RESUMEN
Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.
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Neoplasias , Poliploidía , Núcleo Celular , Cromatina/genética , Genoma , Humanos , Neoplasias/genética , Neoplasias/terapiaRESUMEN
We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.
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Aneuploidia , Puntos de Control del Ciclo Celular , Neoplasias/genética , Poliploidía , Animales , Supervivencia Celular , Evolución Molecular , Humanos , Neoplasias/patologíaRESUMEN
To evaluate the outcomes of total eradication therapy (TET), designed to eradicate all sites of visible cancer and micrometastases, in men with newly diagnosed oligometastatic prostate cancer (OMPCa). Men with ≤ 5 sites of metastases were enrolled in a prospective registry study, underwent neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiation (RT) to prostate bed/pelvis, stereotactic body radiation therapy (SBRT) to oligometastases, and adjuvant hormonal therapy (HT). When possible, the prostate-specific membrane antigen targeted 18F-DCFPyL PET/CT (18F-DCFPyL) scan was obtained, and abiraterone was added to neoadjuvant HT. Twelve men, median 55 years, ECOG 0, median PSA 14.7 ng/dL, clinical stages M0-1/12 (8%), M1a-3/12 (25%) and M1b-8/12 (67%), were treated. 18F-DCFPyL scan was utilized in 58% of cases. Therapies included prostatectomy 12/12 (100%), neoadjuvant [docetaxel 11/12 (92%), LHRH agonist 12/12 (100%), abiraterone + prednisone 6/12 (50%)], adjuvant radiation [RT 2/12 (17%), RT + SBRT 4/12 (33%), SBRT 6/12 (50%)], and LHRH agonist 12/12 (100%)]. 2/5 (40%) initial patients developed neutropenic fever (NF), while 0/6 (0%) subsequent patients given modified docetaxel dosing developed NF. Otherwise, TET resulted in no additive toxicities. Median follow-up was 48.8 months. Overall survival was 12/12 (100%). 1-, 2-, and 3-year undetectable PSA's were 12/12 (100%), 10/12 (83%) and 8/12 (67%), respectively. Median time to biochemical recurrence was not reached. The outcomes suggest TET in men with newly diagnosed OMPCa is safe, does not appear to cause additive toxicities, and may result in an extended interval of undetectable PSA.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/terapia , Anilidas/administración & dosificación , Antígenos de Superficie/sangre , Quimioterapia Adyuvante , Terapia Combinada , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel/administración & dosificación , Glutamato Carboxipeptidasa II/sangre , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Humanos , Calicreínas/sangre , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nitrilos/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Radiocirugia , Radioterapia Adyuvante , Tasa de Supervivencia , Compuestos de Tosilo/administración & dosificaciónRESUMEN
BACKGROUND: Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies. METHODS: A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa. RESULTS: Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease. CONCLUSIONS: However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.
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Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Imagen Molecular , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/metabolismo , Terapia Combinada , Humanos , Masculino , Imagen Molecular/métodos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/terapia , Trazadores Radiactivos , Radiofármacos/química , Recurrencia , Resultado del TratamientoRESUMEN
In post-fetal life, hematopoiesis occurs in unique microenvironments or 'niches' in the marrow. Niches facilitate the maintenance of hematopoietic stem cells (HSCs) as unipotent, while supporting lineage commitment of the expanding blood populations. As the physical locale that regulates HSC function, the niche function is vitally important to the survival of the organism. This places considerable selective pressure on HSCs, as only those that are able to engage the niche in the appropriate context are likely to be maintained as stem cells. Since niches are central regulators of stem cell function, it is not surprising that molecular parasites like neoplasms are likely to seek out opportunities to harvest resources from the niche environment. As such, the niche may unwittingly participate in tumorigenesis as a leukemic or neoplastic niche. The niche may also promote metastasis or chemo-resistance of hematogenous neoplasms or solid tumors. This review focuses on what is known about the physical structures of the niche, how the niche participates in hematopoiesis and neoplastic growth and what molecules are involved. Further understanding of the interactions between stem cells and the niche may be useful for developing therapeutic strategies.
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Células de la Médula Ósea , Médula Ósea/fisiología , Animales , Neoplasias de la Médula Ósea , Citocinas/fisiología , Hematopoyesis , Células Madre Hematopoyéticas , Células Madre Mesenquimatosas , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. RESULTS: Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. CONCLUSION: Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes.
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Neoplasias de la Médula Ósea/secundario , Endolina/metabolismo , Metástasis de la Neoplasia/fisiopatología , Neoplasias de la Próstata/patología , Neoplasias de la Médula Ósea/fisiopatología , Adhesión Celular , Quimiocina CXCL12 , Quimiocinas CXC/fisiología , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/fisiología , Humanos , Masculino , Antígeno Prostático Específico , Células Tumorales CultivadasRESUMEN
OBJECTIVES: To enumerate the amount of circulating tumor cells (CTCs) in patients with advanced prostate cancer and to investigate the relationship between these numbers, prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) expression, and clinical parameters. METHODS: Whole blood was collected in proprietary CellSave tubes. Mononuclear cell fractions were isolated using epithelial cell antibody-coated magnetic nanoparticles. On one half of each immunomagnetically enriched cell fraction, automated fluorescent microscopy was used to identify the epithelial tumor cells. From the remainder of each sample, RNA extraction, cDNA synthesis, and polymerase chain reaction amplification of PSA and PSM were performed. RESULTS: Eighty-four patients with advanced prostate cancer submitted 130 samples for analysis. Intact CTCs were identified in 62% of samples; 83.3% of CTC-positive and 0% of CTC-negative samples were reverse transcriptase-polymerase chain reaction positive for PSA and PSM (P = 0.001). A significant positive correlation was found between the CTC number and PSA (r = 0.49), alkaline phosphatase (r = 0.47), and lactate dehydrogenase (r = 0.55) levels, and a significant negative correlation with hemoglobin (r = -0.35). The initial Gleason grade, prior therapy, current therapy, and type of metastasis (bone, soft tissue) did not correlate significantly with the CTC number. CONCLUSIONS: The presence of intact CTCs and the expression of PSA and PSM demonstrated robust agreement. The tumor cell numbers reflected current disease status and correlated significantly with the clinical disease indicators of PSA, hemoglobin, and liver function tests. These findings warrant further investigation of the diagnostic and prognostic value of enumerating intact CTCs.
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Separación Inmunomagnética , Células Neoplásicas Circulantes/patología , Neoplasias de la Próstata/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Superficie/análisis , Progresión de la Enfermedad , Glutamato Carboxipeptidasa II/análisis , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/químicaRESUMEN
Docetaxel, a semisynthetic taxane, has exhibited significant single-agent activity against prostatic tumors. In phase I/II studies, single-agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of > or =50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel's clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a twofold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer.
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Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis , Ciclo Celular/efectos de los fármacos , Docetaxel , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes bcl-2 , Humanos , Masculino , Paclitaxel/administración & dosificación , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Tubulina (Proteína) , Células Tumorales Cultivadas , Proteína bcl-XRESUMEN
Prostate cancer is the most frequently diagnosed cancer in American men. Screening for prostate-specific antigen (PSA) has led to earlier detection of prostate cancer, but elevated serum PSA levels may be present in non-malignant conditions such as benign prostatic hyperlasia (BPH). Characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms may identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer. Using microarrays of complementary DNA, we examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. We assessed two of these genes-hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase-at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome. Thus, the integration of cDNA microarray, high-density tissue microarray, and linked clinical and pathology data is a powerful approach to molecular profiling of human cancer.
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Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Serina Endopeptidasas/metabolismo , Biomarcadores de Tumor/genética , ADN Complementario , ADN de Neoplasias , Humanos , Inmunohistoquímica , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-pim-1 , Valores de Referencia , Serina Endopeptidasas/genéticaRESUMEN
E-cadherin is a calcium 2+-dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship. To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA). Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P =.012), higher Gleason score (P =.18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P =.09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P =.01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion. The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.
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Adenocarcinoma/metabolismo , Cadherinas/metabolismo , Neoplasias de la Próstata/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Resistencia a Antineoplásicos , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: A Phase II study was initiated to evaluate the effectiveness of an oral regimen of etoposide and estramustine in patients with early recurrent prostate carcinoma. METHODS: Patients with early recurrent prostate carcinoma as indicated by an increasing prostate specific antigen (PSA) level and without any evidence of metastatic disease were treated with oral etoposide 50 mg/m2/day and estramustine 15 mg/kg/day in divided doses for 21 days, followed by a 7-day rest period. Patients received a maximum of four cycles. RESULTS: Eighteen patients were entered in this study. The median serum PSA was 3.1 (range, 0.3-30.3) at the time of entry into the trial. Sixteen patients were assessable for response. Serum PSA declined to undetectable levels in 13 patients with 2 additional patients meeting the criteria for partial response; the median duration of response was 8.5 months (range, 1-18 months). Most patients developed gastrointestinal, cardiac, or hematologic complications. Grade 3 toxicities included neutropenia (one patient), deep venous thrombosis (three patients), and chest pain (one patient). One patient developed acute myelogenous leukemia (French-American-British, acute myelogenous leukemia M5) 23 months after initiating the chemotherapy. CONCLUSIONS: The combination of oral etoposide and oral estramustine resulted in a high rate but only a short duration of response in patients with early recurrent prostate carcinoma. The regimen was poorly tolerated, and the toxicity was significant. This regimen should not be considered standard therapy for the treatment of early recurrent prostate carcinoma, but further exploration of treatment in this setting is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Estramustina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Resultado del TratamientoRESUMEN
OBJECTIVES: We report the isolation and characterization of a novel prostate cancer cell line derived from a vertebral metastatic lesion, Vertebral-Cancer of the Prostate (VCaP). METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to a lumbar vertebral body of a patient with hormone refractory prostate cancer. This tissue was aseptically xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18 expression immunochemistry for PSA (prostate specific antigen), RT PCR for PAP (prostatic acid phosphatase) and northern blot and western blot analysis to determine expression of Rb and p53, were performed. Androgen receptor expression was measured by transient transfection with a luciferase reporter construct. RESULTS: VCaP cells are immortal in vitro and can be passaged serially in vivo. They express large quantities of prostate specific antigen (PSA). This cell line also expresses prostatic acid phosphatase (PAP), cytokeratin-18 and the androgen receptor, and is androgen sensitive in vitro and in vivo. CONCLUSIONS: This cell line was derived from a metastatic tumor to the vertebrae of a prostate cancer patient. It exhibits many of the characteristics of clinical prostate carcinoma, including expression of PSA, PAP, and AR. We believe that VCaP will be a useful addition to the existing models of prostate cancer, and enable more advanced study of the mechanisms of prostate cancer progression and metastasis.
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Técnicas de Cultivo de Célula/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Columna Vertebral/secundario , Células Tumorales Cultivadas/citología , Fosfatasa Ácida , Animales , División Celular , Células Epiteliales/química , Células Epiteliales/citología , Femenino , Humanos , Cariotipificación , Queratinas/análisis , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/genética , Proteínas Tirosina Fosfatasas/análisis , ARN Mensajero/análisis , Receptores Androgénicos/genética , Neoplasias de la Columna Vertebral/genéticaRESUMEN
BACKGROUND: The lack of appropriate, clinically relevant, cell-based model systems has limited prostate cancer research and the development of new therapeutic modalities. Here we report the isolation and characterization of a new adherent prostate cancer cell line, derived from the dura mater of a cancer patient. METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to the dura mater of a patient with hormone refractory prostate cancer. This tissue was xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18, androgen receptor, and PAP (prostatic acid phosphatase) expression, RT PCR for PAP, PSMA (prostate specific membrane antigen), expression and northern and western blot analysis to determine expression of Rb and p53, were performed. RESULTS: DuCap grows in vitro (passage 55), forms colonies in soft agar, produces tumors in SCID mice (xenograft passage 12), and is androgen sensitive. DNA content was hypertriploid. PSA was detected in mouse serum and media. Cells were AR, PAP and cytokeratin-18 positive by immunocytochemistry. PSMA and PAP were detected by RT-PCR. AR, P53, and Rb were expressed in Northern blot analysis. P53 protein was detected in Western blot analysis but Rb protein was not. CONCLUSIONS: This cell line exhibits many phenotypic characteristics of clinical prostate carcinoma, including expression of PSA, PSMA, PAP and AR.
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Técnicas de Cultivo de Célula/métodos , Células Epiteliales/citología , Neoplasias de la Próstata/patología , Células Tumorales Cultivadas/citología , Andrógenos/farmacología , Animales , División Celular/efectos de los fármacos , Duramadre , Femenino , Citometría de Flujo , Humanos , Cariotipificación , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/secundario , Ratones , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Neoplasias de la Próstata/genética , ARN Mensajero/análisis , Proteína de Retinoblastoma/genética , Células Tumorales Cultivadas/efectos de los fármacos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: The combination of oral estramustine and oral etoposide has generated response rates of 40-50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS: Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M(2)/day, days 1-21 every 28 days. Patients received a median of two cycles of therapy. RESULTS: Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS: This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Andrógenos/metabolismo , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Estramustina/administración & dosificación , Etopósido/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Resultado del Tratamiento , Trombosis de la Vena/inducido químicamenteRESUMEN
OBJECTIVES: To investigate the molecular machinery of docetaxel (Taxotere)-initiated death signaling on prostate cancer cell lines LNCaP and PC-3. Taxotere is a member of the taxane family of chemotherapeutic agents. It has been shown to disrupt microtubule dynamics causing mitotic arrest, which leads to cell death. Taxotere has demonstrated induction of cell death in LNCaP and PC-3 cells. However, the pathways by which apoptosis occurs differ in each cell line. METHODS: The prostate cancer cell lines, LNCaP and PC-3, were treated with 40 nM Taxotere for various lengths of time (0.5 to 24 hours). Western blot analysis was used for protein analysis. RESULTS: LNCaP cells demonstrated caspase-3 and caspase-7 cleavage, and PC-3 cells demonstrated only caspase-8 and BH3-interacting domain death agonist cleavage. Only LNCaP cells were observed to express clusterin expression; PC-3 cells expressed a novel apoptosis inhibitor, survivin. CONCLUSIONS: In this study, we demonstrated two distinctly different Taxotere-induced apoptotic pathways in LNCaP and PC-3 cells that may be of clinical importance when treating prostate cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Asociadas a Microtúbulos , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Neoplasias de la Próstata/patología , Taxoides , Western Blotting , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Clusterina , Docetaxel , Glicoproteínas/efectos de los fármacos , Glicoproteínas/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis , Masculino , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/metabolismo , Proteínas de Neoplasias/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Survivin , Células Tumorales CultivadasRESUMEN
Apoptosis is a selective process of programmed cell death that plays an important role in both physiologic and malignant states. In neoplastic disease, the rate at which a tumor grows depends on cell deletion as well as cell proliferation. It has been shown in several types of tumors that more aggressive tumors usually have a higher proliferative activity as well as an increased rate of apoptosis. The same characteristics seem true of renal neoplasms, as the frequency of apoptosis has been positively correlated with tumor grade, stage, and size in renal cell carcinoma (RCC) (1). Apoptosis is closely related to proliferative activity, tumor differentiation, and depth of invasion in transitional-cell carcinoma of the renal pelvis and ureter (2). The mechanisms of cell-cycle control, proliferation, and apoptosis are key issues in the biology and prognosis of RCCs. The expression of bcl-2 and p53 has been implicated in the control of apoptosis in tumorigenesis, and as a possible pathway to which cancer treatments could be directed. A reciprocal correlation was found between apoptosis and p53 positivity in RCC suggesting that the presence of mutant p53 is a negative regulator of apoptosis (3).
RESUMEN
The majority of men with progressive prostate cancer develop metastases with the skeleton being the most prevalent metastatic site. Unlike many other tumors that metastasize to bone and form osteolytic lesions, prostate carcinomas form osteoblastic lesions. However, histological evaluation of these lesions reveals the presence of underlying osteoclastic activity. These lesions are painful, resulting in diminished quality of life of the patient. There is emerging evidence that prostate carcinomas establish and thrive in the skeleton due to cross-talk between the bone microenvironment and tumor cells. Bone provides chemotactic factors, adhesion factors, and growth factors that allow the prostate carcinoma cells to target and proliferate in the skeleton. The prostate carcinoma cells reciprocate through production of osteoblastic and osteolytic factors that modulate bone remodeling. The prostate carcinoma-induced osteolysis promotes release of the many growth factors within the bone extracellular matrix thus further enhancing the progression of the metastases. This review focuses on the interaction between the bone and the prostate carcinoma cells that allow for development and progression of prostate carcinoma skeletal metastases.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Próstata/patología , Transducción de Señal , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Neoplasias Óseas/metabolismo , Calcio/metabolismo , Quimiocinas CXC/metabolismo , Humanos , Masculino , Metaloproteinasas de la Matriz/metabolismo , Proteína Relacionada con la Hormona Paratiroidea , Hormonas Peptídicas/metabolismo , Neoplasias de la Próstata/metabolismo , Células del Estroma/metabolismoAsunto(s)
Biomarcadores de Tumor/análisis , Biopsia con Aguja , Antígeno Ki-67/análisis , Prostatectomía , Neoplasias de la Próstata/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Índice Mitótico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugíaAsunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Difosfonatos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias Óseas/complicaciones , Humanos , Masculino , Dolor/tratamiento farmacológico , Dolor/etiología , Cuidados Paliativos , Pamidronato , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Estramustine in combination with other chemotherapeutic agents has demonstrated synergy in hormone-refractory prostate cancer. Docetaxel has demonstrated antineoplastic activity in a variety of chemotherapeutic-unresponsive tumors. We evaluated the effects of estramustine and docetaxel in preclinical models of prostate cancer. METHODS: Cell viability of PC-3 and MAT-LyLu (MLL) cells were assessed 48 hr after drug treatment. For in vivo studies, each flank of five animals in six groups was injected with 1 x 10(6) MLL cells: control, estramustine, docetaxel (low- and high-dose), and low- and high-dose docetaxel with estramustine. Animals were treated on days 4 and 11, and sacrificed on day 14. RESULTS: The IC(50) value for docetaxel was 2 nM in the PC-3 cells and 40 nM in the MLL cells. The addition of 100 nM of estramustine did not alter the IC(50) value for PC-3 cells. In the MLL cells, however, the IC(50) value was lowered to 15 nM. In vivo, low-dose docetaxel with estramustine demonstrated antineoplastic activity similar to that of high-dose docetaxel alone, suggesting additive activity between the drugs. CONCLUSIONS: These results demonstrate that when used in combination, docetaxel and estramustine can be more effective at lower dosages than when the individual drugs are used alone.