviral potential of transcripts targeted to the non-coding regions (NCRs) of foot-and-mouth disease virus (FMDV) RNA have been studied during transient and constitutive expression in susceptible BHK-21 cells. Transient expression of antisense transcripts corresponding to the 5' and 3'NCRs, alone or in combination, confers specific inhibition of homologous (serotype C) virus infection in BHK-21 cells. Constitutive expression of antisense 5'NCR transcripts (5'AS) exerted higher levels of inhibition to homologous and heterologous (serotypes O, A, Asia, SAT 1, SAT 2 and SAT 3) FMDV infection, as estimated by a 10-fold reduction in virus titre in the supernatants from infected clones and by a plaque reduction assay. These inhibitions were also observed, albeit to a lesser extent, in clones stably expressing antisense 3'NCR transcripts. The antiviral response was specific for FMDV, as the picornavirus encephalomyocarditis virus was not inhibited in any of the transformed cell lines. In all cases, a correlation was found between the level of transcript expression and the extent of virus inhibition. The potential to efficiently inhibit FMDV, including isolates representing the seven serotypes, by expressing interfering 5'AS transcripts opens the possibility of developing transgenic animals with a reduced susceptibility to FMDV.

Foot-and-mouth disease virus: a long known virus, but a current threat.

Foot-and-mouth disease virus (FMDV) was the first animal virus identified. Since then, FMDV has become a model system in animal virology and a considerable amount of information on its structure, biology and vaccinology has been obtained. However, the disease that this virus produces (FMD) still constitutes one of the main animal health concerns. In this review, we have attempted to summarise the state of the knowledge in different basic and applied areas of FMDV research, with emphasis on those aspects relevant to the control of the disease.

Heterotypic inhibition of foot-and-mouth disease virus infection by combinations of RNA transcripts corresponding to the 5' and 3' regions.

Strategies to inhibit RNA virus multiplication based on the use of interfering nucleic acids have to consider the high genetic polymorphism exhibited by this group of viruses. Here, we report high levels of heterotypic inhibition of foot-and-mouth disease virus (FMDV) infective particle formation in cotransfection experiments of susceptible cell lines with infections viral RNA and combinations of viral transcripts. The interfering molecules used include the following regions on type C FMDV RNA: (i) sequences from the 5' region, spanning the proximal part of the internal ribosome entry site element and the two functional initiator AUGs; and (ii) the 3' terminal region including the 3' end of 3D gene and the complete 3' non-coding region. Combination of 5' antisense RNA molecules with either sense or antisense RNA molecules from the 3' region resulted in inhibition of up to 90% of the infectivity of homologous type C FMDV RNA. The inhibition was dose-dependent and specific, as no reduction was observed in the plaque-forming units recovered from RNA of swine vesicular disease virus, a related picornavirus. Interestingly, high levels-of intertypic inhibition, about 60% or higher, were observed when viral RNAs of serotypes O and A were analysed. These levels of inhibition are consistent with the levels of nucleotide homology exhibited by the viruses analysed in the target sequences. Inhibition of virus yield was also observed in FMDV-infected cells transiently expressing the interfering RNAs. Thus, transcripts of the FMDV RNA corresponding to the 5' and 3' regions specifically inhibit FMDV particle formation in a serotype-independent manner.