Inhibition of prostate cancer growth by estramustine and colchicine

Hormone-refractory prostate cancer continues to be associated with a very poor prognosis. Agents that inhibit microtubule function have been found to be cytotoxic to prostate cancer cells in preclinical and clinical settings. It was the aim of this study to assess the activity of estramustine and colchicine, two microtubule inhibitors, in hormone-refractory prostate cancer. In clinically achievable concentrations, the combination of estramustine and colchicine was cytotoxic to both the Dunning rat prostate adenocarcinoma cell line MAT-LyLu (MLL) and human prostate cancer cells (PC-3). Microtubule function was assessed in vitro to evaluate possible mechanisms of action. In motility and cell cycle analysis assays, estramustine and colchicine inhibited cellular motility but not cell cycle transit. In vivo, these two agents both inhibited the growth of implanted Dunning rat prostate adenocarcinoma MLL cells but did not appear to have additive effects. The use of oral colchicine in the treatment of hormone-refractory prostate cancer requires further investigation.     

In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines

BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.     

A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer

OBJECTIVE: To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS: In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS: Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS: In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.     

Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer

OBJECTIVE: To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AND METHODS: In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS: In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013). CONCLUSION: Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.     

Estradiol causes a dose-dependent stimulation of prostate growth in castrated beagle dogs

BACKGROUND: We analyzed the cytotoxic properties of the new heterodinucleoside phosphate dimer 5-FdU-NOAC, which is composed of the cytotoxic drugs 5-FdU and N(4)-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) against human prostate tumor cells. METHODS: 5-FdU-NOAC effects on cell proliferation, cell cycle distribution, thymidylate synthase activity, and apoptosis were investigated in vitro in the two human prostate carcinoma cell lines DU-145 and PC-3 and compared to cells treated with the corresponding single drugs 5-FdU and NOAC. RESULTS: Treatment of the cells with 5-FdU-NOAC resulted in IC(50) values of 3.9-5 microM and in a complete inhibition of cell proliferation at 200 microM after 96 hr compared to 5-FdU, where 10% of the cells remained resistant. Flow cytometric analysis revealed cell cycle perturbations in S-phase only in the DU-145 cells. 5-FdU-NOAC caused 50% inhibition of thymidylate synthase after 90 min at 0.6 microM in both cell lines. Apoptotic cell fractions in DU-145 (66%) and in PC-3 (34%) cells were found after treatment with 5-FdU-NOAC for 96 hr. DNA fragmentation further confirmed the induction of apoptosis. CONCLUSIONS: 5-FdU-NOAC inhibits thymidylate synthase and cell cycle progression causing proliferation arrest and apoptosis in DU-145 and PC-3 cells, suggesting a potential role of 5-FdU-NOAC for the treatment of prostate cancer.     

Effectiveness of taxanes-based chemotherapy against hormone-refractory prostate carcinoma

We performed an investigative and clinical study of docetaxel, and evaluated its efficacy against hormone-refractory prostate carcinoma (HRPC). In an in vitro experiment, docetaxel suppressed the human prostate cell line proliferation not only in an androgen-dependent cell line, LNCaP, but also in androgen-independent cell line, PC-3, in a dose-dependent manner. In an in vivo experiment applying an SCID mouse xenograft model with PC-3, docetaxel administration suppressed the tumor growth more than 95%. In a clinical study, eight cases were enrolled to low-dose (20 mg/m2/wk) weekly regimen and an other eight to high-dose (60 mg/m2/wk) administration of docetaxel every three weeks. A prostate specific antigen (PSA) decline of more than 50% were observed in 4 (50%) in the low-dose group and 5 (63%) in the high-dose group. The median time to progression and overall survival were 8.5 and 13.2 months in the low-dose group and more than 5.5 and 8.5 months in the high-dose one, respectively. This regimen was well tolerated, and the incidence of adverse effect was relatively low and light. Grade 3 neutropenia or leukocytopenia without fever was seen in three patients (18.8%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed. In conclusion, docetaxel-based chemotherapy was well tolerated and an active treatment for HRPC cases.     

Chemotherapy agents and timing of chemotherapy in prostate cancer management

In 2005, it is estimated that more than 30,000 men will die from metastatic hormone-refractory prostate cancer. For decades, no chemotherapeutic agent demonstrated a survival benefit in these patients, although two randomized clinical trials demonstrated a clear palliative benefit using mitoxantrone combined with a corticosteroid. However, beginning in 1999, a series of phase-2 trials were performed using docetaxel, either as a single agent or in combination with estramustine. Preliminary data implied a survival improvement, with median survivals reported to be 14 to 23 months. Prostate-specific antigen levels dropped by more than 50% in 38% to 48% of patients treated with docetaxel. These findings were confirmed in two phase-3 randomized trials in which docetaxel with and without estramustine have demonstrated a survival benefit using chemotherapy in the treatment of hormone-refractory prostate cancer.     

Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer

PURPOSE: We evaluated the independent response rate of dexamethasone before docetaxel and estramustine administration as measured by changes in serum prostate specific antigen (PSA) in patients with androgen independent prostate cancer. MATERIALS AND METHODS: A total of 12 patients received 20 mg. dexamethasone orally every 6 hours for 3 doses repeated every 3 weeks before starting cytotoxic therapy with estramustine and docetaxel. After progression on dexamethasone 280 mg. estramustine orally 3 times daily on days 1 to 5 and 70 mg./m.2 docetaxel intravenously for 1 hour on day 2 were given. RESULTS: None of the patients initially treated with dexamethasone monotherapy (median 1 cycle, range 1 to 5) had a PSA decline of 50% or greater. Median PSA increase on monotherapy was 47% (range 0% to 22%). On estramustine and docetaxel therapy PSA decreased 50% or greater in 11 patients (92%, 95% confidence intervals [CI] 60 to 99) and 80% or greater in 7 (58%, 95% CI 29 to 84), and normalized in 5 (42%, 95% CI 16 to 71), with a median duration of response of 153 (range 42 to 371), 132 (range 84 to 287) and 84 (range 21 to 174) days, respectively. Median times to reach 50% and 80% decreases in baseline PSA were 21 (range 21 to 209) and 63 (range 21 to 138) days, respectively. In 9 patients (75%, 95% CI 43 to 93) PSA decreased at least 50% by week 9. Of 4 patients with bidimensionally measurable disease 3 had a partial response. Median time to progression was 263 days (range 91 to 378). CONCLUSIONS: Administration of 20. mg. dexamethasone orally every 6 hours for 3 doses every 3 weeks does not significantly contribute to the PSA response rate of estramustine and docetaxel.     

Single-agent chemotherapy with docetaxel significantly reduces PSA levels in patients with high-grade localized prostate cancers

OBJECTIVE: Chemotherapy has been shown to be effective in the management of prostate cancer in patients with androgen-independent metastatic disease, however, a survival benefit has not been demonstrated yet. Docetaxel alone or in combination with estramustine has been shown to exhibit a high level of activity in the treatment of hormone-refractory prostate cancer. To date there are only few reports on chemotherapy for localized prostate cancer. METHODS: The efficacy and safety of neoadjuvant chemotherapy with docetaxel as a single agent given prior to radical retropubic prostatectomy (RRP) has been evaluated in 5 patients presenting with Gleason score 8 prostate cancers at biopsy. RESULTS: The mean reduction in prostate-specific antigen levels in the 5 patients was 66.5% (range 47.6-94.0%). Histology after RRP yielded pT2N0MxR0 prostate cancers in all subjects. Testosterone and secretoneurin levels were not significantly affected by docetaxel monotherapy. CONCLUSIONS: Although the use of neoadjuvant chemotherapy prior to RRP is still experimental, the dramatic prostate-specific antigen decrease during chemotherapy and the pathologic findings after radical prostatectomy are encouraging. Studies including larger number of patients will have to confirm the present results.     

Development of weekly high-dose calcitriol based therapy for prostate cancer

Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50% in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50% reduction) in 81% of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population.     

Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to chemotherapy. The sphingolipid ceramide and its analogs have been demonstrated to exert antitumor activity in many cell types; however, the effectiveness of these analogs has been limited by potency and solubility. This study focuses on the effects of novel highly soluble cationic pyridinium-ceramides, alone and in combination with various chemotherapeutic agents, on cell survival, telomerase activity, and cell cycle arrest in HNSCC cell lines in vitro. METHODS: The concentration of pyridinium-ceramides and chemotherapeutic agents that inhibited cell growth by 50% (IC50) was determined by MTT cell survival assays. The cell cycle profiles were determined by flow cytometry. Telomerase activity was determined by telomerase repeat amplification protocol (TRAP) assay. RESULTS: Treatment of the human UM-SCC-22A (SCC of the hypopharynx) cells, as well as various other HNSCC cell lines, with C6-Pyr-Cer resulted in the inhibition of cell survival with an IC50 concentration of approximately 250 to 300 nM at 96 hours, whereas its IC50 was greater than 1000 nM in noncancerous Wi-38 human lung fibroblasts, and adult human epidermal keratinocytes. Moreover, treatment with C6-Pyr-Cer also resulted in cell cycle arrest in G0/G1, which correlated with a significant inhibition of telomerase activity in UM-SCC-22A cells. Additional results demonstrated that the combination of C6-Pyr-Cer with gemcitabine (GMZ) or doxorubicin (DOX), which have the lowest IC50 concentrations among various chemotherapeutic drugs in these cells, enhances the effects of these drugs in the inhibition of telomerase and cell growth. CONCLUSIONS: These data suggest that the novel C6-Pyr-Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC.     

Synthetic retinoid CD437 induces S-phase arrest and apoptosis in human prostate cancer cells LNCaP and PC-3

BACKGROUND: Exposure of prostate carcinoma cell lines to retinoids, which function through the classical retinoic acid nuclear receptor, (RARs) or retinoid X receptors (RXRs), results in minimal cytostatic inhibition of cell proliferation. METHODS: Growth inhibition and various regulatory responses were investigated in two human prostate carcinoma cell lines (LNCaP and PC-3) treated with or without a synthetic retinoid, CD 437. RESULTS: Incubation of prostate carcinoma cell lines with a novel retinoid CD437 resulted in the marked inhibition of proliferation. LNCaP and PC-3 possessed IC50 values for CD437 of 375 nM and 550 nM, respectively. Incubation with 1 microM CD437 for 24 hr resulted in 100% and 60% inhibition of growth in LNCaP and PC-3 cells, respectively. Simultaneously, cell flow cytometric analyses revealed a dramatic increase of the cell population in S phase, in both LNCaP (from 38.6% up to 86.7%) and PC-3 (27.9% to 55.7%), and a decreased proportion of cells in G2 phase, in LNCaP (from 23.7% down to 1.2%) and PC-3 (14.9% to 2.2%), indicating a significant S-phase arrest. The cell growth inhibition and S-phase arrest in these cells were followed by apoptosis, as revealed by the acquisition of the characteristic cell morphology including the appearance of apoptotic bodies, and further confirmed by cellular DNA fragmentation. CD437-induced-S phase arrest was associated with upregulated mRNA levels of p21waf1/cip1/sdi1 in both LNCaP (p53+/+) and PC-3 (53-/-) cells. CONCLUSIONS: CD437 represents a unique retinoid that induces S-phase arrest and apoptosis in both androgen-dependent (LNCaP) and -independent (PC-3) human prostate cancer cells, suggesting a potential role of CD437 in the treatment of human prostate cancer.     

Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer

BACKGROUND: The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy. METHODS: PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts. RESULTS: We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80% of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111% overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80% tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70%) in mice survival. CONCLUSIONS: These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.     

Docetaxel and bortezomib downregulate <Emphasis Type="Italic">Bcl-2</Emphasis> and sensitize PC-3-<Emphasis Type="Italic">Bcl-2</Emphasis> expressing prostate cancer cells to irradiation

Background  Currently, docetaxel is used to treat hormone-refractory metastatic prostate cancer. Docetaxel not only inhibits microtubule formation but can also downregulate expression of Bcl-2, a known antiapoptotic oncogene. Furthermore, the 26S proteasome inhibitor bortezomib can downregulate Bcl-2 expression. Previously, we demonstrated that overexpression of Bcl-2 renders cells resistant to radiation therapy. In this study, we investigated whether treating human prostate cancer cells with docetaxel, bortezomib, or both could modulate Bcl-2 expression and whether such modulation could render Bcl-2-overexpressing cells more susceptible to radiation. Methods  PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with docetaxel and/or bortezomib in addition to irradiation were analyzed in vitro for proliferation, clonogenic survival, cell cycle phase distribution, and expression of Bcl-2 and Bcl-xL proteins. Results  Docetaxel and bortezomib alone had significant cytotoxic effects. In addition, docetaxel, bortezomib, or radiation resulted in a G2M phase arrest in PC-3-Bcl-2, whereas only docetaxel or radiation did so in PC-3-Neo cells. Both cell lines were more sensitized to radiation’s killing effects when treated with the combination of docetaxel and bortezomib than when treated with either agent alone. Furthermore, docetaxel and bortezomib-treated cells exhibited marked changes in the expression of Bcl-2 and Bcl-xL. Conclusions  This is the first study to demonstrate that docetaxel and bortezomib in combination can effectively sensitize Bcl-2-overexpressing human prostate cancer cells to radiation effects by modulating the expression of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the combination of docetaxel and bortezomib in prostate cancer.     

Inhibitory effect of zinc on human prostatic carcinoma cell growth.

BACKGROUND: Normal human prostate accumulates the highest levels of zinc of any soft tissue in the body. In contrast, the zinc level in prostate cancer is markedly decreased from the level detected in nonprostate tissues. Despite these relationships, the possible role of zinc in the growth of normal and malignant prostate has not been determined. METHODS: Growth inhibition and various regulatory responses were investigated in two human prostate carcinoma cell lines (LNCaP and PC-3), treated with or without zinc. RESULTS: Incubation of the prostate carcinoma cell lines with physiological levels of zinc resulted in the marked inhibition of cell growth. A lower 50% inhibition of cell growth (IC50) value for zinc (about 100 ng/ml) was detected in LNCaP cells, which are androgen-responsive, whereas androgen-independent PC-3 cells exhibited a higher IC50 for zinc (about 700 ng/ml). Incubation with 1 microg/ml zinc resulted in maximum inhibition of growth in both cell lines. These inhibitory effects of zinc correlated well with the accumulation of zinc in the cells. Simultaneously, cell flow cytometric analyses revealed a dramatic increase of the cell population in G2/M phase, in both LNCaP (2.3-fold vs. control) and PC-3 (1.9-fold vs. control), and a decreased proportion of cells in S phase (LNCaP, -51.4%; PC-3, -23%), indicating a G2/M phase arrest. The cell growth inhibition and G2/M arrest in these cells were accompanied by an increase in apoptosis, as demonstrated by the characteristic cell morphology and further confirmed by cellular DNA fragmentation. The specificity of zinc-induced apoptosis was identified by ethylenediamine-tetraacetic acid (EDTA)-chelation, which abolished the zinc effect on cellular DNA fragmentation. The zinc-induced G2/M phase arrest and apoptosis were accompanied by increased mRNA levels of p21(Waf1/Cip1/Sdi1) in both LNCaP (p53+/+) and PC-3 (p53-/-) cells. CONCLUSIONS: These results suggest that zinc inhibits human prostatic carcinoma cell growth, possibly due to induction of cell cycle arrest and apoptosis. There now exists strong evidence that the loss of a unique capability to retain high levels of zinc is an important factor in the development and progression of malignant prostate cells.     

Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2

BACKGROUND: Studies suggest that triiodothyronine (T3) and cognate nuclear receptors (hTR) are involved in regulation of prostatic cell growth and differentiation. To probe mechanisms for T3 effects, we studied prostate carcinoma cells, investigating the effect of T3 on expression of the B-cell translocation gene 2 (BTG2), which regulates the G1/S transition of the cell cycle. METHODS: Effects of T3 on cell proliferation were determined by (3)H-thymidine incorporation. T3 modulation of BTG2 expression was investigated using immunoblots, Northern blots, and transient gene expression assays. The putative T3 response element was determined by electrophoretic mobility shift assay. RESULTS: T3 (0.1-1,000 nM) enhanced threefold the proliferation of prostate carcinoma cells and human androgen-dependent prostate carcinoma cells (LNCaP), but not PC-3 cells. T3 also inhibited BTG2 gene expression in LNCaP cells. Reporter assays showed that T3 downregulates by 50% promoter activity of the BTG2 gene in LNCaP cells but not PC-3 cells or thyroid-hormone receptor (TRbeta1)-overexpression PC-3 cells. Deleting the putative thyroid hormone response element (TRE; AGCGATGACCTCAGCG) blocked the inhibitory effect of T3 on BTG2 promoter activity. Electrophoretic mobility shift assays with purified TRbeta1 from in vitro translation, or with nuclear extracts from LNCaP cells and PC-3 cells, demonstrated the presence of T3 receptor binding sites in the TRE region. CONCLUSIONS: These results suggested that the T3 upregulates proliferation of LNCaP cells by downregulating BTG2 gene expression through the consensus TRE pathway.     

Prostate cancer: future strategies for chemotherapy management

Chemotherapy is one the therapeutic options in prostate cancer. Docetaxel once every three weeks is the current standard for castration-refractory disease with cancer-related symptoms. The docetaxel plus estramustine association is likely more active than docetaxel alone. Docetaxel is currently tested in early stages: first results of phase III trials are expected by 2009-2010.     

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

PURPOSE: 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. MATERIALS AND 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.     

Inhibition of prostate cancer growth by vinblastine and tamoxifen

Hormone refractory prostate cancer continues to be an aggressive and fatal disease. Agents which inhibit microtubule function have been found to be cytotoxic to prostate cancer cells in preclinical and clinical settings. It was the aim of this study to assess the activity of tamoxifen and vinblastine, two microtubule inhibitors, in hormone refractory prostate cancer. In clinically achievable concentrations, the combination of tamoxifen and vinblastine was cytotoxic to both Dunning rat prostate adenocarcinoma cell line MAT-LyLu (MLL) and human prostate cancer cells (PC-3). In cell cycle analysis assays, tamoxifen and vinblastine inhibited cell cycle transit. In vivo, these two agents inhibited the growth of implanted MLL cells. It appears that tamoxifen and vinblastine may be effective agents for the treatment of patients with hormone refractory prostate cancer.