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Titolo:
Experimental therapeutics with a new 10-deazaaminopterin in human mesothelioma: Further improving efficacy through structural design, pharmacologic modulation at the level of MRP ATPases, and combined therapy with platinums
Autore:
Khokhar, NZ; She, Y; Rusch, VW; Sirotnak, FM;
Indirizzi:
Mem Sloan Kettering Canc Ctr, Lab Mol Therapeut, Program Mol Pharmacol & Expt Therapeut, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA Mem Sloan Kettering Canc Ctr New York NY USA 10021 New York, NY 10021 USA
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 10, volume: 7, anno: 2001,
pagine: 3199 - 3205
SICI:
1078-0432(200110)7:10<3199:ETWAN1>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
MALIGNANT PLEURAL MESOTHELIOMA; ORGANIC-ANION TRANSPORTER; HUMAN-TUMOR XENOGRAFTS; PROTEIN GENE MRP1; 10-DEAZA-AMINOPTERIN SERIES; ANTITUMOR-ACTIVITY; FOLATE ANALOGS; LUNG-CANCER; L1210 CELLS; METHOTREXATE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Sirotnak, FM Mem Sloan Kettering Canc Ctr, Lab Mol Therapeut, Program Mol Pharmacol & Expt Therapeut, 1275 York Ave, New York, NY 10021 USA Mem SloanKettering Canc Ctr 1275 York Ave New York NY USA 10021
Citazione:
N.Z. Khokhar et al., "Experimental therapeutics with a new 10-deazaaminopterin in human mesothelioma: Further improving efficacy through structural design, pharmacologic modulation at the level of MRP ATPases, and combined therapy with platinums", CLIN CANC R, 7(10), 2001, pp. 3199-3205

Abstract

Studies described here sought to evaluate the therapeutic potential of a new 10-deazaaminopterin analogue, 10-propargyl-10-deazaaminopterin (PDX), alone and in combination with platinum compounds In the treatment of human pleural mesothelioma. In vitro studies documented 25-30-fold and 3-fold, respectively, greater cytotoxic potency of PDX compared with methotrexate and another 10-deazaaminopterin, edatrexate, against VAMT-1 and JMN cell lines derived from human mesothelioma. These tumor cell lines were also inhibited by platinum compounds. Cisplatin (CDDP) was somewhat more inhibitory than oxaloplatin and >1 log order in magnitude more inhibitory than carboplatin (CBCDA). Against the JMN tumor xenografted in nude mice, whereas methotrexate and, more so, edatrexate, were potently growth inhibitory, only PDX brought about substantial regression. By comparison, CDDP and CBCDA, but not oxaloplatin were markedly growth inhibitory to this same tumor in vivo. This high level of therapeutic activity of PDX could be additionally enhanced by coadministration of probenecid, an inhibitor of canicular multispecific organic anion transporter/multidrug resistance-related protein (MRP)-like ATPases, which increased the number of complete regressions by > -3 fold. Canicular multispecific organic anion transporter/MRP genes, primarily 1, 3, 4, 5, and 7, were In fact expressed in these human mesothelioma cell lines as determined by real-time reverse transcription-PCR. These same MRP genes, including, to a lesser extent, MRP-4, were also expressed in pleural mesotheliomas derived from patients as shown by the same methodology. When combinedwith CDDP or CBCDA, PDX achieved 2-fold greater overall regression of the JMN tumor with a 3-4-fold increase in complete regressions, although some attenuation of dosages of each were required in the combination. These results strongly suggest that PDX has significant potential in the treatment of human pleural mesothelioma, particularly when coadministered with probenecid or combined with platinum compounds.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 19:17:27