RESUMO
There is considerable variation in the severity of preparative regimen-related toxicity (RRT) in hematopoietic stem-cell transplantation (HSCT). This variation has been recognized to be due, in part, to the wide variation in the pharmacokinetics (PK) of high-dose chemotherapy (HDC). Consequently, therapeutic drug modeling and pharmacokinetic-directed therapy (PKDT) represents an attractive strategy in this setting. Advances in our understanding of drug metabolism, the nature of the active metabolites, and the ability to measure drug concentrations have led to the point where for some agents it is now possible to treat to a given PK end point with a great deal of reliability. In-depth knowledge of the PK and pharmacodynamics (PD) associations of the agents employed in the high-dose setting will make possible more efficient research into preparative regimen dosing intensity and comparisons of different preparative regimens as well as safer HSCT overall. In this review, we discuss PK and PD studies of high-dose cyclosphamide, melphalan, thiotepa, carmustine, cisplatin, carboplatin, paclitaxel, docetaxel, and busulfan.
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Agonistas Mieloablativos/farmacocinética , Agonistas Mieloablativos/uso terapêutico , Farmacocinética , Resultado do TratamentoAssuntos
Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Doença da Hemoglobina SC/fisiopatologia , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/fisiopatologia , Evolução Fatal , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Doença da Hemoglobina SC/complicações , Humanos , Pessoa de Meia-Idade , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologiaAssuntos
Antineoplásicos/administração & dosagem , Transplante de Medula Óssea , Transplante de Células-Tronco Hematopoéticas , Neoplasias/terapia , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/terapia , Neoplasias Cerebelares/terapia , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Humanos , Meduloblastoma/terapia , Neoplasias/tratamento farmacológico , Oligodendroglioma/terapia , Sarcoma de Ewing/terapia , Resultado do TratamentoRESUMO
The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from <10% to virtually 100%. Further, the 2-hour infusion of i.v. Bu gave a time to maximum plasma concentration following drug administration similar to that of oral Bu (2 hours and 1.8 hours, respectively), and i.v. Bu had a clearance similar to that of oral Bu. Based on the data in this study, we suggest that the optimal (starting) dose of i.v. Bu (in combination with Cy) in our forthcoming phase 2 trial should be on the order of 0.8 mg/kg to target an area under the curve (AUC) of 1100 to 1200 micromol/L per minute. This would secure myeloablation and engraftment but save the vast majority of patients from the increased risk of serious hepatic veno-occlusive disease that has been reported when the AUC level exceeds 1500 micromol/L per minute. Bu administration via the i.v. route will assure complete bioavailability and reliable systemic drug exposure with more predictable blood levels and, therefore, possibly lower the risks for serious/life-threatening toxicity, graft rejection, and recurrent leukemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/efeitos adversos , Acetamidas/efeitos adversos , Administração Oral , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Disponibilidade Biológica , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Ciclofosfamida/administração & dosagem , Portadores de Fármacos/efeitos adversos , Feminino , Neoplasias Hematológicas/terapia , Humanos , Infusões Intravenosas , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Segurança , Solventes/efeitos adversosRESUMO
Epstein-Barr virus (EBV)-induced lymphoproliferative disease and cytomegalovirus (CMV) infection are major causes of morbidity and mortality in individuals with compromised cellular immunity. Although anti-viral pharmacological agents exist, severe side effects such as myelosuppression often limit the application of these medications. Infusion of ex vivo-expanded, virus-specific cytotoxic T-lymphocytes (CTL) has been proven to be safe and efficacious for the prophylaxis and treatment of EBV and CMV complications. While EBV-specific CTL can be readily and reliably produced with EBV-immortalized B-lymphoblastoid cell lines (BLCL) as stimulators, current protocols for CMV-specific CTL, which use CMV-infected fibroblasts as stimulators, may be associated with alloreactivity and the need for cloning, as well as the potential for exposure to human blood-born infectious agents. Our laboratory has developed a novel system to generate EBV/CMV-bi-specific CTL by co-culturing PBMC with autologous BLCL expressing a CMV protein pp65 (BLCLpp65) (Sun et al., 1999). pp65, an immunodominant CMV antigen, is transduced into BLCL by a recombinant retrovirus MSCVpp65. While low in alloreactivity, BLCLpp65-stimulated CTL are cytolytic to autologous cells infected with EBV or CMV, and this cytotoxicity is mediated by polyclonal, CD8+, MHC Class I-restricted T-cells. Further experiments revealed that retroviral transduction and expression of pp65 do not compromise the capacity of presenting EBV antigens, and T cells stimulated by BLCLpp65 recognize clinical strains of CMV (Sun et al., 2000). These data indicated that BLCLpp65 could substitute for BLCL as antigen presenting cells in adoptive immunotherapy against EBV-LPD, with the benefit of providing protection against CMV reactivation. This protocol is a Phase I/II study to examine the toxicity associated with and the immunologic effects of ex vivo simultaneously expanded EBV- and CMV-specific CTL for prophylaxis against EBV and CMV complications in recipients of CD34 selected/T-cell depleted stem cell transplants (SCT). EBV/CMV-specific CTL will be generated from peripheral blood mononuclear cells (PBMC) of EBV/CMV-seropositive donors in a course of from 21-28 days by weekly stimulation with autologous BLCLpp65. Qualified CTL will be administered to consenting patients at 40, 60, and 80 days post-transpOFF criteria of molecular virology and immunological reconstitution, which include blood levels of pp65 antigen and EBV viral DNA, and virus-specific CTL precursor frequency. Patients will also be tested for replication-competent retrovirus at 3, 6, and 12 month intervals post-transplant to ensure bio-safety.
Assuntos
Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/genética , Infecções por Vírus Epstein-Barr/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 4/genética , Linfócitos T Citotóxicos/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD34 , Antígenos CD8/metabolismo , Linhagem Celular , Criança , Pré-Escolar , Técnicas de Cocultura , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/terapia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Feminino , Genes MHC Classe I , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/genética , Retroviridae/metabolismo , Fatores de Tempo , Transdução Genética , Proteínas da Matriz Viral/genéticaRESUMO
CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Antineoplásicos Hormonais/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Modelos de Riscos Proporcionais , Receptores de Estrogênio , Risco , Análise de Sobrevida , Tamoxifeno/uso terapêutico , Transplante Autólogo , Falha de TratamentoRESUMO
PURPOSE: Breast cancer has a poorer prognosis among black women than among white women. This review was conducted to determine whether this disparity reflects the direct impact of race on likelihood of cure or on time to death from breast cancer or stems from the interaction of race with tumor stage and patient age. PATIENTS AND METHODS: We analyzed data from 115,838 patients with localized (node-negative) and regionally metastatic (node-positive) breast cancer from the Surveillance, Epidemiology, and End-Results (SEER) Program of the National Cancer Institute. Parametric analysis was used to determine the independent prognostic value of age, stage, and race. Linear regression and distribution analyses were also used to examine the interaction of these covariates. RESULTS: The prevalence of regionally metastatic disease, relative to localized disease, declined with increased age among white patients and those classified as "other," but remained relatively constant among black patients. Parametric analysis showed a smaller cured fraction and shorter time to death when patients with regional disease were compared with those with localized disease. A similar disparity was found when black patients were compared with those classified as white or other. CONCLUSION: Age and race have a significant association with tumor stage. In addition, our data show that race has an independent impact on the clinical course of breast cancer and diminishes both the likelihood of cure and time to death among uncured patients.
Assuntos
Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/etnologia , Grupos Raciais , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etnologia , Carcinoma Ductal de Mama/mortalidade , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Taxa de SobrevidaRESUMO
A newly formed National Comprehensive Cancer Network (NCCN) panel on bone marrow transplantation has the task of ensuring the incorporation of allogeneic and autologous transplantation into all disease guidelines where significant evidence exists to warrant their inclusion. The panel is further charged with ensuring that there is consistency among guidelines regarding the use of marrow transplantation. A preliminary review of existing NCCN guidelines found that marrow transplantation was appropriately included for the treatment of the common hematologic malignancies of adults, including acute myeloid leukemia, chronic myeloid leukemia, myelodysplasia, multiple myeloma, Hodgkin's disease, and the malignant lymphomas. Frequent refinements regarding lymphomas will be necessary, particularly in rapidly evolving areas, such as multiple myeloma and myelodysplasia, and conditions with changing definitions, such as malignant disease. The increasing volume of data supporting the use of autologous bone marrow transplantation in advanced primary and responding metastatic breast cancers needs to be reflected in the breast cancer guideline if it is to remain credible. Well-designed and well-conducted clinical trials are the most appropriate setting for all bone marrow transplantations and patient referral to these trials remains the standard of care in all settings.
Assuntos
Transplante de Medula Óssea , Neoplasias Hematológicas/terapia , Guias de Prática Clínica como Assunto , Adulto , Criança , Humanos , Leucemia Mieloide/terapia , Linfoma/terapia , Terminologia como Assunto , Transplante HomólogoRESUMO
The maintenance of hematopoietic progenitor cells as assayed in the mixed colony (CFU-GEMM) assay in human long-term bone marrow cultures was compared between normal allogeneic marrow transplantation donor collections and those from candidates for high-dose therapy and autologous bone marrow transplantation (ABMT). To be eligible for ABMT, patients were required to have a histologically normal appearing bone marrow and therefore any tumor contamination was at minimal levels and detectable only after evaluation of the cultured harvests. Marrow from 15 normal donors, 36 patients with breast cancer, and 30 patients with Hodgkin's disease was evaluated. The number of mononuclear cells placed in culture was standardized. In all groups, significantly more progenitor cells were recovered at 4-6 weeks of culture that at 12-14 weeks. At 4-6 and 12-14 weeks, there were no significant differences in the number of progenitor cells recovered from the cultures of normal donors and tumor negative cultures of breast cancer or Hodgkin's disease patients. However, following 4-6 and 12-14 weeks of culture, progenitor cell numbers of cultures which contained breast cancer cells were significantly higher than the pooled values for cultures from the concurrent normal controls, and those from breast cancer and Hodgkin's disease patients with tumor negative cultures. These results suggest that minimal breast cancer cell contamination of the bone marrow can influence the production of marrow progenitor cells. Exposure to prior chemotherapy or radiation therapy does not appear to be the cause of this effect. The most likely mechanism is the local production of cytokines by the tumor cells, although a process involving direct adhesive contact of the tumor cells with hematopoietic cells, which is sometimes observed in semisolid cultures, cannot be excluded.
Assuntos
Células da Medula Óssea , Neoplasias da Mama/patologia , Células-Tronco Hematopoéticas/citologia , Doença de Hodgkin/patologia , Técnicas de Cultura/métodos , Humanos , Antígeno Ki-1/análise , Mucina-1/análise , Fatores de TempoRESUMO
PURPOSE: To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS: Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS: Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION: Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Transplante AutólogoRESUMO
High dose chemotherapy and stem-cell rescue (bone marrow transplantation) is used increasingly in the treatment of malignant disorder. Numerous trials have demonstrated the effectiveness of bone marrow transplantation in the treatment of non-Hodgkin's lymphoma. However, there are many unanswered questions as to the role of high-dose therapy in certain subtypes of lymphoma, the timing of transplant, and even the type of transplant to perform. An attempt will be made to clarify many of these unanswered questions. The utilization of high-dose therapy for non-Hodgkin's lymphoma is recommended for most patients who have relapsed after initial therapy. Transplantation in first remission is not recommended routinely. Allogeneic bone marrow transplantation should by reserved for individuals with poorly responding disease or in individuals with bone marrow involvement. The precise roles of purging and transplantation of individuals with low grade lymphoma are being investigated.
Assuntos
Transplante de Medula Óssea , Linfoma não Hodgkin/terapia , Purging da Medula Óssea , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Recidiva , Condicionamento Pré-Transplante , Transplante Autólogo , Transplante HomólogoRESUMO
We report a novel means to purge bone marrow of a specific subset of prostate carcinoma cells based on transductional and genetic selectivity. Using both adenovirus-polylysine-DNA complexes and E1A/B-deleted replication-deficient adenoviruses, we have demonstrated a transductional preference of these vectors for the prostate carcinoma cell lines DU 145, LNCaP, and PC-3 over primary human bone marrow cells and the leukemia cell line KG-1. We have also shown a genetic selectivity of an anti-erbB-2 intracellular single-chain antibody (sFv) encoding adenovirus, Ad21, for the erbB-2-positive prostate carcinoma cell lines DU 145 and LNCaP. Delivery of Ad21 resulted in cytotoxicity to the DU 145 and LNCaP, but not PC-3, cell lines and reduced the clonogenic capacity of DU 145 cells cultured alone or mixed with various ratios of irradiated human bone marrow. Finally, quantitative, competitive reverse transcription polymerase chain reaction (QC-RT-PCR) analysis demonstrated that Ad21 could effectively reduce DU 145 and erbB-2-positive primary prostate tumor contamination in bone marrow cultures. Delivery of Ad21 had no effect on the ability of progenitor cells to form colonies. These results suggest that an anti-erbB-2 sFv-encoding adenoviral vector is efficacious for removal of erbB-2-positive prostate carcinoma cells from human bone marrow, and demonstrates a novel method for ex vivo genetic purge of malignant cells from bone marrow for autologous bone marrow transplantation (ABMT) therapy.
Assuntos
Medula Óssea/fisiologia , Carcinoma/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Neoplasias da Próstata/genética , Adenoviridae/genética , Adenoviridae/metabolismo , Anticorpos , Medula Óssea/virologia , Células da Medula Óssea , Carcinoma/patologia , Carcinoma/virologia , Humanos , Masculino , Reação em Cadeia da Polimerase , Neoplasias da Próstata/patologia , Neoplasias da Próstata/virologia , RNA Mensageiro/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Células-Tronco/fisiologia , Transdução Genética , Células Tumorais CultivadasRESUMO
PURPOSE: A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS: The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION: High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Transplante de Medula Óssea , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Infusões Intravenosas , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/efeitos dos fármacos , Recidiva , Indução de Remissão , Fatores de Risco , Estomatite/induzido quimicamente , Análise de SobrevidaRESUMO
The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (Vmax), 0.097 mmol h-1 l-1; Michaelis constant for HU elimination (KM), 0.323 mmol/l; renal clearance (ClR), 90.8 ml/min; volume of distribution (Vd), 0.186 x (body weight) + 25.4 l; absorption rate constant (Ka), 2.92 h-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration.
Assuntos
Hidroxiureia/farmacocinética , Neoplasias/metabolismo , Administração Oral , Adulto , Idoso , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/uso terapêutico , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/tratamento farmacológico , Análise de RegressãoRESUMO
We report a case of type I cryoglobulinemia with cold agglutinin activity complicating allogeneic bone marrow transplantation. To our knowledge, this complication has not been previously reported. We also discuss possible etiologic mechanisms for this unusual event.
Assuntos
Aglutininas , Transplante de Medula Óssea/efeitos adversos , Crioglobulinemia/etiologia , Crioglobulinas , Feminino , Humanos , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
This paper will demonstrate the advantages of pursuing an integrated model of care that utilizes one staff of caregivers in one facility for all phases of patient care from the time of patient evaluation through the time the patient returns to the care of his or her primary physician. We took the opportunity afforded by the development of a new program at the University of Alabama at Birmingham, the Bone Marrow Transplantation (BMT) Program, to reconsider as many variables as possible in an attempt to develop a model of care that would represent the best of all worlds, i.e., high levels of quality of care, quality of life, staff job enrichment, patient convenience, operational efficiency, and cost reduction.
Assuntos
Transplante de Medula Óssea , Institutos de Câncer/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Assistência Centrada no Paciente/organização & administração , Alabama , Eficiência Organizacional , Hospitais Universitários , Humanos , Técnicas de Planejamento , Administração de Linha de ProduçãoRESUMO
Phase I and II trials have demonstrated that high-dose chemotherapy with autologous hematopoietic stem cell rescue is effective 'consolidation' chemotherapy for patients with responding metastatic breast cancer. In this study 26 women with metastatic breast cancer responding to lower dose combination chemotherapy were treated with 18 g/m2 of hydroxyurea added to the widely used combination of cyclophosphamide (CY) 6 g/m2 and thiotepa 600 mg/m2. Hematopoietic stem cell support was provided in the form of previously collected cryopreserved marrow or peripheral blood stem cells if there were malignant cells in the marrow. The patients ranged in age from 25 to 51 years with a median of 43 years. Three patients (12%) died of toxicity, one from Candida pneumonia and the other two from pulmonary and central nervous system bleeding secondary to platelet consumption associated with high fever and renal dysfunction, a syndrome we have seen with approximately the same frequency as a complication of other 'marrow transplant level' chemotherapy. The 1 and 2 year progression-free survivals are projected to be 42% and 27%, respectively. Patients in complete remission or with only residual radiographic abnormalities in bone prior to this therapy had 67% and 58% 1 and 2 year progression-free survival probabilities. High-dose hydroxyurea can safely be added to the CY and thiotepa combination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Transplante de Células-Tronco Hematopoéticas , Adulto , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Hidroxiureia/administração & dosagem , Pessoa de Meia-Idade , Metástase Neoplásica , Tiotepa/administração & dosagem , Transplante AutólogoRESUMO
Autologous bone marrow transplantation has permitted the clinical investigation of dose-intense chemotherapy for solid tumors as well as hematologic malignancies. The most widely studied solid tumor is breast cancer, the most common malignant disease cause of death in women under the age of 55 years in the United States. Promising results in terms of disease-free, chemotherapy-free survival have been achieved for patients with low-dose chemotherapy-sensitive metastatic disease. Issues such as the selection of drugs to be used in combination chemotherapy for both the induction phase and the high-dose therapy phase, the timing of high-dose therapy, the role of peripheral stem cells, and marrow purging remain under intensive investigation. The rational extension of this strategy into the adjuvant and neoadjuvant settings is also under study.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Neoplasias da Mama/terapia , Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Feminino , HumanosRESUMO
The ability to measure intracellular deoxyribonucleoside triphosphate (dNTP) pool sizes is important for understanding the intracellular metabolism of DNA synthesis and repair. We have developed an improved method for measuring intracellular dNTP pool size by high-performance liquid chromatography (HPLC). Previous methods have enabled accurate measurement of dNTPs only in concentrations greater than approximately 10 pmol per 10(6) cells due to the inability to partially purify cell extracts, to the inability to apply extracts from extremely large numbers of cells, to the lack of efficient columns, to the presence of incompatible solvents, and to the inability to inject large volumes. We have modified a low-pressure strong anion-exchange column pre-step developed by others to concentrate and partially purify oxidized cell extracts while at the same time eluting them in a more compatible solvent for HPLC injection. The HPLC column is a YMC ODS-AQ column operating in a combined hydrophobic-interaction chromatography-reversed-phase chromatography mode. The injection and elution solvents are both phosphate-based. Using this method it is possible to measure intracellular dNTP levels well below 0.5 pmol per 10(6) cells or at the sensitivity of the DNA polymerase assay.