Enhanced transgene expression in androgen independent prostate cancer gene therapy by taxane chemotherapeutic agents.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
The potential synergy of gene therapy with docetaxel and paclitaxel may be an important direction for future therapy for metastatic androgen independent prostate cancer.
Li
Yingming
Y
Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9110, USA.
Okegawa
Takatsugu
T
Lombardi
Donald P
DP
Frenkel
Eugene P
EP
Hsieh
Jer-Tsong
JT
D000256:Adenoviridae / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D000077143:Docetaxel; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*; D043823:Taxoids; D019076:Transgenes; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel