[Quality of life after radical surgery and radiotherapy for advanced or recurrent laryngeal and hypopharyngeal cancers]. / Evaluation de la qualité de vie après chirurgie radicale et radiothérapie dans le traitement de tumeurs avancées ou récidivantes du pharyngolarynx.

AIM: To determine the functional disabilities and overall quality of life of patients operated for advanced (Stages III-IV) or recurrent squamous cell carcinomas (SCCA) after radiation therapy of the (pharyngo)larynx. METHODS: From 1984 to 1997, 135 patients were consecutively treated for SCCA of the (pharyngo)larynx. There were 118 men and 17 women with a mean age of 60 years. The University of Washington QOL questionnaire (UW-QOL) (Deleyiannis et al) was administered to 19 long term survivors. Self-administered scale consisting of nine domains affected by treatment for head and neck cancer: pain, physical appareance, global activity, entertainement, employment, chewing, swallowing, speech and shoulder function. For each patient, a total score and weighted score were determined. Descriptive statistics were used. RESULTS: 9/19 patients reported that compared with one year prior to the diagnosis of cancer their general health was the same. Pain resolved in 78%; the physical appearance was juged not modified in 52% of the cases. Chewing and swallowing functions were respected in 94% of the cases. These functions were considered as very important in 53% and 68% respectively. Five patients are still at work; 11 patients retired. Work was considered as very important for 9/19 patients. Speech rehabilitation permitted a modified but well understandable communication in 63% of the cases. This function was considered by 88% of the patients as very important. Finally, 73% of the patients (14/19) reported having a good to excellent overall QOL. CONCLUSION: Though disabling, pharyngolaryngectomies do not necessarily translate into worse overall QOL; ultimate disabilities are widely variable. Many factors such family, friends, personal leisure, activities, employement, cultural habits were important and depending on each patient in enjoyement of life's estimation.

Antisense PNA tridecamers targeted to the coding region of Ha-ras mRNA arrest polypeptide chain elongation.

We have previously described the rational design of mutation-selective antisense oligonucleotides targeted to codon 12 of oncogenic Ha-ras mRNA. In order to further improve the biological efficacy of these unmodified oligonucleotides, we have studied three different classes of modifications: peptide nucleic acid backbone (PNA), sugar modification (2'-O-methyl) and phosphoramidate linkage (PN). We show that PNA is unique among the investigated steric blocking agents in its ability to specifically inhibit the translation of Ha-ras mRNA in vitro. The PNA-RNA hybrid (Tm=86 degrees C), which is not dissociated by cellular proteins and resists phenol extraction and urea denaturing conditions, specifically blocks the translation of mutated Ha-ras mRNA. A PNA tridecamer which forms with wild-type Ha-ras mRNA a duplex with a central mismatch had little effect on mRNA translation. Codon 12 is located close to the translation initiation site and hybridization of the PNA at this position may interfere with the assembly of the translation initiation complex. To test whether polypeptide chain elongation can also be blocked, we have targeted PNA tridecamers to codons in the 74, 128 and 149 regions. These PNAs form equally stable duplexes as that formed by the PNA targeted to the codon 12 region (ten G.C base-pairs out of 13). We show that PNA-RNA duplexes block the progression of the 80 S ribosome. Therefore, it is possible to arrest translation with concomitant production of a truncated protein by using duplex-forming PNA oligonucleotides targeted to a G+C-rich sequences. Our data demonstrate for the first time that a non-covalent duplex can arrest the translation machinery and polypeptide chain elongation.

Polyethylenimine but not cationic lipid improves antisense activity of 3'-capped phosphodiester oligonucleotides.

Lipofectin, which is a mixture of neutral lipid with a cationic lipid, has been widely used to enhance cellular delivery of phosphorothioate, 2'-sugar-modified, and chimeric antisense oligonucleotides. Phosphodiester oligonucleotides delivered with Lipofectin usually do not elicit antisense activity probably because cationic lipid formulations do not sufficiently protect unmodified oligonucleotides from nuclease degradation. We show that a cationic polymer, polyethylenimine (PEI), improves the uptake and antisense activity of 3'-capped 20-mer and 12-mer antisense phosphodiester oligonucleotides (PO-ODN) targeted to different regions of Ha-ras mRNA and to the 3'-untranslated region (3'-UTR) of C-raf kinase. In contrast, PEI, which forms a very stable complex with the 20-mer phosphorothioate oligonucleotide (PS-ODN), does not enhance its antisense activity. Using fluorescently labeled carriers and ODN, we show that PEI-PS-ODN particles are very efficiently taken up by cells but PS-ODN is not dissociated from the carrier. Our results indicate that carrier-ODN particle size and stability and ODN release kinetics vary with the chemical nature of the ODN and the carrier being transfected into the cells. The very low cost of PEI compared with cytofectins and the increased affinity for target mRNA and decreased affinity for proteins of PO-ODN compared with PS-ODN make the use of PEI-PO-ODN very attractive.