RESUMEN
BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.
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Dioxoles/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Tetrahidroisoquinolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Estudios de Cohortes , Dioxoles/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Orquiectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Sarcoma/patología , Sarcoma/cirugía , Tetrahidroisoquinolinas/efectos adversos , Trabectedina , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
PURPOSE: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy. METHODS: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression. RESULTS: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003). CONCLUSION: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Interleucina-6/inmunología , Mitoxantrona/administración & dosificación , Prednisona/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/patología , Carcinoma/cirugía , Humanos , Interleucina-6/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Mitoxantrona/efectos adversos , Metástasis de la Neoplasia , Orquiectomía , Prednisona/efectos adversos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Insuficiencia del TratamientoRESUMEN
Increases of individual beta tubulin isotypes in antimicrotubule drug resistant cell lines have been reported by several laboratories. We have previously described elevations in beta(III)and beta(IVa)isotypes in estramustine and paclitaxel resistant human prostate carcinoma cells. To investigate further the function of beta tubulin isotypes in antimicrotubule drug response, human prostate carcinoma cells that normally have very low to undetectable levels of beta(III)were stably transfected with beta(III)cDNA in pZeoSV system. An 18 bp haemagglutinin (HA) epitope tag was added at the 3' end prior to cloning into the vector. Cells were transfected with pZeoSV or pZeoSV-beta(III)plasmids and selected in the presence of Zeocin. Immunofluorescent staining of the transfectant cells have shown significant expression and incorporation of HA-tagged beta(III)tubulin into cellular microtubules. Quantitation of Western blots revealed the HA-tagged beta(III)levels to be approximately 7-fold higher than the vector control cells. RT-PCR analysis confirmed the increase at the transcript level and also revealed a collateral increase of beta(II)and beta(IVb)transcripts. Cell viability assays indicated that sensitivity of beta(III)transfected cells to various antimicrotubule agents was similar to vector transfected cells: IC50 values for estramustine, paclitaxel, colchicine and vinblastine were 4 microM, 4 nM, 22 nM and 2 nM, respectively for both cell lines. Thus, overexpression of beta(III)isotype in human prostate carcinoma cells by stable transfection failed to confer antimicrotubule drug resistance to these cells. Counterregulatory increases of endogenous beta(II)and beta(IVb)tubulin isotypes in these beta(III)transfected cells may be a compensatory mechanism used by the cells to overcome the effects of elevated beta(III)levels on the cellular microtubules. These results highlight the difficulty in isolating the contribution of single tubulin isotypes in drug response studies.
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Microtúbulos/efectos de los fármacos , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/metabolismo , Tubulina (Proteína)/metabolismo , Antineoplásicos/farmacología , Colchicina/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Estramustina/farmacología , Vectores Genéticos/administración & dosificación , Humanos , Masculino , Proteínas de Neoplasias/genética , Paclitaxel/farmacología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/ultraestructura , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Tubulina (Proteína)/genética , Células Tumorales Cultivadas/efectos de los fármacos , Vinblastina/farmacologíaRESUMEN
Although their ultimate value in prostate cancer therapy remains to be defined in randomized trials, docetaxel and paclitaxel are active agents in HRPC. Combination therapies using either of these taxanes plus oral EMP show reproducible antitumor activity that appears to be greater and more durable than that of single-agent treatment. Although the optimal combination and schedule have not been determined, weekly paclitaxel and EMP and docetaxel given every 3 weeks or by weekly infusion with EMP are useful treatment options for patients with progressive HRPC. The gastrointestinal toxicity of EMP has been reduced by intermittent rather than continuous administration, and other toxicities may be reduced further by use of intravenous EMP. Although there has been progress, the median time to progression of 5 to 6 months for current taxane-based therapies suggests that they will not have major impact on overall survival for patients with HRPC. Greater benefit may be possible earlier in the course of prostate cancer, and the activity of the taxane-EMP combinations is sufficient to justify clinical trials of adjuvant or neoadjuvant chemotherapy for selected groups of patients with locally advanced and poor-prognosis tumors. Armed with many new molecularly targeted agents that may interact favorably with taxanes, it should be possible to build on current antimicrotubule regimens to improve activity in HRPC. Taxane-EMP combinations provide a platform on which to test additional agents that may enhance the apoptotic response or circumvent cellular stress adaptations that confer drug resistance. Further elucidation of signaling pathways that regulate microtubule dynamics and programmed cell death after exposure to microtubule inhibitors would provide a more rational guide for integrating specific inhibitors of signal transduction with current taxane-based therapies. Pharmacokinetic and pharmacodynamic studies will play a key role in the development of future taxane-based therapies for prostate cancer.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Microtúbulos/efectos de los fármacos , Paclitaxel/análogos & derivados , Paclitaxel/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Dexametasona/administración & dosificación , Docetaxel , Esquema de Medicación , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Estramustina/administración & dosificación , Etopósido/administración & dosificación , Genes bcl-2 , Humanos , Hidrocortisona/administración & dosificación , Masculino , Mitosis/efectos de los fármacos , Mitoxantrona/administración & dosificación , Estudios Multicéntricos como Asunto , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Cuidados Paliativos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Resultado del Tratamiento , Tubulina (Proteína)/metabolismoRESUMEN
Menogaril is a semisynthetic anthracycline that is less cardiotoxic than doxorubicin in a preclinical model. We conducted a phase II trial to determine the activity of menogaril in hormone-refractory prostate cancer. Between October 1985 and November 1987, 32 eligible patients were enrolled and were divided into good- and poor-risk categories, the latter being defined by prior radiotherapy to less than one third of the marrow-containing skeleton. Good-risk patients received a starting dose of 200 mg/m2 by 60-minute IV infusion, whereas the poor-risk patients received 160 mg/m2. Treatment was repeated every 3 weeks until disease progression. Menogaril caused leukopenia in 90% of patients, of whom 47% had grade III or IV toxicity. Thrombocytopenia was uncommon and mild, with only three patients (9%) experiencing grade II toxicity. Nonhematologic toxicity included mucositis (9%), and mild weight loss in 33% of patients. Nine patients (28%) had stable disease of 3 or more months' duration. There were no objective partial or complete responses. The median time to progression for the entire group was 10 weeks, and the median survival time for all patients was 24 weeks. Because of appreciable toxicity and limited antitumor activity, further study of menogaril cannot be recommended in hormone-refractory prostate cancer.
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Antibióticos Antineoplásicos/uso terapéutico , Menogaril/uso terapéutico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
PURPOSE: Phase II studies were conducted to evaluate the safety and efficacy of the interferon inducer Poly ICLC at low doses in advanced renal cancer and relapsed or refractory lymphoma. PATIENTS AND METHODS: Twenty-nine patients with advanced renal carcinoma and eleven patients with lymphoma were treated with poly ICLC. Patients received 0.25 mg/m2 of poly ICLC intravenously twice weekly three days apart until progression or unacceptable toxicity. RESULTS: There were no objective responses. Six patients with renal carcinoma had stable disease as best response with one patient receiving 62 weeks of therapy. Toxicity included grade 3 anemia in 8 patients and grade 4 anemia in one patient. All patients were anemic prior to entry with a median grade 2 anemia at baseline. Grade 4 neutropenia, thrombocytopenia and injection site pain occurred in one patient each. Grade 3 fever, chills or fatigue occurred in four, three, and three patients respectively. Any grade fever occurred in 10 patients (25.6%) and any grade chills occurred in 9 patients (23.1%). CONCLUSION: Poly ICLC at this dose and schedule is well tolerated in both patient populations and is inactive in renal carcinoma.
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Carboximetilcelulosa de Sodio/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Inductores de Interferón/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Poli I-C/administración & dosificación , Polilisina/administración & dosificación , Adulto , Anciano , Carboximetilcelulosa de Sodio/efectos adversos , Carboximetilcelulosa de Sodio/análogos & derivados , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Inductores de Interferón/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Poli I-C/efectos adversos , Polilisina/efectos adversos , Polilisina/análogos & derivados , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Perillyl alcohol (POH) is a monoterpene with anticarcinogenic and antitumor activity in murine tumor models. Putative mechanisms of action include activation of the transforming growth factor beta pathway and/or inhibition of p21ras signaling, leading to differentiation or apoptosis. In this Phase I trial, 17 patients took POH p.o. three times daily for 14 days of each 28-day cycle. The starting dose of POH was 1600 mg/m2/dose, with escalations to 2100 and 2800 mg/m2/dose in subsequent cohorts. Chronic nausea and fatigue were dose-limiting toxic effects at 2800 mg/m2. Grade 1-2 hypokalemia was common at 2100 and 2800 mg/m2. Although POH could not be detected in plasma, two of its metabolites, dihydroperillic acid (DHPA) and perillic acid (PA), were measured in plasma and urine on days 1 and 15 after the first and last doses of POH, respectively. Both area under the concentration versus time curve and peak plasma concentration (Cmax) values increased with dose and exhibited high intersubject variability. Day 15 DHPA Cmax values ranged from a mean +/- SD of 22.6+/-12 microM at 1600 mg/m2/dose to 42.4+/-15.24 microM at 2800 mg/m2/dose. Corresponding mean +/- SD Cmax values for PA were 433.2+/-245.8 and 774.1+/-439.6 microM. One patient treated at the 2800 mg/m2/dose had markedly prolonged plasma levels of both PA and DHPA and developed grade 3 mucositis. POH treatment did not consistently alter the expression of p21ras, rap1, or rhoA in peripheral blood mononuclear cells obtained from patients treated at the highest dose level. The metabolites PA and DHPA did not change expression or isoprenylation of p21ras in MCF-7 breast or DU145 prostate carcinoma cells at concentrations that exceeded those achieved in patient plasma after POH treatment. We conclude that POH at 1600-2100 mg/m2 p.o. three times daily is well tolerated on a 14-day on/14-day off dosing schedule. Inhibition of p21ras function in humans is not likely to occur after POH administration at safe doses of the present oral formulation.
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Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Monoterpenos , Neoplasias/metabolismo , Terpenos/efectos adversos , Terpenos/farmacocinética , Administración Oral , Adulto , Anciano , Antineoplásicos Fitogénicos/uso terapéutico , Ciclohexenos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/biosíntesis , Proteínas Proto-Oncogénicas p21(ras)/sangre , Terpenos/sangre , Terpenos/uso terapéutico , Terpenos/orina , Células Tumorales CultivadasRESUMEN
OBJECTIVES: To compare the accuracy of a bone marrow magnetic resonance imaging (MRI) protocol in patients at high risk of metastatic disease with radioisotopic bone scans, the standard method for detection of bony metastases in patients with prostate cancer. METHODS: The study group consisted of 19 men with prostate cancer who underwent a bone marrow MRI between November 1993 and February 1996. This protocol images the marrow of the thoracolumbar spine, sacrum, pelvis, and femurs. Indications for MRI included an equivocal bone scan and/or staging of locally advanced or recurrent disease. The findings on MRI and bone scan were compared and the results correlated with the subsequent clinical patient outcome. RESULTS: The bone marrow MRI protocol detected metastatic disease in 1 (7%) of 13 patients with negative bone scans. Four patients had an indeterminate bone scan: 2 had true-positive MRIs, 1 a true-negative MRI, and 1 a false-positive MRI on the basis of subsequent clinical follow-up. Two patients with positive bone scans had true-positive MRIs. CONCLUSIONS: Although not recommended for routine staging, MRI was useful in this study for clarifying an equivocal bone scan. The bone marrow MRI protocol images a high yield volume of the bony skeleton and is fast and economical compared with obtaining many focused MRI scans of these areas separately. These preliminary data suggest that further investigation of its clinical utility for staging locally advanced or recurrent disease is justified.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/secundario , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/secundario , Imagen por Resonancia Magnética , Neoplasias de la Próstata/patología , Protocolos Clínicos , Humanos , Masculino , Cintigrafía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Chemotherapy has a limited impact on adenocarcinoma of the stomach. Although biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) and interferon-alpha (IFN-alpha) has improved the outcomes of patients with metastatic colorectal carcinoma compared with 5-FU alone, this approach has not been extensively evaluated in the treatment of advanced gastric carcinoma. METHODS: Twenty-seven patients with bidimensionally measurable, metastatic gastric carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 received the combination of IFN-alpha (5 million U/m2 administered subcutaneously daily on Days 1-7), LV (500 mg/m2 administered intravenously over 30 minutes immediately after IFN-alpha on Days 2-6), and 5-FU (370 mg/m2 given as an intravenous bolus 60 minutes after LV on Days 2-6), with treatment repeated every 4 weeks. Oral cryotherapy was administered routinely before each dose of 5-FU to reduce the incidence of severe stomatitis. RESULTS: The median age of the patients was 58 years (range, 20-76), and 22 patients had residual, unresectable primary lesions. The median number of cycles received was 3 (range, 1-11). Of 24 patients who received at least 2 cycles of treatment, 15 (62.5%) did not require dose reduction for toxicity during the initial 2 cycles. The predominant toxicities were gastrointestinal: diarrhea and stomatitis of Grade 3-4 occurred in 28.6% and 35.7% of patients, respectively. Other severe (Grade 3-4) toxicities were granulocytopenia (which occurred in 21.4% of patients) and fatigue (in 10.7%). Fever and flu-like symptoms were common but usually mild. Of 24 patients who were evaluable for response, 3 had partial responses (PR) of 16, 23, and 33 weeks' duration, respectively, for a response rate of 12.5% (95% confidence interval = 2.7-32.4%). Two additional patients had reductions in tumor size sufficient for PR, but scans to document the minimum required response duration of 4 weeks were not obtained before progressive disease occurred. The median progression-free and overall survivals were 2.5 and 7.8 months, respectively. CONCLUSIONS: Although this regimen can be administered safely with appropriate supportive care to patients with good performance status, it has limited therapeutic activity in patients with advanced gastric carcinoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Agranulocitosis/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Neoplasias Gástricas/patología , Estomatitis/inducido químicamente , Resultado del TratamientoRESUMEN
Metastatic germ-cell tumors of the testis are highly curable with cisplatin-based chemotherapy. Although cisplatin-based chemotherapy is generally well tolerated and rarely causes severe neurotoxicity, there is little information to guide the treatment of patients with neuromuscular disorders. The authors report the successful treatment of a patient with testicular cancer and spinal muscular atrophy, an inherited degenerative neuromuscular disease.
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Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Germinoma/complicaciones , Germinoma/tratamiento farmacológico , Atrofia Muscular Espinal/complicaciones , Neoplasias Testiculares/complicaciones , Neoplasias Testiculares/tratamiento farmacológico , Adulto , Humanos , MasculinoRESUMEN
To investigate the role of beta-tubulin isotype composition in resistance to paclitaxel, an anti-microtubule agent, human prostate carcinoma (DU-145) cells were intermittently exposed to increasing concentrations of paclitaxel. Cells that were selected and maintained at 10 nM paclitaxel (Pac-10) were fivefold resistant to the drug. Pac-10 cells accumulated radiolabelled paclitaxel to the same extent as DU-145 cells and were negative for MDR-1. Analysis of Pac-10 and DU-145 cells by flow cytometry showed similar cell cycle patterns. Immunofluorescent staining revealed an overall increase of alpha- and beta-tubulin levels in Pac-10 cells compared with DU-145 cells. Examination of beta-tubulin isotype composition revealed a significant increase in betaIII isotype in the resistant cells, both by immunofluorescence and by western blot analysis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the isotypes confirmed the increase observed for the betaIII by exhibiting ninefold higher betaIII mRNA levels and also showed fivefold increase of the betaIVa transcript. In addition, analysis of paclitaxel-resistant cells that were selected at increasing levels of the drug (Pac 2, 4, 6, 8 and 10) exhibited a positive correlation between increasing betaIII levels and increasing resistance to paclitaxel. Increased expression of specific beta-tubulin isotypes and subsequent incorporation into microtubules may alter cellular microtubule dynamics, providing a defence against the anti-microtubule effects of paclitaxel and other tubulin-binding drugs.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Microtúbulos/efectos de los fármacos , Proteínas de Neoplasias/análisis , Paclitaxel/farmacología , Neoplasias de la Próstata/química , Tubulina (Proteína)/análisis , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Resistencia a Antineoplásicos , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
Antimicrotubule drugs are used as chemotherapeutic agents due to their effects on essential cellular functions such as mitosis, organelle transport and maintenance of cell shape. When used in combination, paclitaxel with estramustine or vinblastine has demonstrated activity against hormone refractory prostate cancer. To understand the mechanism of resistance that develops in patients as a result of antimicrotubule drug therapy, we exposed human prostate carcinoma cells to IC20 and IC40 doses of estramustine, paclitaxel or vinblastine for 48 h and examined the beta-tubulin (the cellular target) isotype composition. The results revealed an increase in the betaIII-tubulin isotype as a result of drug treatment both at protein and message levels. In addition, examination of human brain cell lines with different intrinsic levels of betaIII showed that cell lines with higher betaIII levels were more resistant to paclitaxel. These results are in agreement with our previous findings in human prostate carcinoma cell lines that were made resistant to estramustine or paclitaxel and suggest an important function for betaIII in antimicrotubule drug resistance. Also, the complete coding sequence of human betaIII tubulin reported here will provide molecular tools for future investigations.
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Antineoplásicos Alquilantes/farmacología , Antineoplásicos Fitogénicos/farmacología , Estramustina/farmacología , Paclitaxel/farmacología , Neoplasias de la Próstata/metabolismo , Tubulina (Proteína)/genética , Vinblastina/farmacología , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN Complementario , Resistencia a Medicamentos , Humanos , Masculino , Microtúbulos , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Tubulina (Proteína)/biosíntesis , Tubulina (Proteína)/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
PURPOSE: To evaluate the antitumor activity of 96-hour paclitaxel and daily oral estramustine phosphate (EMP) in patients with metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Thirty-four patients with adenocarcinoma of the prostate that progressed after one or more hormonal therapies and a trial of antiandrogen withdrawal were enrolled onto this phase II trial. Patients received paclitaxel 120 mg/m2 by 96-hour intravenous (i.v.) infusion on days 1 through 4 of each 21-day cycle, together with daily oral EMP 600 mg/m2/d, continuously. RESULTS: Four of nine patients with measurable disease had objective responses (one complete response [CR] and three partial responses [PRs]) in liver (two patients) or nodes (two patients) of 2, 6, 8, and 20 months' duration. Of 25 assessable patients with metastases limited to bone, 14 had a > or = 50% decline in pretreatment prostate-specific antigen (PSA) level sustained for at least 6 weeks and seven had a > or = 80% decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a > or = 50% decline of PSA and nine (28.1%) had a > or = 80% decrease. The main toxicities (> or = grade 2) were nausea, fluid retention, and fatigue, which occurred in 33%, 33%, and 24.2% of patients. Median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time is 69 weeks. CONCLUSION: The combination of EMP and 96-hour paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Estramustina/administración & dosificación , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: beta-tubulin, the intracellular target of several antimicrotubule agents, is encoded by at least six genes and exists as multiple isotypes with tissue-specific expression. Previous in vitro studies indicated that tubulin isotype composition may affect polymerization properties, dynamics, and sensitivity to drugs. METHODS: To investigate the isotype composition of beta-tubulin in human prostate, tissues were collected from 26 patients after radical prostatectomy and sections were stained with isotype-specific antibodies. RESULTS: beta IV tubulin is the predominant isotype in benign prostatic hyperplasia (BPH) and adenocarcinoma, showing significantly stronger immunohistochemical expression than beta II and beta III, particularly in Gleason's grade 3 and 4 cancers. Staining for the beta II isotype was invariably weak and often absent in BPH and normal glands. There was a marked increase in beta II isotype stain from BPH to cancer in 77% of the patients, suggesting that the expression of this isotype is related to malignant status. CONCLUSIONS: The beta II tubulin isotype is a potential marker for prostate adenocarcinoma. The possibility that tumor beta-tubulin isotype composition may effect the response to antimicrotubule drug therapy in prostate cancer and other tumors merit investigation.
Asunto(s)
Carcinoma/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Tubulina (Proteína)/metabolismo , Carcinoma/patología , Humanos , Inmunohistoquímica/métodos , Isomerismo , Masculino , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Coloración y EtiquetadoRESUMEN
The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Ácido Aspártico/análogos & derivados , Fluorouracilo/uso terapéutico , Leucovorina/farmacología , Metiltioinosina/farmacología , Ácido Fosfonoacético/análogos & derivados , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Ácido Aspártico/administración & dosificación , Ácido Aspártico/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Interacciones Farmacológicas , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Humanos , Leucovorina/administración & dosificación , Masculino , Metiltioinosina/administración & dosificación , Persona de Mediana Edad , Ácido Fosfonoacético/administración & dosificación , Ácido Fosfonoacético/farmacologíaRESUMEN
Estramustine (EM), an antimicrotubule agent, is effective against hormone-refractory prostate cancer when used in combination with vinblastine or paclitaxel. To understand the effect of EM on beta-tubulin, a cellular target for this class of drugs, human prostate carcinoma cells (DU-145) were made resistant to EM, and two cell lines were selected at 12- (EM-12) and 15-microMolar (EM-15) concentrations of the drug. These cell lines exhibited 8- to 9-fold resistance to EM and 2- to 4-fold cross-resistance to paclitaxel. Immunofluorescent staining of the cells with beta-tubulin isotype-specific antibodies showed an approximately 6-fold increase in the beta(III)-tubulin levels and moderate increase in overall beta-tubulin levels in EM-resistant cells when compared to DU-145 cells. This increase of beta(III) isotype was confirmed by Western analysis. A reverse transcriptase-PCR assay was also employed using beta-tubulin isotype-specific primers to quantify beta-tubulin isotype RNA. A 4-fold increase in beta(III) and a 3-fold increase in beta(IV alpha) transcript were seen in both EM-resistant cell lines. These results indicate that overexpression of specific beta-tubulin isotypes may play a role in the cellular defense against EM and other antimicrotubule agents.
Asunto(s)
Antineoplásicos/farmacología , Estramustina/farmacología , Neoplasias de la Próstata/metabolismo , Tubulina (Proteína)/genética , Secuencia de Bases , Cartilla de ADN/química , Resistencia a Medicamentos , Técnica del Anticuerpo Fluorescente Indirecta , Expresión Génica , Humanos , Masculino , Datos de Secuencia Molecular , ARN Mensajero/genética , Tubulina (Proteína)/metabolismo , Células Tumorales CultivadasRESUMEN
Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Ácido Aspártico/análogos & derivados , Fluorouracilo/farmacocinética , Neoplasias/tratamiento farmacológico , Ácido Fosfonoacético/análogos & derivados , Tioinosina/análogos & derivados , Tionucleótidos/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Ácido Aspártico/farmacología , Femenino , Fluorouracilo/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Ácido Fosfonoacético/farmacología , ARN Neoplásico , Tioinosina/farmacocinética , Tioinosina/farmacología , Tionucleótidos/farmacocinéticaRESUMEN
Combination antimicrotubule therapy with estramustine phosphate (EMP) and vinblastine has reproducible activity in metastatic hormone-refractory prostate cancer (HRPC) with an objective response rate of 31%. Although paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 24-hour infusion was inactive in HRPC, 0.5 to 1.0 nmol/L concentrations of paclitaxel combined with EMP exerted synergistic cytotoxicity in DU-145 androgen-independent human prostate cancer cell lines. Based on these results, we treated 24 patients with HRPC using the combination of paclitaxel 120 to 140 mg/m2 by 96-hour intravenous infusion every 3 weeks plus daily oral EMP at 600 mg/m2/d. Of seven patients with measurable soft tissue metastases, three have attained partial responses and a fourth patient is nearing partial response status. Of 16 patients with bone-only disease evaluated by change in serum prostate-specific antigen levels, 11 patients (68.8%) have had decreases of > or = 50% from pretreatment baseline. The prostate-specific antigen decrease has exceeded 80% in six of 16 (37.5%) patients. For all 23 evaluable patients, the prostate-specific antigen has decreased by > or = 50% in 15 (65.2%) and by > or = 80% in eight (34.7%). Grade 4 leukopenia occurred in one of 21 patients treated at the paclitaxel dose of 120 mg/m2/96 hr and one of three patients treated at 140 mg/m2/96 hr. The incidence of nausea (50%) and peripheral edema (37.5%) was similar to that associated with single-agent EMP. These results demonstrate that 96-hour paclitaxel plus EMP is active in HRPC and provide further evidence that the rational combination of antimicrotubule agents leads to synergistic antitumor activity in HRPC.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundario , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Diarrea/inducido químicamente , Esquema de Medicación , Resistencia a Antineoplásicos , Estramustina/administración & dosificación , Fatiga/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Hormonas/farmacología , Humanos , Masculino , Náusea/inducido químicamente , Paclitaxel/administración & dosificación , Antígeno Prostático Específico/análisis , Neoplasias de la Próstata/diagnóstico , Resultado del TratamientoRESUMEN
Estramustine phosphate is a unique antimitotic agent that binds to tubulin and microtubule-associated proteins. Preclinically, estramustine combined with other microtubule inhibitors, like vinblastine or paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), produced additive or greater antimitotic and cytotoxic effects. Clinically, the estramustine/vinblastine combination has significant activity in hormone-refractory prostate cancer. We have begun a phase I study of paclitaxel by 96-hour continuous infusion every 3 weeks combined with daily oral estramustine (600 mg/m2). Eighteen patients with refractory solid tumors have received paclitaxel doses ranging from 80 to 140 mg/m2. Grade 3 or 4 granulocytopenia occurred in one of seven and two of four patients treated at the 120- and 140-mg/m2 dose levels, respectively. The latter two patients experienced grade 3 mucositis and had mean plasma paclitaxel levels exceeding 0.1 mumol/L. Other toxicities, principally nausea and hepatic function abnormalities, have been mild. The apparent steady-state concentrations of paclitaxel 100 and 120 mg/m2 administered with estramustine are similar to those reported for single-agent paclitaxel administered as a 96-hour infusion at doses of 100 and 120 mg/m2. In contrast, at the 140 mg/m2 dose level, paclitaxel concentrations increased throughout the infusion, and steady state was not reached in three of the four patients treated. Objective responses have been observed in two of three patients with adenocarcinoma of the esophagus and in two patients with hormone-resistant prostate cancer and measurable soft tissue metastases. Two additional patients with prostate cancer have been treated with the estramustine/paclitaxel combination, one achieving a major response and the other stable disease. The recommended phase II dose for 96-hour infusional paclitaxel with daily oral estramustine is at least 120 mg/m2. Studies to determine the effect of estramustine on paclitaxel pharmacokinetics are continuing. The antitumor activity observed merits phase II studies of this combination in hormone-resistant prostate cancer and other malignancies.