Regulation of growth factors in hormone‐ and drug‐resistant prostate cancer cells by synergistic combination of docetaxel and octreotide

OBJECTIVE

To evaluate the effects of combined treatment with docetaxel and octreotide, a somatostatin analogue, on human hormone‐ and drug‐refractory prostate cancer cell lines, PC‐3 and DU‐145, and on some growth factors related to tumour growth and angiogenesis in prostate cancer.

MATERIALS AND METHODS

A cell proliferation assay was used to assess the cytotoxicity of the drugs. To verify apoptosis, both DNA fragmentation (by enzyme‐linked immunosorbent assay) and caspase 3/7 activity were measured. We also investigated the effect of combined docetaxel and octreotide on growth factors secreted from prostate cancer cells using a human growth factor antibody array.

RESULTS

The combination of docetaxel and octreotide resulted in significant synergistic cytotoxic activity and apoptosis, which was dose‐ and time‐dependent. The combined treatment also resulted in significantly less secretion of stem cell factor and platelet‐derived growth factor‐AB in PC‐3 cells, and transforming growth factor‐β and basic fibroblast growth factor in DU‐145 cells, than in untreated controls.

CONCLUSION

Octreotide, a somatostatin analogue, combined with docetaxel might provide a rationale treatment option for hormone‐refractory prostate cancer cells, not only by direct inhibition of cell proliferation but also by inhibiting the secretion of growth factors.     

Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy

OBJECTIVES

To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re‐introduce chemosensitivity in a docetaxel‐resistant, androgen‐independent human prostate cancer model.

PATIENTS AND METHODS

A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG‐P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC‐3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel‐resistant cell subline (PC‐3dR) was developed and analysed.

RESULTS

sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5‐fold in the newly developed docetaxel‐refractory PC‐3dR cell line compared with parental PC‐3 cells. There was a dose‐dependent and sequence‐specific decrease in sCLU levels in PC‐3dR cells using OGX‐011, an antisense oligonucleotide against human sCLU. OGX‐011 and small‐interference RNA both chemosensitized PC‐3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC‐3dR cells were significantly increased when OGX‐011 was combined with docetaxel. In vivo, growth of PC‐3dR xenografts in nude mice was synergistically inhibited by OGX‐011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively).

CONCLUSION

The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel‐refractory cells, and provide preclinical proof of principle for clinical trials testing OGX‐011 in second‐line chemotherapy regimens for patients with docetaxel‐refractory prostate cancer.     

ADAMTS1, a putative anti‐angiogenic factor,is decreased in human prostate cancer

OBJECTIVE

To investigate the expression of ‘ADAM metallopeptidase with thrombospondin type I motif, 1’ (ADAMTS1) in human prostate cancer, and to study its relationship to microvessel density (MVD) and metastasis. ADAMTS1 has been described as an anti‐angiogenic and antitumour factor, but its function in prostate cancer is unknown.

PATIENTS AND METHODS

ADAMTS1 expression was evaluated by immunohistochemistry in specimens obtained by transurethral resection of the prostate from patients with hormone‐naïve and hormone‐refractory prostate tumours, including adjacent benign tissue. A semiquantitative scoring system was used for evaluating the staining. MVD was quantified by counting the number of CD34‐positive blood vessels.

RESULTS

ADAMTS1 was strongly expressed in the luminal epithelial cells in benign prostate glands, whereas expression was significantly lower in prostate cancer cells. There was no obvious difference between hormone‐naïve and hormone‐refractory tumours, and ADAMTS1 expression did not correlate with Gleason score. However, in hormone‐refractory tumours from patients with metastatic disease, the expression of ADAMTS1 was significantly lower than in tumours from patients without metastases. Furthermore, the MVD was higher in hormone‐refractory than in hormone‐naïve tumours and benign tissue, and MVD correlated with Gleason score. There was no association between ADAMTS1 and MVD in the hormone‐naïve tumours, while hormone‐refractory tumours with low ADAMTS1 expression had a higher MVD than those with moderate/high expression.

CONCLUSION

ADAMTS1 expression is decreased in prostate cancer, and might be involved in the early steps of prostate cancer development. Further, ADAMTS1 might have an anti‐angiogenic and antimetastatic role in hormone‐refractory prostate cancer, where low ADAMTS1 expression is associated with a high MVD and metastasis.     

Genistein combined polysaccharide enhances activity of docetaxel, bicalutamide and Src kinase inhibition in androgen-dependent and independent prostate cancer cell lines

OBJECTIVE

To determine the benefit of genistein combined polysaccharide (GCP) in combination with the androgen receptor antagonist bicalutamide, the antimicrotubule taxane docetaxel, and the Src kinase inhibitor pp2 as part of a treatment regimen for advanced prostate cancer (CaP).

MATERIALS AND METHODS

The growth inhibitory and apoptotic effects of GCP in combination with bicalutamide, docetaxel and pp2 were evaluated in both the androgen‐dependent LNCaP line, and three androgen‐independent lines: CWR22Rv1, PC‐3, and LNCaP‐R273H. The LNCaP‐R273H model is an LNCaP variant expressing a p53^GOF allele; like CWR22Rv1 and PC‐3, it is able to grow in a minimal androgen environment. The effects of GCP treatment in combination with the aforementioned drugs were measured using an MTT assay, Western blotting, flow cytometric analysis, and caspase activation assay. Altered schedules of drug administration were explored using combinations of GCP and docetaxel.

RESULTS

GCP potentiated the activity of docetaxel in all four cell lines, resulting in growth inhibition and increased apoptosis. The combination of GCP and bicalutamide had enhanced activity in both the LNCaP and LNCaP‐R273H lines, which may better represent patient tumour cells after progression to androgen independence. Administration of docetaxel followed by GCP resulted in a synergistic interaction in LNCaP cells, with increased apoptosis. By contrast, GCP administered first showed subadditivity, probably resulting from GCP‐mediated induction of G1 arrest interfering with docetaxel activity.

CONCLUSION

These data suggest that GCP, an isoflavone‐enriched compound with minimal side‐effects and far superior intestinal absorption rate of genistein, has significant clinical potential in combination with docetaxel, bicalutamide or targeted agents for the treatment of advanced CaP.     

BCG directly induces cell cycle arrest in human transitional carcinoma cell lines as a consequence of integrin cross-linking

Background

Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied.

Methods

We investigated the effects of androgen on glycogen phosphorylase (GP), glycogen synthase (GS) and on glycogen accumulation in the androgen-receptor (AR) reconstituted PC3 cell line containing either an empty vector (PC3-AR-V) or vector with HPV-E7 (PC3-AR-E7) and the LNCaP cell line.

Results

Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P) had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number.

Conclusion

Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.     

Combination of docetaxel and vandetanib in docetaxel-sensitive or resistant PC3 cell line

ObjectiveTo examine the anti-proliferative effect of the combination of docetaxel, the cornerstone of modern chemotherapy for prostate cancer, and vandetanib, a potent inhibitor of VEGFR-2 tyrosine kinase, applied to the representative hormone-refractory human prostate cancer cell line PC3. The aim is to analyze if a supra-additive/synergic effect of the combined treatment on cell viability exists and to understand the molecular key-factors involved. We first hypothesized an effect of vandetanib in modulation the function of MDR1, leading to a longer retention of docetaxel inside the cell. It may also be possible that vandetanib could modulate the docetaxel-induced changes in expression of prosurvival and proapoptotic proteins, leading to a positive balance forward cell death.Materials and methodsWe used PC3 cells either wild type (PC3wt) or with acquired resistance to docetaxel (PC3R), characterized by a higher expression of MDR1. We studied both mRNA and protein, the expression of EGF and VEGF receptors at a basal level and after each treatment, as well as the expression of cell cycle and apoptosis related genes.ResultsCell proliferation data suggested a supra-additive cytotoxic effect of the combination of docetaxel plus vandetanib, when given together or with the sequence vandetanib followed by docetaxel. We did not observe any effect of vandetanib on MDR1, in the PC3R cell lines, characterized by a higher pump expression than PC3wt. On the other side, we defined a number of key factors involved in the pro- and anti-survival balance, which regulation, by single drugs and/or by combined treatment, could explain the effect on cell cytotoxicity; also where there are apparently contradictory results.ConclusionsOur data suggest that combined treatment with vandetanib and docetaxel alters the balance of proapoptotic and prosurvival proteins, ultimately leading to potentiation of docetaxel-induced apoptosis in human prostate cancer cells in vitro, irrespective of cells being sensitive or resistant to docetaxel.     

Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer

OBJECTIVES

To evaluate the efficacy of docetaxel/carboplatin (DC)‐based chemotherapy as first‐ and second‐line chemotherapy for patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

We retrospectively identified all patients with HRPC treated with DC‐based chemotherapy at the Dana‐Farber Cancer Institute. Regimens either included estramustine (EDC) or not (DC). We identified patients who received EDC as first‐line chemotherapy and patients who received DC as second‐line or subsequent chemotherapy. Patients treated with EDC received 20–70 mg/m² docetaxel every 1–4 weeks, estramustine 140 mg three times daily and carboplatin (area under the curve, AUC), (4–6) every 3–4 weeks. Patients treated with DC received docetaxel 50–70 mg/m² and carboplatin AUC (4–6) every 3–4 weeks.

RESULTS

In all, the study included 54 patients; 24 received EDC and 30 DC (median age 62.8 and 66.9 years, respectively); their prostate‐specific antigen (PSA) level at the start of chemotherapy was 112.7 and 213.3 ng/mL, respectively. There were declines of ≥50% in PSA level in 88% and 20% in the two groups, respectively. The median overall survival was 17.7 and 14.9 months in the EDC and DC groups, respectively. The most common reversible grade 4 toxicity with either regimen was neutropenia (4% and 7% in EDC and DC, respectively).

CONCLUSIONS

DC‐based chemotherapy is well tolerated and active in HRPC. Adding carboplatin to docetaxel provides an additional activity in 20% of patients as a second‐line or subsequent chemotherapy.     

Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: results of a multicentre, randomized phase II trial

OBJECTIVE

To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m² on day 1 (arm A), or docetaxel 70 mg/m² on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1–5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate‐specific antigen (PSA) level.

RESULTS

Forty‐five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by ≥50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time.

CONCLUSION

These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.     

Cryoablative response of prostate cancer cells is influenced by androgen receptor expression

OBJECTIVE

To investigate in prostate cancer cells the consequences of androgen‐insensitivity (AI) development on the cellular and molecular responses to freezing, as a challenge in prostate cancer treatment occurs when the androgen‐sensitive (AS) phenotype switches to an AI phenotype, the latter of which is often refractory to many therapies.

MATERIALS AND METHODS

PC‐3 (AI) and LNCaP (AS) were each genetically altered to express the opposite phenotype and subjected to an in vitro freezing model. Viability, caspase inhibitor and Western blot studies were used to determine the basis of the differential responses of AI and AS cells.

RESULTS

LNCaP high‐passage cells, formed by repeated passage of LNCaP (AS) cells, were AI and showed a phenotypic shift to freeze resistance matching the freeze response of PC‐3 cells (AI). While stably transfected androgen receptor (AR)‐transfected cells (PC‐3 AR) had a freezing sensitivity similar to that of the LNCaP (AS) cell line. Importantly, AI cell lines survived and recovered from freezing exposure to temperatures as low as ?40 °C whereas AS cell lines did not. Caspase inhibition studies and related fluorescent probes showed an elevated level of apoptotic involvement in both AS cell lines after freezing compared with their AI counterparts. Western blot analysis showed that AR expression was modified after exposure to freezing.

CONCLUSION

This study suggests that AS cancers may be far more sensitive to a freezing insult and this might be linked to elevated apoptosis and caspase activity. As such, cryoablation may prove most effective in cancer cells that have not yet progressed to a more resistant AI phenotype, but both generic variants can be fully ablated at sufficiently low temperatures.     

Mitogenic and anti-apoptotic actions of adipocyte-derived hormone leptin in prostate cancer cells

OBJECTIVE

To investigate the proliferative and anti‐apoptotic effects of leptin on human prostate cancer cells, and the role of related signalling pathways in mediating these actions, as obesity is a possible risk factor for prostate cancer and leptin, an adipocyte‐derived hormone, has mitogenic action in various cell types.

MATERIALS AND METHODS

Two human prostate cancer cell lines, DU145 and PC‐3, were treated with leptin (5–100 ng/mL) for up to 48 h. Under serum‐free conditions, cell proliferation was measured using a colorimetric tetrazolium assay and apoptosis by an enzyme‐linked immunosorbent assay measuring cell death. Also, the phosphorylation of ERK1/2 and Akt was detected by Western blotting, and specific inhibitors of mitogen‐activated protein kinase (MAPK) (PD98059; 40 µm ) and phosphatidylinositol 3‐kinase (PI3‐K, LY294002; 40 µm ) were used to evaluate the role of these signalling pathways.

RESULTS

Leptin dose‐dependently increased the cell number in both cell lines for up to 48 h of incubation, the mean (sem ) percentage of the control being 189 (4.3)% for DU145 and 173 (7.5)% for PC‐3 (100 ng/mL leptin, 48 h; P < 0.01). Leptin also significantly reduced the number of apoptotic cells after 24 h of treatment, dose‐dependently caused ERK1/2 and Akt phosphorylation; pretreatment with inhibitors of MAPK and PI3‐K inhibited these responses.

CONCLUSION

These results show that chronic increases in leptin might enhance the growth of prostate cancer via the MAPK and PI3‐K pathways. Further studies are needed to investigate whether the ability of leptin to stimulate mitogenic/anti‐apoptotic signal transduction pathways could represent a target for anticancer drug discovery.     

Syndecan‐1 expression in prostate cancer and its value as biomarker for disease progression

OBJECTIVE

To evaluate the association between syndecan‐1 (CD138) expression and prostate cancer.

PATIENTS AND METHODS

We evaluated syndecan‐1 expression using a recently constructed tissue microarray of prostatic samples taken from 243 patients, corresponding to 1400 cores, with 69.8%, 5.6%, 17.6% and 7% of the cores representing localized prostate cancer, high‐grade prostatic intraepithelial neoplasia, benign prostate tissue and hormone refractory/metastatic disease, respectively.

RESULTS

Metastatic cases had the highest frequency and membranous staining intensity for syndecan‐1 overexpression, followed by hormone refractory and localized disease (83.3% vs 34.8% and 25.7%, respectively). There was no significant difference in the frequency of membranous syndecan‐1 expression between localized prostate cancer and benign glands (25.7% vs 24.7% of cases, respectively). However, benign glands showed significantly higher intensity staining than localized prostate cancer. We found no significant association between syndecan‐1 expression and any of the following: Gleason score, pathological stage, surgical margin status and biochemical recurrence.

CONCLUSION

The current available evidence, from the present and previous studies, show that syndecan‐1 is not an independent predictor of recurrence or tumour‐specific survival, diminishing its significance as a clinical marker.     

The use of estramustine phosphate in the modern management of advanced prostate cancer

What’s known on the subject? and What does the study add? Estramustine phosphate has anti‐tumour properties and it improves patient outcomes if combined with other chemotherapy agents such as doeetaxel. The efficacy of estramustine phosphate in selected patients and its safety profile, provided used with any low‐molecular‐weight heparin support its use as a second‐line treatment in hormone‐resistant prostate cancer.

OBJECTIVES

• ? Estramustine phosphate is a nitrogen mustard derivative of estradiol‐17β‐phosphate and has anti‐tumour properties.
• ? Interest in estramustine has been renewed because of the results of clinical studies showing improved patient outcomes if estramustine is combined with other chemotherapy agents such as docetaxel.

PATIENTS AND METHODS

• ? Relevant clinical studies using chemotherapy combinations including estramustine are discussed.
• ? Efficacy and safety outcomes are summarized.

RESULTS

• ? Combination therapy with estramustine and docetaxel can increase PSA response rates, improve quality of life and increase median patient survival compared with chemotherapy regimens that do not include estramustine.
• ? Although the overall tolerability of estramustine is favourable, its use can be associated with an increased risk of thromboembolic events.

CONCLUSIONS

• ? The identification of suitable patient groups and the effective management of the risk of thromboembolism with the adjunct of low‐molecular‐weight heparins support the use of estramustine as an effective second‐line treatment strategy in hormone‐resistant prostate cancer.
• ? These promising findings warrant further investigation in a randomized clinical trial.

     

Elevated physiological levels of folic acid can increase in vitro growth and invasiveness of prostate cancer cells

What's known on the subject? and What does the study add? Evidence has emerged identifying folic acid supplementation as a potential risk factor for cancer development or progression. Long‐term folic acid supplementation has been shown to increase the risk of prostate cancer development by three‐fold. Sarcosine is a byproduct of folate metabolism and has been proposed as a biomarker for aggressive prostate cancer phenotypes. We looked at the effects of physiologically relevant levels of folic acid on in vitro prostate cancer cell growth and invasion, and demonstrated that higher levels can have the effect of increasing both of these biological processes. We also show that these changes toward a more aggressive phenotype are not linked to increased sarcosine levels, however other metabolic pathways may be involved.

OBJECTIVES

• ? To investigate the effects of different folic acid concentrations on the growth and invasiveness of prostate cancer cell lines.
• ? To determine if observed changes are correlated with changes in levels of the potential prostate cancer biomarker, sarcosine, a byproduct of folate metabolism.

MATERIALS AND METHODS

• ? The prostate cancer cell lines PC‐3, LNCaP and DU145 were cultured in media containing 4, 20 or 100 nm of folic acid and assayed for growth over 9 days by counting viable cells at 3‐day intervals, or for invasion by passage through a Matrigel‐coated transwell membrane.
• ? Cells grown in the different folic acid media were collected and subjected to metabolomic analysis by gas chromatography and mass spectrometry to measure levels of intracellular sarcosine.

RESULTS

• ? The results show that higher levels of folic acid can increase cell growth in PC‐3 and LNCaP prostate cancer cell lines, and may also increase the invasive capacity of PC‐3, LNCaP and DU145 cells.
• ? We did not observe a correlation between increased invasion from higher folic acid concentrations and levels of sarcosine, but there were significant changes in other metabolites in cells grown in higher levels of folic acid.

CONCLUSION

• ? These findings suggest that folic acid has an important and potentially negative role in prostate cancer progression.

     

Dimeric naphthoquinones, a novel class of compounds with prostate cancer cytotoxicity

What’s known on the subject? and What does the study add? Sexual function is often impaired after radical prostatectomy (RP) resulting in reduced sexual activity and sexual bother. The main focus in the literature concerning sexual adverse effects has been on erectile dysfunction and impairment of sexual function rather than the actual sexual bother it causes, although the sexual bother is most important to the individual patient’s quality of life. The relation between these measures, and in particular pre‐operative prediction of post‐operative sexual bother, has only been studied limitedly and with varying results. Some studies have found good mental health, low levels of pre‐operative sexual bother, and higher education to be associated with absence of post‐operative sexual bother, but another study could not identify any pre‐operative predictors of a post‐operative sexual bother. Severe sexual bother after RP were reported by 64% to 95% of the patients three years after operation, and the prevalence was associated with the level of pre‐treatment sexual bother and pre‐operative nerve‐preservation. On the other hand, others have reported that only 43% of men have sexual bother 2 years after RP. However, none of these studies stratified patients according to their pre‐operative sexual activity and most of them were American. It has been shown that American findings concerning sexual bother may not always be valid for non‐American patients due to differing sex role expectations thus warranting the need for more non‐American studies. This study has shown that two thirds of patients experienced sexual bother one year after RP. We have identified patients with increased risk of experiencing overall sexual bother post‐operatively: those who report pre‐operative sexual bother, those who are sexually active before RP, and those who display neurotic personality‐traits. Another important finding was that the proportion of patients who experienced bother relevant to having impaired post‐operative SF was significantly higher among pre‐operatively sexually active patients than those who had been inactive. This study adds knowledge that patients’ pre‐operative sexual activity, sexual bother and personality should be taken into account to be able to give individualized information about the risk of getting sexual bother after RP.

OBJECTIVES

• ? To evaluate the cytotoxicity of dimeric naphthoquinones (BiQs) in prostate cancer cells.
• ? To assess the interaction of dimeric naphthoquinones with common therapies including radiation and docetaxel.

MATERIALS AND METHODS

• ? The cytotoxicity of 12 different dimeric naphthoquinones was assessed in androgen‐independent (PC‐3, DU‐145) and androgen‐responsive (LNCaP, 22RV1) prostate cancer cell lines and in prostate epithelial cells (PrECs).
• ? BiQ2 and BiQ11 were selected for determination of dose response, effects on colony formation and initial exploration into mechanism of action.
• ? Synergistic effects with radiation and docetaxel were explored using colony‐forming and MTT assays.

RESULTS

• ? At concentrations of 15µM, BiQ2, BiQ3, BiQ11, BiQ12, and BiQ15 demonstrated cytotoxicity in all prostate cancer cell lines.
• ? Treatment with BiQs limited the ability of prostate cancer cells to form colonies in clonogenic assays.
• ? Exposure of prostate cancer to BiQs increased cellular reactive oxygen species (ROS), decreased ATP production, and promoted apoptosis.
• ? BiQ cytotoxicity was independent of NADP(H):quinone oxidoreductase 1 (NQO1) activity in PrECs, PC‐3 and 22RV1, but not DU‐145 cells.
• ? Exposure of prostate cancer cells to radiation before treatment with BiQs increased their activity allowing for inhibitory effects well below the IC₅₀s of these compounds in PrECs.
• ? Co‐administration of BiQs with docetaxel had minimal additive effects.

CONCLUSIONS

• ? Dimeric naphthoquinones represent a new class of compounds with prostate cancer cytotoxicity and synergistic effects with radiation. The cytotoxic effect of these agents is probably contributed to by the accumulation of ROS and mitochondrial dysfunction.
• ? Further studies are warranted to better characterize this class of potential chemo‐therapeutics.

     

Circulating endothelial cells as a therapeutic marker for thalidomide in combined therapy with chemotherapy drugs in a human prostate cancer model

OBJECTIVE

To investigate how thalidomide confers its survival benefit in prostate cancer, by assessing its effect on circulating endothelial cells (CECs) and progenitors (CEPs) in a combined therapy of thalidomide and chemotherapy drugs in a human prostate cancer xenograft model, as in clinical trials patients treated with both thalidomide and docetaxel had a >50% decrease in prostate‐specific antigen (PSA) levels and longer median overall survival than those treated with docetaxel monotherapy.

MATERIALS AND METHODS

A human prostate cancer xenograft model was used to evaluate the effect of either thalidomide, docetaxel or a combination of the two drugs on circulating ECs. Drug treatment was continued for 17 days, and tumours were measured two or three times a week. Blood samples were taken at three different time points: before the treatments, 4 days and 17 days into the treatments, and CECs and CEPs were measured by flow cytometry analysis.

RESULTS

There was an increased level of apoptotic/dead CECs shortly after the intravenous injection of docetaxel, and the addition of thalidomide further increased the apoptotic/dead CEC level, showing that thalidomide enhances the cytotoxicity of docetaxel against tumour vascular ECs.

CONCLUSION

Thalidomide increased the apoptotic/dead CEC level and enhanced the cytotoxicity of docetaxel against tumour vascular ECs, confirming its antiangiogenic property in vivo in combined anticancer treatments. In addition, there was a correlation between the increased apoptotic/dead CEC levels early in the treatment and antitumour efficacy later, suggesting that the apoptotic/dead CEC level could be used as a marker, at an early stage, to predict tumour response to antiangiogenic therapies.     

Docetaxel as a vital option for corticosteroid-refractory prostate cancer

Objectives  

The efficacy of docetaxel (TAX) chemotherapy for corticosteroid-refractory refractory prostate cancer (CRPC) is uncertain.