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 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 of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP.


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 microM), 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 Dx). Since treatment of mice with the MTD of PC or DC 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 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 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, the observed 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.
Vanhoefer
U
U
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, Germany.
Cao
S
S
Harstrick
A
A
Seeber
S
S
Rustum
Y M
YM
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000077143:Docetaxel; D005354:Fibrosarcoma / Q000188:drug therapy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D043823:Taxoids; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D043823:Taxoids