Treatment Of Hormone-refractory Prostate Cancer Research Articles

Liposomal imatinib–mitoxantrone combination: Formulation development and therapeutic evaluation in an animal model of prostate cancer

Mitoxantrone plus prednisone is a palliative treatment for hormone-refractory prostate cancer (HRPC) but without survival benefit. Imatinib has shown activity against HRPC but only in the preclinical setting. Our previous in vitro cytotoxicity screening study established that their free combination act additively to inhibit proliferation of PC-3 cells. We aim to develop a liposomal imatinib-mitoxantrone (LIM) formulation with improved in vivo therapeutic activity. Imatinib and mitoxantrone were simultaneously co-loaded into DSPC/Chol liposomes by means of a (NH4)2SO4-generated proton gradient method. The optimized formulation was characterized in terms of mean size diameter, loading parameters and drug retention in human serum. In vivo antitumor activity of developed LIM formulation was evaluated in a nude mice bearing subcutaneous PC-3 xenograft model. LIM formulation exhibited maximal encapsulation efficiency (>95%) and enhanced drug retention for both drugs. Additionally, this LIM formulation, administered at a low mitoxantrone dose (0.5 mg/kg), showed a tumor inhibition activity (TGI = 66.7% and 4.0-fold tumor volume increase) slightly superior to that of liposomal mitoxantrone (LM) at 2 mg/kg (TGI = 53.0% and 4.2-fold volume increase). Therefore, therapeutic activity of mitoxantrone was significantly improved by co-loading with imatinib since a four times lower dose was needed to achieve an equivalent growth inhibition effect. The loading parameters and drug retention properties of our LIM formulation, combined with its in vivo antitumor activity, make this formulation an excellent strategy to improve the therapeutic index of mitoxantrone and a promising candidate for clinical development in prostate cancer therapy.

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G2/M arrest. G2/M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bcl-xL and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G2/M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-xL. Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer.

Efficacy and toxicity of mitoxantrone and oral etoposide in the treatment of hormone-refractory prostate cancer: pilot study.

To evaluate the efficacy and toxicity of the association of mitoxantrone and oral etoposide. Twelve consecutive patients with metastatic hormone-refractory prostate cancer were treated with mitoxantrone and oral etoposide. Toxicity, response rate and response duration were assessed. Partial response was observed in two patients (response duration of seven and four months) and one patient had stable disease (during four months). Mitoxantrone and oral Etoposide were well tolerated and did not affect tolerability to subsequent chemotherapy. Mitoxantrone and oral etoposide association is an active and well-tolerated regimen in hormone-refractory prostate cancer.

Flavokawain B, a kava chalcone, induces apoptosis via up‐regulation of death‐receptor 5 and Bim expression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth

Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. We have shown that flavokawain B (FKB), a kava chalcone, is about 4- to 12-fold more effective in reducing the cell viabilities of androgen receptor (AR)-negative, HRPC cell lines DU145 and PC-3 than AR-positive, hormone-sensitive prostate cancer cell lines LAPC4 and LNCaP, with minimal effect on normal prostatic epithelial and stromal cells. FKB induces apoptosis with an associated increased expression of proapoptotic proteins: death receptor-5, Bim and Puma and a decreased expression of inhibitors of apoptosis protein: XIAP and survivin. Among them, Bim expression was significantly induced by FKB as early as 4 hr of the treatment. Knockdown of Bim expression by short-hairpin RNAs attenuates the inhibitory effect on anchorage-dependent and -independent growth and caspase cleavages induced by FKB. These findings suggest that the effect of FKB, at least in part, requires Bim expression. In addition, FKB synergizes with TRAIL for markedly enhanced induction of apoptosis. Furthermore, FKB treatment of mice bearing DU145 xenograft tumors results in tumor growth inhibition and increases Bim expression in tumor tissues. Together, these results suggest robust mechanisms for FKB induction of apoptosis preferentially for HRPC and the potential usefulness of FKB for prevention and treatment of HRPC in an adjuvant setting.

Chimiothérapie en phase précoce d’hormonorésistance des cancers de prostate métastatiques : quelles indications ?

Treatment of hormone-refractory prostate cancer remains a source of debate. Since 2004, docétaxel-based chemotherapy has become the standard treatment as it has demonstrated efficacy on overall survival in two randomized studies. In some studies, chemotherapy seems to be also effective on pain relief. The adverse effects occur more frequently than with others chemotherapy (mitoxantrone) but are moderated and aren't responsible of specific mortality. These facts encourage to begin the chemotherapy as earlier as possible even before metastases appear. Some studies have even raised the issue of an initiation of chemotherapy before the onset of hormone independence. However these arguments might be use with caution. The treated patients have a limited life expectancy and a 2 months gain of survival may be of limited value. Furthermore, even low side effects can generate a morbidity on these fragile patients especially when they are initially asymptomatic. Thus, an early initiation of chemotherapy must be discussed case by case, on an individual basis. The prognosis factors and alternative therapeutic options based on new molecules used in metastatic cancer might also be considered for the therapeutic decision.

Abstract LB-35: A monoclonal sphingosine 1-phosphate antibody inhibits intratumoral hypoxia and sensitizes to docetaxel in prostate cancer animal model

Abstract The reduction in the normal level of tissue oxygen tension or hypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, increased tumor growth, and resistance to treatments. The activation of the transcription factor hypoxia-inducible factor 1α (HIF-1α) has been identified as the master mechanism of adaptation to hypoxia. In a recent study (Ader et al, Cancer Res, 2008), we identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway, which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1α activity under hypoxic conditions Indeed, we have shown that SphK1 activity (which generates S1P) was rapidly stimulated under low oxygen conditions. The pharmacological inhibition and RNA silencing of SphK1 activity could prevent the accumulation of HIF-1α and its transcriptional activity in multiple cancer cell lineages - including prostate - suggesting a canonical pathway. We have suggested that inhibiting the SphK1/S1P signaling, that is up-regulated under low oxygen tension, might help normalizing the tumor microenvironment and increase tumor sensitivity to radiation and chemotherapy, in the broader concept of « normalization of tumor vessels » as tumor oxygenation is known to enhance response to chemotherapy and radiation (reviewed in Ader et al., Cancer Res, 2009). S1P is believed to exert most of its actions as a specific ligand for a family of five cognate G protein-coupled receptors to elicit paracrine or autocrine signaling cascades. We now provide evidence that inhibition of the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its transcriptional activity in prostate cancer cells exposed to hypoxia. More importantly, in an orthotopic (o.t) xenograft model of prostate cancer, we show that a monoclonal antibody directed against S1P markedly reduces intratumoral hypoxia and modifies vessel architecture within 5 days of treatment. Finally, we demonstrate for the first time that a monoclonal antibody directed against S1P could sensitize to the antitumoral effects of docetaxel, the ‘gold standard’ treatment for hormone-refractory prostate cancer. Indeed, a 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/green fluorescent protein model established in nude mice. The combination anti-S1P antibody together with docetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel treatment but also markedly reduced the occurrence and number of metastases. In conclusion, these data establish the proof-of-concept that blocking the exogenous action of S1P, by reducing intratumoral hypoxia, can sensitize to docetaxel-based chemotherapy in prostate cancer animal model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-35.

Abstract 5659: Down-regulation of hTERT sensitizes chemotherapeutic effects of docetaxel in human prostate cancer cells via suppression of PIM-1 oncogene

Abstract Taxanes comprise some of the most widely used cancer chemotherapeutic agents for various cancers. Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. However, despite the recently demonstrated survival benefits of docetaxel-based chemotherapy, most patients will move from response to progression within 6 months. Moreover, effective concentrations of docetaxel have side effects including localized erythema of the extremities with edema followed by desquamation, severe neuropathy, fatigue, and weakness which can have debilitating effects in patients with prostate cancer. One reason for disease progression is the up-regulation of PIM-1 expression following docetaxel treatment of prostate cancer cells. PIM-1 is a serine-threonine kinase that promotes survival by inhibiting the activity of apoptotic proteins. In a recent study, we observed that a telomerase suppressing small molecule MST-312, and hTERT siRNA down-regulated PIM-1 protein level in prostate cancer cells. These results prompted us to investigate whether combination of docetaxel with inhibition of telomerase by MST-312 or TERT siRNA would have synergistic effects on prostate cancer cell growth and induce death. Treatment of PC3 cells with 1 nM of docetaxel for 3 days substantially promoted the viability of cells compared to the control, with a 27% increase in cell number. This increase was associated with the up-regulation of PIM-1. Treatment of telomerase inhibitory concentration (2 μM) of MST-312 over 3 days resulted in a 51% decrease in cell viability relative to the 1 nM docetaxel treated groups, associated with a decrease in PIM-1 protein levels. More interestingly, treatment of 2 μM MST-312 with 1 nM docetaxel for 3 days resulted in 72% reduction in cell viability compared to docetaxel alone and 43% reduction in cell viability compared to MST-312 alone. This combined treatment also resulted in lower levels of PIM-1 activity than MST-312 or docetaxel treatment alone. These results suggest that there is synergy between the combination of telomerase inhibitor MST-312 with docetaxel in the treatment of metastatic prostate cancer. This can be explained by the down-regulation of PIM-1 kinase that promotes resistance to docetaxel treatment. These findings suggest potential clinical benefit by the combined use of docetaxel and telomerase inhibitors for prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5659.

Abstract 1394: Pro-apoptotic and anti-tumorigenic effects of a naturally occurring proteasome inhibitor on hormone-refractory prostate cancer

Abstract A major mode by which cancer cells evade death is by an acquired ability to suppress apoptosis. In hormone refractory prostate cancer, the overexpression of pro-survival/anti-apoptotic proteins results in resistance to chemo- and radio-therapy. Hence, developing co-therapies that sensitize cells to standard treatment regimens by overcoming this apoptotic block could improve treatment outcomes in advanced prostate cancer. The naturally occurring proteasome inhibitor celastrol has been previously reported to inhibit DNA damage processing and synergize with radiotherapy to kill PC-3 cells. To further explore the mechanism by which celastrol might potentiate cell death, several lines of questioning were explored. First, the open question regarding whether or not celastrol inhibits DNA damage repair, not simply processing, was tested in the comet assay. The tail moments measured in cells treated with celastrol, irradiated and allowed to recover were significantly greater than those in untreated cells, indicating that DNA damage repair was inhibited. In other experiments, cells treated with celastrol displayed an increased expression of the pro-apoptotic, BH3 only protein Noxa. This correlated with an increase in apoptotic cell death which was further augmented by ionizing radiation treatment. The pro-survival protein NFkB is tightly controlled by IkB-alpha binding. Proteasome inhibition can suppress the pro-survival activity of NFkB by decreasing the turnover of IkB-alpha. Indeed, IkB-alpha was found to accumulate in celastrol treated cells. Further, NFkB target gene activation was markedly reduced. To test the feasibility of celastrol treatment in animals, the PC-3 xenograft model in the athymic nude mouse was employed. When celastrol was combined with radiotherapy, tumor volume decreased, apoptosis increased, angiogenesis decreased, and NFkB target gene mRNA levels were found to be lower. Taken together, these data show that celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage repair and augmenting apoptosis through suppressing NFkB activation and increasing the protein levels of Noxa. Celastrol may hold promise as a co-therapy with radiation for the treatment of hormone-refractory prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1394.

The Establishment of Dendritic Cell-Tumor Fusion Vaccines for Hormone Refractory Prostate Cancer Cell

PurposeDendritic cell (DC)-based tumor vaccine is an attractive modality for the treatment of hormone-refractory prostate cancer (HRPC) because it has some efficacy and few side effects in patients with poor general conditions. The aim of this study was to establish which is the most effective DC vaccine for the treatment of HRPC. We compared DC vaccine sensitized with tumor lysate and a fusion vaccine of DCs and tumor cells.Materials and MethodsThe DU145 cancer cell line was purchased from the American Type Culture Collection. DCs were cultured from peripheral blood monocytes. Peripheral blood monocytes were cultured in RPMI 1640 medium supplemented with interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor, and 10% fetal calf serum. Tumor necrosis factor-alpha was added on day 7 to support maturation. Functional activity was measured in three groups: the DC single-culture group, the DC culture group with DC vaccine sensitized with tumor lysates, and the DC culture group prepared with tumor fusion vaccine made from irradiated tumor cells and monocyte-derived DCs by the polyethylene glycol method.ResultsBy FACS analysis, the rate of DC-tumor fusion vaccine was 20.3±3%. The IL-12 level produced by the DC-tumor fusion vaccine was significantly higher than that of DCs pulsed with tumor lysate (p<0.05). Also, the generation of interferon-γ by tumor-specific T cells in the DC-tumor fusion vaccine group was superior to that of DCs pulsed with tumor lysate (p<0.05). In addition, the T cells of the tumor lysate-pulsed DCs and tumor fusion vaccine had 1.6 and 2.5 times the functional activity, respectively, of the DC single-culture group in killing tumor cells in the cytotoxicity assay.ConclusionsThe DC-tumor fusion vaccine seems to be more effective than DC single-culture or DC-tumor lysate vaccine in the treatment of HRPC.

What's New in Hormone-refractory Prostate Cancer Treatment

Prostate cancer represents the most common cancer in men in US and the fifth in men in Korea. For the patients with advanced prostate cancer, androgen deprivation therapy (ADT) remains the gold standard. However, patients with metastatic prostate cancer treated with ADT frequently develop hormone-refractory status (HRPC). Recent large randomized clinical trials demonstrated that docetaxel-based chemotherapy enhance survival and improve the quality of life in patients with HRPC. Although docetaxel-based chemotherapy has become the standard treatment for HRPC, PSA responses rarely exceed 50% and median survival is still less than 2 years. Therefore, there is a need for newer agents that can improve outcomes. This review focuses on the current therapies for the treatment of HRPC, including new cytotoxic agents, antiproliferative agents, antitumor vaccine and antiangiogenic agents. These approaches yielded expected or disappointing results in the phase II or III trials. Interpretation of these trials is sometimes complicated by discordant radiographic and PSA responses. Further investigation in search of more predictive new markers is warranted. Docetaxel-based chemotherapy has become the first-line standard treatment for HRPC, but the survival results are not satisfactory. Therefore, newer agents are being developed with promising results in phase II trials. These new agents should demonstrate higher patient survival rate in phase III studies on a larger scale in order to be approved for clinical use.

Docetaxel–ST1481 sequence exerts a potent cytotoxic activity on hormone‐resistant prostate cancer cells by reducing drug resistance‐related gene expression

The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines. The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. Our results show that the Doc --> ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer.

Celastrol Potentiates Radiotherapy by Impairment of DNA Damage Processing in Human Prostate Cancer

Celastrol is an active ingredient of traditional herbal medicine and has recently been identified as a potent natural proteasome inhibitor. In the present study, we evaluated the radiosensitizing potential of celastrol in the human prostate cancer PC-3 model. Clonogenic assays were performed to determine the radiosensitizing effect of celastrol. Apoptosis was examined by flow cytometry using Annexin V and propidium iodide staining and by a caspase-3 activation assay. DNA damage processing was examined by immunofluorescent staining and Western blot for phosphorylated H2AX (gammaH2AX). The PC-3 xenograft model in the athymic nude mouse was used for the determination of the in vivo efficacy of celastrol combined with radiotherapy. The tumor samples were also analyzed for apoptosis and angiogenesis. Celastrol sensitized PC-3 cells to ionizing radiation (IR) in a dose- and schedule-dependent manner, in which pretreatment with celastrol for 1 h followed by IR achieved maximal radiosensitization. Celastrol significantly prolonged the presence of IR-induced gammaH2AX and increased IR-induced apoptosis. Celastrol, combined with fractionated radiation, significantly inhibited PC-3 tumor growth in vivo without obvious systemic toxicity. The combination treatment increased gammaH2AX levels and apoptosis, induced cleavage of poly(adenosine diphosphate-ribose)polymerase and Mcl-1, and reduced angiogenesis in vivo compared with either treatment alone. Celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage processing and augmenting apoptosis. Celastrol might represent a promising new adjuvant regimen for the treatment of hormone-refractory prostate cancer.

A review of the patterns of docetaxel use for hormone refractory prostate cancer (HRPC) at the Princess Margaret Hospital

e16161 Background: Docetaxel is standard of care for the treatment of HRPC, based on two large randomized clinical trials. The aim of this study was to determine if docetaxel use and effectiveness in routine clinical practice was similar to that seen in the TAX 327 randomized phase III clinical trial. Methods: A retrospective chart review was undertaken to assess patterns of docetaxel use for HRPC at our institution for the 2-year period since its approval for the first-line treatment of HRPC in 2005. Results: Eighty-eight patients, median age 71 and baseline PSA 107, received docetaxel in the first line setting. Main reasons for initiating docetaxel were rising PSA (90%) and progressive symptoms (71%). Eighteen percent of patients received docetaxel for rising PSA alone. A median of 7 cycles was administered. PSA response rates were 61%, time to response 1.5 months, and response duration 6.8 months. Disease progression was the most common reason for treatment discontinuation (36%). Main toxicities were fatigue (32%) and neuropathy (22%). Kaplan Meier survival analysis showed median duration of survival was 15.9 months (95% CI 12.4–20.5) from first drug use. 1-year survival was 0.63 (95% CI 0.52–0.72). Post-docetaxel, 36 patients received second-line treatment, mostly with mitoxantrone (89%). Second-line response rates were 22%, and median duration of response was 4 months. Conclusions: In routine clinical practice, docetaxel is a well-tolerated regimen for the treatment of HRPC. Response rates and toxicity profiles were comparable to the randomized trials. However, compared with the TAX 327 clinical trial, survival was slightly shorter than expected (15.9 vs. 18.9 months), possibly due to inclusion of patients with poorer performance status and comorbidities, who may be excluded from clinical trials. Second-line response rates were also comparable with previous reports. No significant financial relationships to disclose.

The impact of docetaxel (D) in an older population of patients with advanced prostate cancer (PC): A simulation study using TAX327 and SEER Medicare data

e16074 Background: The survival benefit of D in treatment of hormone refractory PC (HRPC) has been established in the TAX327 trial, but it is unclear how this benefit would translate in a heterogeneous population. This study sought to simulate the survival impact of D in a population of older pts with M1 PC on androgen deprivation therapy (ADT). Methods: A combination of TAX327 trial data and SEER-Medicare (SM) data were used. In pts age 69+ and randomized to D (every 3 weeks, D3P) or mitoxantrone (M), trial data showed a survival benefit for D. Accordingly, SM pts age 69+ diagnosed with M1 PC between 1994 and 2002 and receiving only ADT were selected. Graphical plots and statistical tests were used to find best-fitting parametric survival functions for D3P, M, and SM pts. The survival benefit for D was imposed on unadjusted and covariate-adjusted SM survival curves. The simulated benefit was assessed at 12 mos and 24 mos post-diagnosis of M1 PC in SM pts. Results: There were 326 TAX327 trial pts (D3P = 159, M = 167) used in the analysis. Median survival was 15.7 mos (12.6 - 19) in the M arm and 18.9 mos [17 - 21.8] in the D3P arm (p = 0.03). There were 3,515 SM pts, based on inclusion criteria. Median survival benefit of D was 3.2 mos based on Kaplan-Meier estimates and 2.4 mos using parametric curves in the TAX327 69+ group. Following covariate-adjustment in the SM sample, at 12 mos post-diagnosis, the median survival in mos was 61.7 (CI 36.3 - 87) in the ADT group and 62 (CI 37.6 - 87.1) in the simulated ADT+D group (i.e., 0.3 mos simulated benefit of D). A 0.8 mos simulated benefit was found if D was initiated 24 mos post diagnosis (in pts more likely to have HRPC). Conclusions: The survival benefit of docetaxel from the TAX327 trial is attenuated in a heterogeneous SEER-Medicare sample, and the simulated survival benefit is larger among patients who are more likely to have hormone refractory prostate cancer. [Table: see text]

A dose-escalating phase I study of biweekly docetaxel in older men with hormone refractory prostate cancer (HRPC)

e16117 Background: Docetaxel has been shown to be effective and is used in the treatment of HRPC. This phase I study is designed to investigate the maximum tolerated dose, tolerability and activity of docetaxel administered on a biweekly schedule in older patients with HRPC. This study will also explore the feasibility of a self-report geriatric assessment tool in this population. Methods: HRPC patients with progression of metastatic disease during hormonal therapy received docetaxel q 2 wks at dose levels of 40 (level 0), 45 (level 1), 50 (level 2), or 55 mg/m2 (level 3). The trial is a conventional phase I 3+3 dose-escalation design. Treatment was continued until progression, refused further treatment, or unacceptable toxicity. Patients were given the Vulnerable Elders Survey (VES-13) for completion every 4 weeks. Results: 16 patients were enrolled in the study. All are evaluable for toxicity, 10 for response. Pts had a median (range) age 76 (72–87). Median doses administered was 6 (range 3–19). The maximum tolerated dose (MTD) was not reached in the study. No dose limiting side effects were reported for any of the dosing levels in the 8 week assessment period. Five patients had a ≥50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. Of the 10 patients with measureable disease, 2 patients (one at dose level 0 and one at dose level 3) achieved a complete response, 2 patients (one at dose level 1 and one at dose 2) achieved a partial response, and 3 patients had stable disease (one each at dose levels 1, 2, and 3). At the time of entry onto the study, 4 patients required narcotic analgesics for bone pain; after treatment, 1 (25%) discontinued their pain medications. The completion rate of the Vulnerable Elders Survey (VES-13) was 94.6%. Conclusions: Biweekly docetaxel can be safely administered in older metastatic HRPC patients and showed activity. For phase II evaluation, a bi-weekly dose of 55 mg/m2 appears to be suitable. The administration of the VES-13 was feasible in this population. [Table: see text]

Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer

e16026 Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m2) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (&gt; 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of &gt;10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. No significant financial relationships to disclose.

Several new agents show promise in treatment for hormone-refractory prostate cancer

Several new agents show promise in treatment for hormone-refractory prostate cancer

Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2, and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both DTX and cisplatin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to DTX and cisplatin treatments. These combinations were also tolerable in mice and superior to either agent alone. As DTX is the standard first-line chemotherapy for HRPC, the development of DTX-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone-refractory and chemoresistant prostate tumors.

Rare sugar d-allose induces programmed cell death in hormone refractory prostate cancer cells

Development of effective agents for treatment of hormone-refractory prostate cancer (HRPC) has become a national medical priority. D-Allose is a monosaccharide (C-3 epimer of glucose) distributed rarely in nature; because of its scarcity and cost, the biological effect has hardly been studied. In the present study, we demonstrated the inhibitory action of D-allose on proliferation of human HRPC cell lines, DU145 and PC-3 in a dose- and time-dependent manner, while human normal prostate epithelial (NPE) cell line, PrEC showed no remarkable effect. In vitro treatment of D-allose resulted in the alteration of Bcl-2/Bax ratio in favor of apoptosis (programmed cell death, PCD) in both the HRPC cell lines, which was associated with the lowering of mitochondrial transmembrane potential (Deltapsi(m)) and the release of cytochrome C (cyt C), the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), and the elevation of calcium concentration in cytosol ([Ca(2+)](c)). D-Allose also induced G1 phase arrest of the cell cycle in DU145 cell line. This study for the first time suggested the antiproliferative effect of D-allose through induction of PCD in HRPC cell lines, which could be due to the modulation of mitochondria mediated intrinsic apoptotic pathway.

Phase II protocol with docetaxel plus prednisone in patients with hormone refractory prostate cancer in two groups: With previous chemotherapy and without chemotherapy

16118 Background: Although treatment of hormone-refractory prostate cancer (HRPC) is difficult, the use of docetaxel every 21 days plus prednisone has been reported as a promising regimen for patients with HRPC. The purpose of this study was the investigation of the efficacy of docetaxel for patients with HRPC and its toxicity. Methods: 95 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and 75 mg of docetaxel per square meter every three weeks. Their mean age was 72 (43-91) years, their median prostate-specific antigen (PSA) level was 204 (38–1100) ng/ml, and the median Gleason score was 8 (7 to 9). Results: Among the 95 patients, 76 patients are evaluated and 19 are not evaluated ( 9 patients are still on chemotherapy and 10 with less than 2 cycles). In 76 evaluated patients 43 (57%) didn’t had previous chemotherapy and 33 (43%) had previous chemotherapy. There is no difference in median age (72 vs 70), median PSA (247 vs 220), median cycles (8 vs 7) or median Follow Up (15 vs 12). There were 5 reported drug related Grade 3 toxicities, dermatological. Only five patients required a blood transfusion. PSA response without previous chemotherapy (nº patients) - 27 (63%) PSA response with previous chemotherapy - 9 (27%) PSA stable without previous chemotherapy - 11(25%) PSA stable with previous chemotherapy - 14(43%) PSA progression without previous chemotherapy - 5(12%) PSA pregression with previous chemotherapy - 10 (30%) Survival Status without previous chemotherapy (43 patients) - 15 months (3–30) Survival Status with previous chemotherapy (33 patients) - 12 months (3–41). Conclusions: Docetaxel plus prednisone is a safe regimen in previous poly-chemotherapy treated hormone refractory prostate cancer patients and still with a good response and efficacy and should be done in first line if chemotherapy. Patients that didn’t had previous chemotherapy live longer (15 months) than whose had previous chemotherapy (12 months). There is a high response in the patients who had Docetaxel in first line of chemotherapy 27 patients (63%), second line 9 patients (27%). No significant financial relationships to disclose.