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Titolo:
Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo
Autore:
Gokhale, PC; McRae, D; Monia, BP; Bagg, A; Rahman, A; Dritschilo, A; Kasid, U;
Indirizzi:
Georgetown Univ, Med Ctr, Dept Radiat Med, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 iat Med, Washington, DC 20007 USA Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA GeorgetownUniv Washington DC USA 20007 Pathol, Washington, DC 20007 USA Georgetown Univ, Med Ctr, Dept Radiol, Washington, DC 20007 USA GeorgetownUniv Washington DC USA 20007 Radiol, Washington, DC 20007 USA ISIS Pharmaceut, Dept Mol Pharmacol, Carlsbad, CA 92008 USA ISIS Pharmaceut Carlsbad CA USA 92008 l Pharmacol, Carlsbad, CA 92008 USA NeoPharm Inc, Bannockburn, IL 60015 USA NeoPharm Inc Bannockburn IL USA 60015 harm Inc, Bannockburn, IL 60015 USA
Titolo Testata:
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT
fascicolo: 2, volume: 9, anno: 1999,
pagine: 191 - 201
SICI:
1087-2906(199904)9:2<191:AROIAR>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHASE-I TRIAL; PHOSPHOROTHIOATE OLIGONUCLEOTIDE; PROTEIN-KINASE; GENE-THERAPY; IONIZING-RADIATION; OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE; SQUAMOUS CARCINOMA; ANTITUMOR-ACTIVITY; NECK-CANCER; TUMOR-CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Kasid, U GeorgetownNW,iv, Med Ctr, Dept Radiat Med, E208,Res Bldg,3970 Reservoir Rd Georgetown Univ E208,Res Bldg,3970 Reservoir Rd NW Washington DC USA 20007
Citazione:
P.C. Gokhale et al., "Antisense raf oligodeoxyribonucleotide is a radiosensitizer in vivo", ANTISENSE N, 9(2), 1999, pp. 191-201

Abstract

Raf-1, a cytosolic protein serine/threonine kinase, plays important roles in cell growth, proliferation, transformation, and cell survival. The aim of the present study was to evaluate the radiotherapeutic efficacy of a fully phosphorothioated and well-characterized antisense raf oligodeoxyribonucleotide (ODN) corresponding to the 3'-untranslated region of human c-raf-1 mRNA (ISIS 5132/5132). Using our recently developed liposome encapsulation of ODN approach, we first compared the pharmacokinetic parameters of a liposomal formulation of 5132 (LE-5132) and 5132. The peak plasma concentrations5 minutes after ODN administrations (30 mg/kg i.v.) were 28.5 mu g/ml and 13.5 mu g/ml for LE-5132 and 5132, respectively. The decrease in plasma concentration of LE-5132 and 5132 followed a biexponential pattern, with initial distribution half-lives (t(1/2 alpha)) of 34.8 minutes and 21.6 minutes,respectively. The terminal half-lives (t(1/2 beta)) with LE-5132 and 5132 were 14.5 hours and 4.3 hours, respectively. The area under the plasma concentration-time curve (AUC) was 5.8 times higher with LE-5132 than with 5132. Significantly higher intact ODN levels could be measured in most organs within 48 hours of administration of LE-5132 compared with 5132 (liver 18.4-fold, spleen, 31-fold, heart 3-fold, lungs 1.5-fold). In kidneys, the levelwas lower with LE-5132 (0.77-fold). LE-5132 composition, unlike 5132, did not affect clotting time in vitro. Significant decline in the level of Raf-1 protein was observed in vitro in relatively radioresistant human laryngeal squamous cell carcinoma cells (SQ-20B) treated with LE-5132 compared withSQ-20B cells treated with equimolar concentration of 5132 or liposome-encapsulated mismatched 5132 (0.5 mu M LE-5132, 71.3% +/- 22.5%; 1.0 mu M LE-5132, 79.6% +/- 16.7%). In addition, LE-5132 appeared to be a more potent antitumor compound than 5132 (p < 0.001). These data established the suitability of LE-5132 for in vivo radiotherapeutic efficacy studies. Intravenous administration of LE-5132 into SQ-20B tumor-bearing athymic mice inhibited Raf-1 expression in tumor tissue compared with blank liposome-treated or untreated control groups. LE-5132 or ionizing radiation (IR) treatment alone caused significant but transient inhibition of SQ-20B tumor growth but not tumor regression. Remarkably, a combination of LE-5132 and IR treatments led to significant and sustained tumor regression for at least 27 days after the last treatment (p < 0.001). Histopathologic examination of tumor samples revealed a significant proportion of cells containing fragmented chromatin in the LE-5132 + IR treatment group as compared with single agent and untreated control groups. These in vivo data support the notion that Raf-1 has proliferative and survival functions and advance the scientific and technologic bases for the use of antisense raf ODN in the management of radioresistant malignancies.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/20 alle ore 12:28:34