ISSN:
1569-8041
Keywords:
docetaxel
;
MRP
;
multidrug resistance
;
nude mice
;
paclitaxel
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Background: Multidrug resistance has been associated with expression ofthe multidrug resistance protein (MRP). Recently, MRP-expression has beendetected in human tumor samples of patients with breast cancer andnon-small-cell lung cancer. Since taxoids are the most active drugs in thetreatment of both tumor entities, the antitumor efficacies of paclitaxel anddocetaxel were compared in nude mice bearing human tumor xenografts thatexpress MRP. Materials and methods: Athymic nude mice (nu/nu) bearing tumor xenograftsof parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (asconfirmed by Northern blot analysis) were treated with the maximum tolerateddoses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50mg/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 docetaxelwas evaluated by the sulphorhodamine B (SRB) assay using the pyridineanalogue PAK-104P (5 µM), a potent inhibitor of MRP-function. Results: At their MTDs both taxoids showed significant activity againstMRP-negative HT1080 xenografts with response rates of 80% (40%CR) for PC and 100% (60% CR) for DC. In contrast, DC wassignificantly more active than PC in nude mice bearing doxorubicin resistantMRP-expressing HT1080/DR4 tumor xenografts (overall response rates:100% (60% CR) for DC; 10% (0% CR) for PC;0% for Dx). Since treatment of mice with the MTD of PC or DC yieldedsimilar 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 7.5 ± 1.8%, respectively), theseresults demonstrate the increase in the therapeutic index for docetaxelagainst MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold,6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PCand DC, respectively. Pyridine analogue PAK-104P completely restored drugsensitivity to PC and DC, while no effect of PAK-104P on parental HT1080cells was observed. Conclusions: Both taxoids, when given at their MTDs, showed significantefficacy against parental HT1080 tumor xenografts. However, docetaxel at itsMTD was significantly more active against MRP-expressing tumor xenografts thanpaclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higherfor PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restoredsensitivity to both taxoids, the observed resistance appears to be related toMRP. These data suggest, that docetaxel is not as readily transported by MRPas paclitaxel leading to an increased therapeutic ratio in MRP-expressingtumors in vivo. Therefore, docetaxel may have therapeutic advantages in theclinical treatment of MRP-expressing tumors.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1008290406221
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