Assuntos
Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Nefropatias/diagnóstico , Administração Oral , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Capecitabina , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/análogos & derivados , Humanos , Nefropatias/complicações , Testes de Função Renal , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Resultado do TratamentoRESUMO
PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 microg/kg) is as safe and effective as daily filgrastim (5 microg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy. PATIENTS AND METHODS: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 60 mg/m(2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 microg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 microg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored. RESULTS: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar. CONCLUSION: A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Paclitaxel/análogos & derivados , Taxoides , Idoso , Neoplasias da Mama/patologia , Preparações de Ação Retardada , Docetaxel , Método Duplo-Cego , Doxorrubicina/administração & dosagem , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/prevenção & controle , Paclitaxel/administração & dosagem , Proteínas RecombinantesRESUMO
BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.
Assuntos
Neoplasias da Mama/diagnóstico , Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Neoplasias da Mama/patologia , Citodiagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Irrigação TerapêuticaRESUMO
Recent studies strongly support the theory that breast precancers such as atypical hyperplasia (AH) and ductal carcinoma in situ (DCIS) are closely related to the development of invasive breast cancer. There is growing belief that reduction in the burden of breast intraepithelial neoplasia (IEN) through intervention may translate into a decreased burden of invasive cancer. Current research is focusing on two issues. First, improved modalities for detecting precancers are needed; breast epithelial cell analysis appears particularly promising. Second, clinical trials are needed that would permit rapid evaluation of agents that can reduce breast cancer risk. Results of the few available trials suggest that several agents may effectively reduce the burden of breast precancer.
Assuntos
Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/fisiopatologia , Carcinoma Intraductal não Infiltrante/terapia , Lesões Pré-Cancerosas/terapia , Inibidores da Aromatase/uso terapêutico , Carcinoma Intraductal não Infiltrante/complicações , Ensaios Clínicos como Assunto , Feminino , Humanos , Hiperplasia , Invasividade Neoplásica , Lesões Pré-Cancerosas/complicações , Fatores de RiscoRESUMO
DFMO (alpha-difluoromethylornithine) is an oral irreversible inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis. DFMO has been shown to have antiproliferative effects against several human cancers, and some studies have suggested that DFMO may have pro-apoptotic and anti-invasive properties as well. DFMO is well tolerated with minimal toxicity but has been associated with ototoxicity with prolonged daily administration. We conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high-dose DFMO in metastatic breast cancer patients. Twenty-one patients were treated with 4800 mg of DFMO p.o. three times a day for 14 days, followed by a 2-week drug holiday on a 28-day cycle. Urinary polyamine and blood DFMO levels were measured at multiple time points during therapy. High-dose DFMO was well tolerated, and no clinically significant ototoxicity was noted. No patient achieved an objective antitumor response; however, one patient with heavily pretreated liver metastases has achieved stable disease for 18 months to date on DFMO. Putrescine, spermine, and spermidine urinary levels were suppressed with DFMO treatment and remained low during the 2-week drug holiday. High-dose DFMO on a schedule of 2 weeks on treatment followed by 2 weeks off is well tolerated, is not associated with ototoxicity, and leads to sustained suppression of urinary polyamine levels. Although not an active cytotoxic agent for metastatic breast cancer, the intriguing prolonged growth arrest of liver metastases in one patient highlights the potential clinical growth inhibitory properties of DFMO. We believe that DFMO is worthy of study as adjuvant therapy in primary breast cancer patients and as a chemopreventive agent.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Eflornitina/uso terapêutico , Poliaminas/urina , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Eflornitina/efeitos adversos , Eflornitina/farmacocinética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Putrescina/urina , Receptores de Estrogênio/análise , Espermidina/urina , Espermina/urina , Fatores de TempoRESUMO
BACKGROUND: Tamoxifen and fenretinide combination therapy has been shown to be an active treatment regimen in metastatic breast cancer patients. This pilot study sought to determine whether the addition of fenretinide to tamoxifen would be associated with antitumor activity in metastatic breast cancer patients who had been previously treated with tamoxifen or who had hormone receptor negative disease. The effect of this therapy on circulating plasma transforming growth factor-beta (TGF-beta) levels and serum lipids was also examined. PATIENTS AND METHODS: Thirty-one patients were treated with tamoxifen (20 mg p.o. daily), and fenretinide (400 mg p.o. daily with a 3-day drug holiday each month). Plasma TGF-beta testing was performed using isoform specific sandwich ELISA. RESULTS: Twenty four of the 31 patients were evaluable for an antitumor response including 14 estrogen receptor (ER) positive patients who had failed prior tamoxifen therapy, seven ER-negative patients, and three hormone therapy naive ER-positive patients. There were no objective antitumor responses; three patients had stable disease for 8, 8, and 24 months. Five patients (16%) discontinued therapy for toxicity (one for grade 3 skin rash and four for abnormal dark adaptation). There was a statistically significant decrease in total cholesterol (median change per patient of -13.5 mg/dl; p = 0.049, a 6.5% decrease), and an increase in HDL levels (median change per patient of +18 mg/dl, p = 0.0001, a 35% increase) with tamoxifen and fenretinide therapy. TGF-beta1 plasma levels were normal in 26 of 28 patients, and no changes in these levels post-treatment were demonstrated. CONCLUSIONS: Tamoxifen and fenretinide therapy is not an active combination in ER negative metastatic breast cancer or in patients whose disease has progressed on tamoxifen. This combination had a beneficial effect on total serum cholesterol and HDL levels with no associated rise in serum triglyceride levels. The 400 mg dose of fenretinide was associated with symptomatic nyctalopia in one-third of patients making it an unsuitable dose for use in breast cancer prevention studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Fenretinida/administração & dosagem , Humanos , Lipídeos/sangue , Pessoa de Meia-Idade , Projetos Piloto , Tamoxifeno/administração & dosagem , Fator de Crescimento Transformador beta/análise , Resultado do TratamentoRESUMO
Oral cyclophosphamide is well tolerated and effective. Published data support its use as part of adjuvant and metastatic breast cancer treatment regimens. Cyclophosphamide has generally been administered at a higher dose intensity when given orally compared with intravenous infusion. However, there is currently no evidence that oral cyclophosphamide is either more toxic or more or less effective than an equivalent dose of intravenous cyclophosphamide. There is evidence in both the adjuvant and metastatic settings that classical oral cyclophosphamide-methotrexate-fluorouracil (CMF) is more effective than intravenous CMF, possibly because of the greater dose intensity of classical CMF. Prolonged administration of oral cyclophosphamide up to high cumulative doses is associated with an elevated risk of a secondary leukaemia. The rates of chemotherapy-related amenorrhoea with oral cyclophosphamide are directly related to the total dose of cyclophosphamide administered and the patient's age. With the growing availability of other oral cytotoxic agents with demonstrated effectiveness in breast cancer, it is likely that oral cyclophosphamide will be incorporated once again into regimens for both metastatic and adjuvant treatment.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Administração Oral , Animais , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Feminino , Fluoruracila/administração & dosagem , Humanos , Metotrexato/administração & dosagemRESUMO
Our previous work in patients undergoing autologous transplant for multiple myeloma (MM) or breast cancer (BC) has shown that retroviral transduction of adult CD34+ cells for 72 hours in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor (SCF) resulted in .01% to 1% long-term marking of peripheral blood and marrow cells (Blood 85:3948, 1995). In this study we compare these previous studies to transduction with no added growth factors, previously shown to result in higher levels of marking in children (Lancet 342:1134, 1993) or transduction in the presence of an autologous stromal layer. Peripheral blood (PB) mononuclear cells were collected via apheresis after high-dose cyclophosphamide and granulocyte colony-stimulating factor. Bone marrow (BM) was also harvested in all patients. One third of both BM and PB collections were enriched for CD34+ cells and transduced with one of two marking vectors containing the neomycin-resistance gene to distinguish cells originating from BM and PB posttransplantation. Cells from 3 MM and 2 BC patients were transduced without growth factors for 6 hours and cells from 2 MM and 2 BC patients were transduced in the presence of autologous marrow stroma. Immediately posttransduction, the percentage of Neo-resistant PB and BM progenitors (colony-forming units) were: 0% to 19% in the 6-hour no growth factor group and 0% to 36% in the autologous stroma group. After conditioning therapy, both transduced and untransduced PB and BM fractions were infused into the patients. Semi-quantitative nested DNA polymerase chain reaction was performed on total, mononuclear, and granulocyte fractions of PB and BM at 1, 3, 6, 9, 12, and 18 months. Poor marking has been observed in both groups, with no consistently positive patients. These results compare unfavorably with our prior experience using growth factors during transduction. Further optimization of transduction conditions and vectors needs to be developed to improve transduction efficiency of adult human repopulating hematopoietic cells.
Assuntos
Medula Óssea/patologia , Técnicas de Transferência de Genes , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Adulto , Medula Óssea/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Feminino , Vetores Genéticos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neomicina/farmacologia , Retroviridae/genética , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Células Estromais/transplante , Transplante AutólogoRESUMO
Inhibitors of topoisomerase I and topoisomerase II have demonstrated synergy when administered sequentially in several tumor models while having a diminished antitumor effect when given concurrently. To explore the potential for clinical sequence-dependent synergy, we instituted a Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advanced malignancies. Thirty-three patients with advanced malignancies or malignancies for whom no standard therapy exists were entered into the study. Topotecan was administered in escalating doses by 72-h continuous infusion on days 1, 2, and 3, followed by a bolus of doxorubicin given on day 5. To explore the hematological toxicity associated with this sequence, bone marrow aspirates were obtained both prior to the topotecan infusion and immediately prior to the doxorubicin in 10 patients to determine by fluorescence-activated cell sorting analysis whether CD34+ cell synchronization was occurring using this sequential schedule. Dose-limiting hematological toxicity occurred at the first dose-level in three of six patients. Therefore, we defined the maximum-tolerated dose (MTD) below our starting dose-level. Further dose-escalation and a new MTD were defined with the addition of granulocyte-colony stimulating factor (G-CSF). The MTD was, therefore, topotecan 0.35 mg/m2/day continuous i.v. infusion on days 1, 2, and 3, followed by doxorubicin 45 mg/m2 on day 5 without G-CSF, whereas the MTD with G-CSF was topotecan 0.75 mg/m2/day by 72-h continuous i.v. infusion, followed by doxorubicin 45 mg/m2 i.v. bolus on day 5. Ten patients with paired bone marrow aspirates obtained before topotecan and before doxorubicin administrations were available for evaluation. In 7 of 10 patients, there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in the proportion of CD34+ cells in S-phase 24 h after the topotecan infusion and prior to doxorubicin compared to the pretreatment values, whereas 1 patient had a decrease in the proportion of CD34+ cells in S phase and 2 patients had no change. Topotecan and doxorubicin with this sequence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoietic progenitor CD34+ cells in S-phase may account for the increased granulocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neoplasias/tratamento farmacológico , Topotecan/efeitos adversos , Adulto , Idoso , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Topotecan/administração & dosagemAssuntos
Anticarcinógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/prevenção & controle , Carcinoma in Situ/prevenção & controle , Carcinoma Ductal de Mama/prevenção & controle , Monoterpenos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Hormônio-Dependentes/prevenção & controle , Tamoxifeno/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Carcinoma in Situ/genética , Carcinoma Ductal de Mama/genética , Ensaios Clínicos como Assunto , Terapia Combinada , Cicloexenos , Desidroepiandrosterona/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Feminino , Genisteína , Humanos , Isoflavonas/uso terapêutico , Limoneno , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/terapia , Retinoides/uso terapêutico , Terpenos/uso terapêuticoRESUMO
PURPOSE: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS: The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION: r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/farmacocinética , Verapamil/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Adulto , Idoso , Anticorpos Monoclonais , Antineoplásicos Fitogênicos/administração & dosagem , Biópsia , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos Cross-Over , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Resultado do Tratamento , Verapamil/sangue , Verapamil/uso terapêuticoRESUMO
We conducted a prospective randomized trial to evaluate the ability of the interleukin-3/granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein, PIXY321, to ameliorate cumulative thrombocytopenia after multiple cycles of 5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide (FLAC) chemotherapy compared with GM-CSF in patients with advanced breast cancer. Fifty-three patients were randomized to receive either PIXY321. 375 microg/m2 twice a day subcutaneously, or GM-CSF, 250 microg/m2 daily subcutaneously after FLAC chemotherapy. PIXY321 was less well tolerated than GM-CSF, with more patients developing chills and local skin reactions and more patients stopping PIXY321 due to intolerance. While no difference in the neutrophil nadirs was seen with the two cytokines, the duration of the absolute neutrophil count less than 1,000/muL for all cycles was significantly longer with PIXY321 than with GM-CSF. Fifty percent of patients treated with multiple cycles of FLAC chemotherapy on both study arms developed dose-limiting thrombocytopenia. No differences in platelet nadirs, duration of thrombocytopenia, or need for platelet transfusions were observed with PIXY321 versus GM-CSF. The average delivered doses of FLAC chemotherapy were somewhat higher in the GM-CSF study arm. PIXY321 was not superior to GM-CSF in ameliorating the cumulative thrombocytopenia observed with multiple cycles of FLAC chemotherapy and was less well tolerated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Neutropenia/terapia , Trombocitopenia/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Transfusão de Plaquetas , Estudos Prospectivos , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
This study utilized a recently developed culture and quantitation system to detect megakaryocyte precursors in CD34+ bone marrow cells from normal donors and breast cancer patients treated with 5-fluorouracil, leucovorin, adriamycin and cyclophosphamide (FLAC). Bone marrow was obtained from patients before and then after their first cycle of FLAC once blood cell counts had recovered. CD34+ cells were isolated and placed in liquid culture with growth factors to stimulate proliferation and lineage commitment. Absorbance values from an enzyme-linked immunosorbent assay were used to quantitate expression of platelet glycoprotein GPIIb/IIIa. There was an increase in absorbance with increasing numbers of cells seeded per culture that was associated with an increase in the number of megakaryocyte lineage cells produced. After 10 days in liquid culture, absorbance values for expression of GPIIb/IIIa from 2,000 normal donor and pre-chemotherapy CD34+ marrow cells were > or = 1.0. Absorbance values from cultures of post-chemotherapy CD34+ cells from four patients were similar to values from pre-chemotherapy CD34+ cells. In contrast, absorbance values from cultures of post-chemotherapy CD34+ cells from two other patients were low (absorbance < 0.5). Low absorbance values for GPIIb/IIIa expression indicate that megakaryocyte production from those CD34+ cells was reduced. Both of those patients developed prolonged thrombocytopenia and platelet nadirs of less than 20,000/microl during FLAC chemotherapy. In contrast, only one out of four patients whose cultures of post-chemotherapy CD34+ cells had absorbance values > or = 1.0 developed platelet nadirs less than 20,000/microl. These results suggest that low platelet nadirs and delayed platelet recovery may be associated with suppressive effects of chemotherapy on recovery of megakaryocyte precursors.
Assuntos
Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Antígenos CD34/biossíntese , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Contagem de Células Sanguíneas , Neoplasias da Mama/tratamento farmacológico , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Fluoruracila/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-3/metabolismo , Interleucina-3/farmacologia , Leucovorina/uso terapêutico , Megacariócitos/metabolismo , Megacariócitos/fisiologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/biossíntese , Proteínas Recombinantes de Fusão/farmacologia , Fator de Células-Tronco/metabolismo , Trombocitopenia/etiologia , Fatores de TempoRESUMO
PURPOSE: In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS: Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS: Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION: Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Paclitaxel/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Contagem de Células Sanguíneas/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Esquema de Medicação , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/etiologia , Falha de Equipamento , Transfusão de Eritrócitos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doenças Hematológicas/sangue , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/terapia , Hematúria/induzido quimicamente , Hematúria/tratamento farmacológico , Terapia por Infusões no Domicílio/instrumentação , Humanos , Mesna/uso terapêutico , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
Phosphorothioate insecticides such as parathion (O,O-diethyl-O-p-nitrophenyl phosphorothioate) undergo P450-dependent oxidative desulfuration, leading to both activation and detoxification of these compounds. Consequently, alterations in P450-dependent oxidative desulfuration may affect the acute toxicities of these insecticides. In the present study, pretreatment of mice with 15% ethanol in the drinking water for 6 days antagonized the acute toxicity of parathion, but not its toxic metabolite paraoxon (O,O-diethyl-O-p-nitrophenyl phosphate), suggesting that ethanol affected the oxidative desulfuration of this insecticide. The presence of ethanol within hepatic microsomal incubations did not alter the P450-dependent formation of paraoxon (activation) and p-nitrophenol (detoxification), although p-nitrophenol levels were increased in the presence of ethanol as a result of inhibition of its biotransformation to 4-nitrocatechol by CYP2E1. Ethanol exposure reduced hepatic pyruvate levels, but had no effect on levels of lactate, isocitrate, alpha-ketoglutarate, and malate. Calculation of cytosolic NAD+/NADH and cytosolic NADP+/NADPH redox ratios did not reveal any detectable difference in redox state between control and ethanol-treated mice. Since ethanol did not alter directly the P450-dependent activation or detoxification of parathion, and did not decrease NADPH levels, ethanol's antagonism of the acute toxicity of parathion may result from reduced availability of O2.
Assuntos
Etanol/administração & dosagem , Inseticidas/toxicidade , Fígado/metabolismo , Paration/toxicidade , Animais , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP2E1 , Sistema Enzimático do Citocromo P-450/metabolismo , Citosol/metabolismo , Etanol/sangue , Etanol/farmacologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Paraoxon/metabolismo , Paration/antagonistas & inibidores , Paration/químicaRESUMO
Cumulative thrombocytopenia is a dose-limiting toxicity of dose-intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety-three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM-CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL-3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Interleucina-3/administração & dosagem , Trombocitopenia/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Injeções Subcutâneas , Interleucina-3/efeitos adversos , Interleucina-3/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Trombocitopenia/induzido quimicamenteRESUMO
PURPOSE: To study the effect of the multidrug-resistance reversal agent R-verapamil on the pharmacokinetic behavior of paclitaxel. METHODS: Six women with breast cancer who received paclitaxel as a 3-hour infusion with and without R-verapamil were monitored with frequent plasma sampling up to 24 hours postinfusion. Paclitaxel concentrations were measured using a reverse-phase high-pressure liquid chromatography assay. RESULTS: Concomitant administration of R-verapamil resulted in a decrease in mean (+/- SD) paclitaxel clearance from 179 +/- 67 mL/min/m2 to 90 +/- 34 mL/min/m2 (P < .03) and in a twofold increase in paclitaxel exposure (area under the curve [AUC]). The mean end-infusion paclitaxel concentration was also twofold higher: 5.1 +/- 1.8 mumol/L versus 11.3 +/- 4.1 mumol/L (P < .03). CONCLUSION: The alteration in paclitaxel pharmacokinetics when paclitaxel and R-verapamil are coadministered complicates the interpretation of response and toxicity data from clinical trials of this drug combination.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Paclitaxel/farmacocinética , Verapamil/uso terapêutico , Neoplasias da Mama/sangue , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Taxa de Depuração Metabólica/efeitos dos fármacos , Paclitaxel/uso terapêuticoRESUMO
The effects of induction of various forms of cytochromes P450 by chemicals like phenobarbital on the hepatic oxidative desulfuration and acute toxicity of the phosphorothioate insecticide parathion have been well-characterized. However, the effects of these chemicals on the metabolism and acute toxicity of the active metabolite paraoxon are less understood. In the present study, daily pretreatment of mice with phenobarbital (intraperitoneally 75 mg/kg) for up to eight days resulted in a transient increase in hepatic microsomal A-esterase activity, with a corresponding transient decrease in serum A-esterase activity (A-esterase was defined as hydrolysis of paraoxon which could be inhibited by EDTA). These alterations could be accounted for by a temporary decrease in the rate of secretion of A-esterase from liver. However, the same pretreatment resulted in a sustained protective effect against the acute toxicity of paraoxon. These data suggest that alterations in A-esterase activity as a result of phenobarbital pretreatment cannot account for the observed antagonism of the acute toxicity of paraoxon. Furthermore, these data demonstrate that the protective effect of phenobarbital pretreatment on phosphorothioate insecticides like parathion cannot be attributed exclusively to alterations in oxidative desulfuration of these compounds.
Assuntos
Hidrolases de Éster Carboxílico/biossíntese , Inseticidas/toxicidade , Fígado/enzimologia , Paraoxon/toxicidade , Fenobarbital/farmacologia , Análise de Variância , Animais , Biotransformação , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Hidrólise , Injeções Intraperitoneais , Inseticidas/administração & dosagem , Inseticidas/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Paraoxon/administração & dosagem , Paraoxon/metabolismo , Fenobarbital/administração & dosagemRESUMO
We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.
Assuntos
Antígenos CD/análise , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Antígenos CD34 , Neoplasias da Mama/patologia , Ciclofosfamida/farmacologia , Feminino , Filgrastim , Fluoruracila/farmacologia , Seguimentos , Genes Reporter , Marcadores Genéticos , Terapia Genética , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Canamicina Quinase , Masculino , Melfalan/farmacologia , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/análise , Proteínas Recombinantes/análise , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Irradiação Corporal TotalRESUMO
A method has been developed to determine true plasma transforming growth factor beta (TGF-beta) levels by using the platelet alpha granule-specific marker, platelet factor 4, to correct for the TGF-beta contributed by platelets degranulated ex vivo. TGF-beta levels were measured on acid-ethanol extracts of human plasma using isoform-specific sandwich enzyme-linked immunosorbent assays. Normal human subjects had 4.1 +/- 2.0 ng/ml TGF-beta1 (range, 2.0-12.0; n = 42), <0.2 ng/ml TGF-beta2, and <0.1 ng/ml TGF-beta3 in their plasma. There were no significant changes with age or with hormonal status, but any given individual showed fluctuations of up to 3-fold in measured plasma TGF-beta levels due to unknown factors. Of 28 patients with advanced metastatic breast cancer, 2 had greatly elevated TGF-beta1 levels, while the rest were in the normal range. The presence of physiologically significant levels of TGF-beta1 in the plasmas of normal human subjects may indicate previously unsuspected endocrine roles for this peptide, while TGF-beta2 and TGF-beta3 appear to act only in a local autocrine/paracrine fashion.