Vanhoefer U, Cao S, Harstrick A, Seeber S, Rustum Y M
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, Germany.
Ann Oncol. 1997 Dec;8(12):1221-8. doi: 10.1023/a:1008290406221.
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.
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.
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.
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.
多药耐药性与多药耐药蛋白（MRP）的表达有关。最近，在乳腺癌和非小细胞肺癌患者的人类肿瘤样本中检测到了MRP表达。由于紫杉类药物是治疗这两种肿瘤实体最有效的药物，因此在携带表达MRP的人肿瘤异种移植物的裸鼠中比较了紫杉醇和多西他赛的抗肿瘤疗效。
用阿霉素（[Dx]10mg/kg静脉推注）、紫杉醇（[PC]50mg/kg静脉输注3小时）或多西他赛（[DC]40mg/kg静脉输注3小时）的最大耐受剂量（MTD）治疗携带亲本人类肉瘤HT1080或表达MRP的HT1080/DR4细胞肿瘤异种移植物的无胸腺裸鼠（nu/nu，经Northern印迹分析证实）。在体外，使用吡啶类似物PAK-104P（5μM），一种有效的MRP功能抑制剂，通过磺酰罗丹明B（SRB）测定法评估阿霉素、紫杉醇和多西他赛的活性。
在其MTD下，两种紫杉类药物对MRP阴性的HT1080异种移植物均显示出显著活性，PC的反应率为80%（40%完全缓解），DC的反应率为100%（60%完全缓解）。相比之下，在携带阿霉素耐药的表达MRP的HT1080/DR4肿瘤异种移植物的裸鼠中，DC比PC活性显著更高（总体反应率：DC为100%（60%完全缓解）；PC为10%（0%完全缓解）；Dx为0%）。由于用PC或DC的MTD治疗小鼠产生的总体毒性相似（HT1080的最大体重减轻：PC为8.6±2.2%；DC为7.5±2.2%；HT1080/DR4的最大体重减轻：PC为11.6±3.0%；DC为7.6±1.8%），这些结果表明多西他赛对表达MRP的肿瘤的治疗指数增加。在体外，HT1080/DR4细胞对阿霉素、PC和DC的耐药性分别比亲本细胞高270倍、6.4倍和2.8倍。吡啶类似物PAK-104P完全恢复了对PC和DC的药物敏感性，而未观察到PAK-104P对亲本HT1080细胞有影响。
两种紫杉类药物在其MTD下对亲本HT1080肿瘤异种移植物均显示出显著疗效。然而，多西他赛在其MTD下对表达MRP的肿瘤异种移植物的活性明显高于紫杉醇。此外，HT1080/DR4细胞对PC（6.4倍）的体外耐药性高于对DC（2.8倍）。由于PAK-104P完全恢复了对两种紫杉类药物的敏感性，观察到的耐药性似乎与MRP有关。这些数据表明，多西他赛不像紫杉醇那样容易被MRP转运，从而导致在体内表达MRP的肿瘤中治疗比率增加。因此，多西他赛在表达MRP的肿瘤的临床治疗中可能具有治疗优势。
