COMPARATIVE ANTITUMOR EFFICACY OF DOCETAXEL AND PACLITAXEL IN NUDE-MICE BEARING HUMAN TUMOR XENOGRAFTS THAT OVEREXPRESS THE MULTIDRUG-RESISTANCE PROTEIN (MRP)

Background. Multidrug resistance has been associated with expression o f the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer a nd non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumo r xenografts that express MRP. Materials and methods: Athymic nude mic e (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analys is) 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 vi tro, the activity of doxorubicin, paclitaxel and docetaxel was evaluat ed by the sulphorhodamine B (SRB) assay using the pyridine analogue PA K-104P (5 mu M), a potent inhibitor of MRP-function. Results. At their MTDs both taxoids showed significant activity against MRP-negative HT 1080 xenografts with response rates of 80% (40% CR) for PC and 100% (6 0% CR) for DC. In contrast, DC was significantly more active than PC i n nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tu mor 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 or DC yielded similar overall toxicity (maximum weight loss for HT1080: P C 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 more resistant 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 obse rved. Conclusions. Both taxoids, when given at their MTDs, showed sign ificant efficacy against parental HT1080 tumor xenografts. However, do cetaxel at its MTD was significantly more active against MRP-expressin g tumor xenografts than paclitaxel. Furthermore, in vitro resistance o f 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, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel lead ing 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.