title: Drug resistance in prostate cancer cell lines is influenced by androgen dependence and p53 status.
abstract: Chemotherapeutic drug resistance remains a significant obstacle in the control of prostate cancer. The influence of p53 and androgen status on the drug response of new cell lines from normal, benign and primary tumour epithelium was investigated. The prostate cell lines 1542-NPTX, BPH-1, 1542-CP(3)TX, 1532-CP(2)TX, 1535-CP(1)TX and LNCaP were exposed to TD(50) doses of etoposide, vinblastine and estramustine for a period of 24 h and re-incubated for a further 4 days before measuring the cell viability by crystal violet vital dye staining assay. The virus-transformed cell lines were found to be approximately ten times more sensitive to etoposide and vinblastine than the non virus-transformed LNCaP cell line. Estramustine proved to be the least toxic drug. The LNCaP cell line emerged as DHT-sensitive against nanomolar concentrations of 5alpha-dihydrotestosterone in charcoal-stripped growth medium. The virus-transformed cell lines were DHT-insensitive. Induction of p21 by (60)Co gamma-irradiation was used to assess the functionality of the p53 gene. p21 induction in the LNCaP cell line reached a peak 7.5 h post-irradiation. No significant p21 induction occurred in the virus-transformed cell lines. We show that the androgen-independent tumour cell lines are more sensitive to etoposide and vinblastine than the androgen dependent cell line, LNCaP. Except for LNCaP cells, etoposide and vinblastine were found to be three- to ten-fold more effective than estramustine. In the benign hyperplasia cell line, BPH-1, only etoposide is highly effective. Etoposide and vinblastine were found to effectively inactivate the androgen-independent cell lines, in which p53 is dysfunctional.
authors.affiliation: Department of Radiation Oncology, Faculty of Health Sciences and Tygerberg Hospital, Tygerberg 7505, South Africa.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Serafin
authors.forename: John M
authors.initials: JM
authors.lastname: Akudugu
authors.forename: Lothar
authors.initials: L
authors.lastname: Bohm
mesh_terms: D000728:Androgens / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D004961:Estramustine / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014747:Vinblastine / Q000494:pharmacology*
chemical_list: D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D004961:Estramustine; D014747:Vinblastine; D005047:Etoposide