Li Yingming, Okegawa Takatsugu, Lombardi Donald P, Frenkel Eugene P, Hsieh Jer-Tsong
Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9110, USA.
J Urol. 2002 Jan;167(1):339-46.
Chemotherapy is often used as a primary therapy for metastatic cancer because it kills cells en masse. However, high doses of chemotherapeutic drugs can cause toxicity in nontarget organs. Gene therapy may provide a better alternative to chemotherapy because its targeting of specific genes may reduce the undesirable toxicity associated with chemotherapy. We evaluated whether the chemotherapeutic agent docetaxel or paclitaxel may be combined with gene therapy to create a new therapeutic regimen for metastatic androgen independent prostate cancer.
The 2 androgen independent prostate cancer cell lines PC-3 and DU 145 were treated with docetaxel or paclitaxel. Three recombinant adenoviruses containing p21WAF-1/CIP1, p53 protein or beta-galactosidase complementary DNA under the control of cytomegalovirus promoter were used to determine transgene expression. They were evaluated by Western blot analysis, beta-galactosidase activity or in vitro growth assays. The [(3)H] labeled E1 deleted adenovirus dl312 was used to determine adenovirus uptake into cells.
Docetaxel and paclitaxel enhanced adenovirus mediated transgene expression. Docetaxel appears to be a more potent growth inhibitor in vitro. Elevated transgene expression in virus infected cells induced by these 2 drugs was produced by increased cytomegalovirus promoter activity rather than increased virus uptake.
The potential synergy of gene therapy with docetaxel and paclitaxel may be an important direction for future therapy for metastatic androgen independent prostate cancer.
化疗常被用作转移性癌症的主要治疗方法，因为它能大量杀死细胞。然而，高剂量的化疗药物会对非靶器官产生毒性。基因治疗可能是化疗的一种更好替代方法，因为其对特定基因的靶向作用可能会降低与化疗相关的不良毒性。我们评估了化疗药物多西他赛或紫杉醇是否可与基因治疗联合，以创建一种针对转移性雄激素非依赖性前列腺癌的新治疗方案。
用多西他赛或紫杉醇处理两种雄激素非依赖性前列腺癌细胞系PC - 3和DU 145。使用三种在巨细胞病毒启动子控制下含有p21WAF - 1/CIP - 1、p53蛋白或β - 半乳糖苷酶互补DNA的重组腺病毒来确定转基因表达。通过蛋白质免疫印迹分析、β - 半乳糖苷酶活性或体外生长试验对其进行评估。使用[³H]标记的E1缺失腺病毒dl312来确定腺病毒进入细胞的摄取情况。
多西他赛和紫杉醇增强了腺病毒介导的转基因表达。多西他赛在体外似乎是一种更强效的生长抑制剂。这两种药物诱导的病毒感染细胞中转基因表达的升高是由巨细胞病毒启动子活性增加而非病毒摄取增加所致。
基因治疗与多西他赛和紫杉醇的潜在协同作用可能是转移性雄激素非依赖性前列腺癌未来治疗的一个重要方向。
