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Titolo:
COMPARATIVE ANTITUMOR EFFICACY OF DOCETAXEL AND PACLITAXEL IN NUDE-MICE BEARING HUMAN TUMOR XENOGRAFTS THAT OVEREXPRESS THE MULTIDRUG-RESISTANCE PROTEIN (MRP)
Autore:
VANHOEFER U; CAO S; HARSTRICK A; SEEBER S; RUSTUM YM;
Indirizzi:
ROSWELL PK CANC INST,DEPT EXPT THERAPEUT,GRACE CANC DRUG CTR,ELM & CARLTON ST BUFFALO NY 14263 ROSWELL PK CANC INST,DEPT EXPT THERAPEUT,GRACE CANC DRUG CTR BUFFALO NY 14263 UNIV ESSEN GESAMTHSCH,W GERMAN CANC CTR,DEPT INTERNAL MED CANC RES ESSEN GERMANY
Titolo Testata:
Annals of oncology
fascicolo: 12, volume: 8, anno: 1997,
pagine: 1221 - 1228
SICI:
0923-7534(1997)8:12<1221:CAEODA>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
HAMSTER OVARY CELLS; LUNG-CANCER; DOXORUBICIN RESISTANCE; P-GLYCOPROTEIN; DRUG-EFFLUX; TAXOL; GENE; LINES; EXPRESSION; TAXOTERE;
Keywords:
DOCETAXEL; MRP; MULTIDRUG RESISTANCE; NUDE MICE; PACLITAXEL;
Tipo documento:
Article
Natura:
Periodico
Citazioni:
57
Recensione:
Indirizzi per estratti:
Citazione:
U. Vanhoefer et al., "COMPARATIVE ANTITUMOR EFFICACY OF DOCETAXEL AND PACLITAXEL IN NUDE-MICE BEARING HUMAN TUMOR XENOGRAFTS THAT OVEREXPRESS THE MULTIDRUG-RESISTANCE PROTEIN (MRP)", Annals of oncology, 8(12), 1997, pp. 1221-1228

Abstract

Background. Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies ofpaclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. Materials and methods: Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v,infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 mu M), a potent inhibitor of MRP-function. Results. At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0%CR) for PC; 0% for Dr). Since treatment of mice with the MTD of PC orDC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%;DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold moreresistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. Conclusions. Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, theobserved resistance appears to be related to MRP. These data suggest,that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 08:40:45