RESUMEN
We examined the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) and 1-beta-D-arabinofuranosyluracil (ara-U) in 19 patients with acute leukemia in order to determine whether ara-C or ara-U accumulate in these fluid compartments over time. Plasma and CSF samples were obtained just prior to the conclusion of the first and seventh, and immediately before the second and eighth, 2-h, twice-daily i.v. infusions of 3 g/m2/dose of ara-C (n = 10), 2 g/m2/dose of ara-C (n = 3), and 0.75 g/m2/dose of ara-C (n = 6). There was no accumulation of ara-C in the plasma or CSF, or of ara-U in the plasma following repeated ara-C infusions, ara-U did accumulate in the CSF; the end-dose 1/end-dose 7 CSF ara-U ratio was 0.35 +/- 0.12 and significantly different from this ratio for CSF ara-C (2.10 +/- 3.01; P = 0.004). The end-dose 7 CSF ara-U level was greater than the end-dose 1 CSF ara-U level in all paired specimens. There was a significant correlation between the dose of ara-C administered and the end-dose plasma ara-C and the end-dose CSF ara-U levels (P less than 0.02). One patient who received 3 g/m2/dose of ara-C developed neurotoxicity; his plasma and CSF ara-C and ara-U levels were not extraordinary during the period of ara-C administration, but he had persistent CSF ara-U demonstrable 75 h after his final ara-C dose. CSF ara-U accumulation might underlie the pathophysiology of ara-C-induced neurotoxicity. Intermediate doses of ara-C given i.v. (0.75 g/m2/dose over 2 h) appeared to generate therapeutic CSF ara-C levels and cleared CSF leukemia in one patient.
Asunto(s)
Arabinofuranosil Uracilo/sangre , Citarabina/sangre , Leucemia Mieloide Aguda/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Adulto , Arabinofuranosil Uracilo/líquido cefalorraquídeo , Arabinofuranosil Uracilo/farmacocinética , Citarabina/líquido cefalorraquídeo , Citarabina/farmacocinética , Citarabina/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/líquido cefalorraquídeo , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Análisis de RegresiónRESUMEN
We reviewed the medical records of 110 consecutive patients at our institution who had acute leukemia and received high-dose cytarabine (Ara-C; HDAC) in order to analyze risk factors associated with HDAC neurotoxicity (NT). There were adequate records on 101 patients who received 147 courses of HDAC. Twenty-six treatment courses (18%) were complicated by NT. The median time of NT onset was 5 days (range, 1 to 10 days), and NT was reversible in 16 of 21 survivors (76%). Patients with severe NT (grades 3 to 4) were less likely to have complete reversal of their neurological deficit than those with mild NT (P less than .1). In our patients, there was no significant association between previously described risk factors (age over 49 years, male gender, CNS disorder, and cumulative HDAC dose greater than 48 g/m2) and incidence of NT. However, treatment courses involving HDAC given during renal insufficiency (serum creatinine greater than or equal to 1.5 mg/dL or an increase in serum creatinine greater than 0.5 mg/dL) were much more likely to be complicated by any degree of NT during administration of HDAC (62%) and severe NT (42%) than those given during normal renal function (8% and 3%, respectively; P less than .001). Of the treatment courses involving patients with estimated creatinine clearances less than 60 mL/min, 76% were complicated by NT compared with 8% of treatment courses involving patients with clearances greater than 60 mL/min (P less than .001). HDAC courses with neurotoxic patients had higher serum creatinines (2.1 +/- 1.4 v 1.1 +/- 0.6 mg/dL), greater increases in serum creatinine (+ 0.5 +/- 0.8 v + 0.07 +/- 0.3 mg/dL), and lower estimated creatinine clearances (61 +/- 35 v 91 +/- 29 mL/min) than those courses with nonneurotoxic patients (P less than .001, all parameters). Patients receiving HDAC during renal insufficiency are at high risk for developing NT. Dose reduction of HDAC should be considered for patients with renal insufficiency.
Asunto(s)
Lesión Renal Aguda/complicaciones , Citarabina/efectos adversos , Enfermedades del Sistema Nervioso/inducido químicamente , Alcoholismo/complicaciones , Citarabina/administración & dosificación , Femenino , Humanos , Hiperbilirrubinemia/complicaciones , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
PURPOSE: To determine the impact of high-dose cytarabine (ARA-C) (HDAC) dose modification, based on renal function, on the incidence of neurotoxicity (NT). PATIENTS AND METHODS: We retrospectively analyzed the records of 256 patients treated with HDAC (> or = 2.0 g/m2 per dose) for acute myelogenous leukemia (AML) at the University of California, San Francisco (UCSF). From 1985 to 1994, a total of 358 cycles of HDAC were administered, using either a twice-daily schedule (n = 208) or a once-daily regimen (n = 48). In 1989, a dose-modification algorithm was initiated at our institution, which reduced ARA-C doses in the setting of renal insufficiency (RI). For patients with a serum creatinine (Cr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in Cr during treatment (deltaCr) of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m2 per dose. For patients with a Cr > or = 2.0 mg/dL or a deltaCr greater 1.2 mg/dL, the dose was reduced to 0.1 g/m2/d. RESULTS: Overall, the incidence of NT was 16% (34 of 208) for patients treated with twice-daily HDAC and 0% (none of 48) for patients treated with daily HDAC (P = .003). NT occurred more often in patients treated on a twice-daily schedule with 3 g/m2 per dose compared with 2 g/m2 per dose (25% v 8%; P = .009). NT occurred in 55% of the twice-daily-treated patients with RI, compared with 7% of those with normal renal function (P = .00001). In patients with RI, NT occurred in none of 11 dose-modified cycles versus five of 11 (45%) total unmodified cycles (P = .01). None of 14 patients treated with once-daily HDAC given during RI developed NT, compared to 55% of patients (23 of 42) receiving twice-daily HDAC during RI (P = .009). By univariate analysis, NT was not associated with patient age or serum alkaline phosphatase, but NT was significantly increased in patients treated with twice-daily HDAC when the serum bilirubin was > or = 2.0 mg/dL compared with twice-daily HDAC given when the total bilirubin was less than 2.0 mg/dL (33% v 14%; P = .017). Multivariate analysis confirmed that RI was the most significant risk factor associated with the development of NT. CONCLUSION: HDAC NT is strongly associated with RI. The risk of HDAC NT can be reduced by the following: (1) routinely reducing the ARA-C dose from 3 to 2 g/m2 per dose; (2) modifying the ARA-C dose based on daily Cr values; and (3) administering HDAC on a once-daily rather than twice-daily schedule.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Citarabina/administración & dosificación , Neoplasias/complicaciones , Enfermedades del Sistema Nervioso/prevención & control , Insuficiencia Renal/complicaciones , Adulto , Antimetabolitos Antineoplásicos/efectos adversos , Citarabina/efectos adversos , Esquema de Medicación , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inducido químicamente , Insuficiencia Renal/fisiopatología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Forty-five patients with untreated, de novo acute myeloid leukemia (AML) were treated with high-dose cytosine arabinoside (Ara-C) plus mitoxantrone or daunorubicin. Forty-two patients entered complete remission with recovery of normal blood counts. Seven of these patients were excluded from further analysis (two, early consolidation chemotherapy; four, early relapse; one, hypersplenism). Of the remaining 35 patients, 20 (57%) developed thrombocytopenia and anemia (with or without neutropenia) a median of 3 weeks after entering complete remission. Post-remission cytopenias were more common in patients receiving mitoxantrone (81%) compared to those receiving daunorubicin (37%; p < 0.003). The cytopenias lasted a median of 54 days. Four of five patients in whom the cytopenias did not recover received mitoxantrone. Leukemia relapse or myelodysplasia did not explain these cytopenias. Post-remission cytopenias resulted in a greater than 90-day delay or prevention of planned autologous bone marrow transplantation in 13 of 17 otherwise eligible patients. We conclude that post-remission cytopenias are common following blood count recovery in AML patients entering complete remission with high-dose Ara-C and mitoxantrone or daunorubicin. Post-remission cytopenias do not necessarily imply leukemia relapse.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide/tratamiento farmacológico , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamente , Enfermedad Aguda , Adolescente , Adulto , Anemia/inducido químicamente , Trasplante de Médula Ósea , Terapia Combinada , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Humanos , Leucemia Mieloide/sangre , Leucemia Mieloide/terapia , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Recurrencia , Inducción de Remisión , Factores de Tiempo , Resultado del TratamientoRESUMEN
A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P<0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P<0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P<0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.
Asunto(s)
Antineoplásicos , Arsenicales , Supervivencia de Injerto/efectos de los fármacos , Leucemia Promielocítica Aguda/terapia , Óxidos , Trasplante de Células Madre de Sangre Periférica , Adolescente , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Trióxido de Arsénico , Arsenicales/administración & dosificación , Arsenicales/efectos adversos , Autoinjertos , Femenino , Humanos , Leucemia Promielocítica Aguda/sangre , Masculino , Persona de Mediana Edad , Óxidos/administración & dosificación , Óxidos/efectos adversosRESUMEN
We have used a new preparative regimen prior to autologous bone marrow transplantation in patients in remission of acute myelogenous leukemia (AML). Sixty-two patients were treated with preparative chemotherapy consisting of 1 mg/kg of busulfan every 6 hours for 4 days (total dose 16 mg/kg) on days -7 to -4 followed by an intravenous infusion of 60 mg/kg of etoposide on day -3. Autologous bone marrow that had been purged with 4-hydroperoxycyclophosphamide was infused on day 0. Thirty-five of the treated patients were in first remission, 21 were in second or third remission, and six had primary refractory AML and required aggressive salvage regimens to achieve remission. Among patients in first remission, one treatment-related death and five relapses have occurred. With a median follow-up of 25 months, the actuarial relapse rate is 19% +/- 8% and the disease-free survival rate is 79% +/- 8% at 3 years. The 16 patients with favorable FAB subtypes (M3 or M4E0) showed an excellent response to this treatment protocol, with no relapses after median follow-up of 35 months. Among patients in second or third remission, there were five treatment-related deaths and five relapses. With a median follow-up of 41 months, the actuarial relapse rate is 30% +/- 11% and the disease-free survival rate is 52% +/- 11% at 3 years. Four of six primary refractory patients died during treatment and one remains in remission with short follow-up. These preliminary data indicate that aggressive preparative regimens followed by the infusion of purged autologous bone marrow may be a promising approach to improving the clinical outcome of adult patients with AML.
Asunto(s)
Trasplante de Médula Ósea/métodos , Busulfano/uso terapéutico , Etopósido/uso terapéutico , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Purgación de la Médula Ósea , Busulfano/administración & dosificación , Etopósido/administración & dosificación , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Persona de Mediana Edad , Premedicación , Inducción de Remisión , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
We report a case of hemolytic uremic syndrome associated with the use of cyclosporine in a heart transplant recipient. The patient manifested many classic signs and symptoms of hemolytic uremic syndrome, and a diagnosis was confirmed by kidney biopsy. Treatment with plasma exchange was effective in halting the hemolysis, but renal function failed to improve. Rechallenge with cyclosporine caused recurrence of microangiopathic hemolysis. Because of concerns regarding allograft rejection, an experimental immunosuppressive agent, RS-61443, was used that was effective in controlling rejection and was not associated with recurrence of hemolytic uremic syndrome.
Asunto(s)
Ciclosporina/efectos adversos , Trasplante de Corazón , Síndrome Hemolítico-Urémico/inducido químicamente , Ciclosporina/uso terapéutico , Síndrome Hemolítico-Urémico/patología , Humanos , Riñón/patología , Masculino , Persona de Mediana EdadRESUMEN
A highly human leukocyte antigen-sensitized heart transplant candidate underwent immunomodulation with intravenous gamma globulin and cyclophosphamide. His panel reactive antibody screen fell from 64% to 14%. He underwent successful orthotopic heart transplantation with a histoincompatible, T-cell cross-match-negative heart without the development of hyperacute rejection. The combination of intravenous gamma globulin and cyclophosphamide may be a simple and effective means to overcome the human leukocyte antigen-barrier in sensitized heart transplant candidates.
Asunto(s)
Ciclofosfamida/administración & dosificación , Rechazo de Injerto/terapia , Insuficiencia Cardíaca/terapia , Trasplante de Corazón/inmunología , Inmunización Pasiva , Inmunosupresores/administración & dosificación , Isoantígenos/sangre , Terapia Combinada , Rechazo de Injerto/inmunología , Insuficiencia Cardíaca/inmunología , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We studied the use of autologous bone marrow transplantation (ABMT) as treatment for acute myeloid leukemia (AML) in adults up to age 60. We used a preparative regimen of busulfan 16 mg/kg plus etoposide 60 mg/kg and bone marrow purged with 100 microg/ml of 4-hydroperoxycyclophosphamide (4HC). We treated 50 first remission patients; there were two treatment-related deaths and 13 relapses. With median follow-up of 6.8 years (minimum 4.5) disease-free survival (DFS) is 70%, relapse rate 27% and overall survival 72%. Patients with favorable cytogenetics had DFS 78% and relapse 18% whereas unfavorable patients had DFS 63% and relapse rate 35%. For 25 patients in second or third remission there were five treatment-related deaths and seven relapses. DFS is 52% and relapse rate 35%. None of six patients with primary refractory AML had long-term disease control. These data support the use of ABMT with an intensive preparative regimen and purged bone marrow as a highly effective treatment for adults with AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Purgación de la Médula Ósea , Trasplante de Médula Ósea , Ciclofosfamida/análogos & derivados , Leucemia Mieloide/terapia , Enfermedad Aguda , Adolescente , Adulto , Busulfano/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Leucemia Mieloide/mortalidad , Leucemia Mieloide/fisiopatología , Persona de Mediana Edad , Trasplante AutólogoRESUMEN
We have previously documented that adults with de novo acute myelogenous leukemia (AML) who are induced into first complete remission with mitoxantrone and high-dose cytarabine are more likely than those induced with daunorubicin and high-dose cytarabine to develop a bone marrow injury pattern with delayed cytopenias after achieving initial complete remission, a phenomenon we have termed post-remission cytopenia syndrome. We therefore retrospectively compared the engraftment kinetics of mitoxantrone and daunorubicin patients following 4-hydroperoxycyclophosphamide (4HC) purged autologous bone marrow transplant (ABMT) with busulfan-etoposide conditioning. Despite equivalent graft colony forming units granulocyte macrophage (CFU-GM), mitoxantrone patients (n = 13) took a median 7 weeks longer to achieve 1.0 x 10(9)/l granulocytes, 5 weeks longer to achieve platelet transfusion independence, and 10 weeks longer to achieve red blood cell transfusion independence, and required more platelet transfusions (P = 0.008), than daunorubicin patients (n = 13). Patients experiencing the post-remission cytopenia syndrome (n = 11) had significantly slower engraftment than those not experiencing the syndrome (n = 15; P < or = 0.04). Two mitoxantrone and five daunorubicin patients have relapsed after ABMT (P = 0.38). We conclude that the type of induction chemotherapy used in untreated adults with de novo AML can influence subsequent engraftment after 4HC-purged ABMT. We believe that mitoxantrone combined with high-dose cytarabine should be avoided as induction chemotherapy in patients for whom 4HC-purged ABMT is planned.
Asunto(s)
Antineoplásicos/uso terapéutico , Purgación de la Médula Ósea , Trasplante de Médula Ósea , Ciclofosfamida/análogos & derivados , Leucemia Mieloide Aguda/terapia , Mitoxantrona/uso terapéutico , Adulto , Ciclofosfamida/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitoxantrona/efectos adversos , Trasplante AutólogoRESUMEN
We studied the efficacy of a two-step approach to autologous stem cell transplantation for patients with advanced acute myeloid leukemia. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) twice daily for 4 days plus etoposide 40 mg/kg by continuous infusion over the same 4 days. Peripheral blood stem cells were collected under granulocyte colony-stimulating factor (G-CSF) stimulation during recovery from this chemotherapy. Step 2, autologous stem cell transplantation, utilized the preparative regimen of oral busulfan 16 mg/kg followed by etoposide 60 mg/kg i.v. During step 1, there were no treatment-related deaths among 28 patients, but two patients did not proceed to transplantation because of failure of mobilization. A median CD34+ dose (x10(6)/kg) of 13.6 was collected. Of 26 patients undergoing autologous transplant, there was one treatment-related death and 12 relapses. With a median follow-up of 5.4 years, 5 year event-free survival (EFS) of all patients entered is 54%. The most important prognostic factor was cytogenetic changes. All seven patients with t(15,17) remained in long-term remission whereas EFS for other patients was 38%. We conclude that this two-step approach to autologous transplantation produces excellent stem cell yields, allows a high percentage of patients to receive the intended therapy, and provides effective treatment.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adulto , Anciano , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Busulfano/administración & dosificación , Recuento de Células , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Citarabina/administración & dosificación , Citogenética , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Pronóstico , Translocación Genética , Trasplante AutólogoRESUMEN
We designed and implemented a new mitoxantrone-based high-dose chemotherapy regimen to minimize pulmonary injury (seen in carmustine-based regimens) in patients with breast cancer. One hundred and ninety-one breast cancer patients (99 stage II/IIIA; 27 stage IIIB; 65 stage IV responsive to conventional-dose chemotherapy) were treated with high-dose chemotherapy (CTM) delivered over 4 days (cyclophosphamide (6 g/m2), thiotepa (600 mg/m2), and mitoxantrone (24-60 mg/m2)) followed by autologous hematopoietic stem cell rescue. Stage II/III patients received chest wall radiation and tamoxifen (if hormone-receptor positive) after CTM. The 5-year event-free survival (EFS) for stage II/IIIA patients with 10 or more involved axillary lymph nodes (n = 80) was 62 +/- 12%. Hormone receptor-positive patients with 10 or more nodes did significantly better than negative patients. The EFS for stage IIIB patients at 5 years was 44 +/- 19%; for stage IV patients at 5 years was 17 +/- 10%. Stage IV patients achieving complete response in viscera and/or soft tissue prior to CTM did significantly better than those achieving a partial response. There were six (3%) treatment-related deaths including two due to diffuse alveolar hemorrhage. There were no episodes of delayed interstitial pneumonitis. There were six severe cardiac events in 91 patients (6.6%) but none after instituting mitoxantrone dose-adjustment in the final 100 patients. We conclude that CTM is associated with a low treatment-related mortality and little pulmonary toxicity. CTM produces excellent outcomes in stage II/IIIA patients with 10 or more involved axillary lymph nodes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Estadificación de Neoplasias , Receptores de Estrógenos/fisiología , Receptores de Progesterona/fisiología , Análisis de Supervivencia , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Resultado del TratamientoRESUMEN
The cytotoxic effects of ketoconazole, an antifungal agent known to have some activity against human prostate cancer, adrenal cancer, and male metastatic breast cancer, were evaluated using colony-growth and clonogenic assays in eight malignant cell lines. The cytotoxicity of ketoconazole showed a dose- and time-dependent pattern, with the following concentrations inhibiting 90% of the growing colonies (IC90): MCF 7 (human breast cancer) 7.25 micrograms/ml, T 47 D (human breast cancer) 9.0 micrograms/ml, MiaPaCa (human pancreatic carcinoma) 10.0 micrograms/ml, COLO 357 (human pancreatic carcinoma), 9.5 micrograms/ml, HCT 8 (human colonic adenocarcinoma) 27.1 micrograms/ml, DU 145 (human prostatic cancer) 40.0 micrograms/ml, AR 42 J (rat pancreatic carcinoma) 9.0 micrograms/ml, and L1210 (murine leukemia) 8.6 micrograms/ml. Since a concentration of 10 micrograms/ml can be achieved in humans, the use of ketoconazole in human malignancies might be worthy of clinical evaluation.
Asunto(s)
Antineoplásicos , Cetoconazol/farmacología , Neoplasias/patología , Animales , Línea Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratas , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
The cytotoxic interactions between etoposide and two fluoropyrimidines (FP), 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd), were determined in L1210 cells by soft agar clonogenic assay and in five human adenocarcinoma cell lines by colony growth assay. The administration of etoposide prior to FP resulted in synergistic cytotoxicity in L1210, HCT-8, Mia PaCa, MCF-7, and T47-D cells while the reverse sequence resulted in additive or antagonistic cytotoxicity in L1210, HCT-8, and Mia PaCa cells. Etoposide prior to FdUrd produced more DNA single strand breaks than expected in L1210 cells, while the reverse sequence produced fewer than expected. The sequence--dependent synergistic cytotoxicity of etoposide--FP correlates with relative DNA single strand break production in L1210 cells.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Etopósido/farmacología , Floxuridina/farmacología , Fluorouracilo/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Animales , Línea Celular , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Cinética , Factores de Tiempo , Células Tumorales Cultivadas/citología , Ensayo de Tumor de Célula MadreRESUMEN
The classic anemia of chronic disease is sideropenic and is the result of subacute or chronic inflammatory illness, including malignancy. Nonsideropenic anemias, by contrast, are the result of failure of vital organs or endocrine glands. The pathophysiology of these anemias is multifactorial, but underlying all of them is absolute or relative hypoerythropoietinemia. Therapy consists of treating the underlying illness and, if necessary, providing packed red blood cell transfusions. Some patients will respond to recombinant erythropoietin injections, which have been shown to result in improved hemoglobins and hematocrits and an enhanced quality of life.
Asunto(s)
Anemia/etiología , Enfermedad Crónica , Anciano , Anemia/clasificación , Anemia/diagnóstico , Anemia/terapia , HumanosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , ADN de Neoplasias/biosíntesis , Interacciones Farmacológicas , Sinergismo Farmacológico , Humanos , Proteínas de Neoplasias/biosíntesis , Neoplasias/metabolismo , Purinas/metabolismo , Pirimidinas/metabolismo , ARN Neoplásico/biosíntesisRESUMEN
We studied the feasibility and efficacy of a two-step approach to Auto-SCT for patients with AML in second remission. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) i.v. every 12 h for 4 days plus etoposide 40 mg/kg total dose by continuous i.v. infusion over the same 4 days. PBSC were collected after G-CSF stimulation during recovery from this chemotherapy. Step 2, auto-SCT, used a preparative regimen of oral BU 16 mg/kg over 4 days followed by etoposide 60 mg/kg i.v. Of the 50 patients entered on Step 1, two died from treatment complications, and seven failed to proceed to transplantation. A median CD34+ cell dose of 5.9 x 10(6)/kg was collected in a median of three collections. With a median follow-up of 8.2 years, 5-year disease-free survival (DFS) is 28%. The most important prognostic factor was cytogenetics, with acute promyelocytic leukemia (APL) patients having a 5-year DFS of 67% compared with 16% for others. We conclude that this two-step approach to autologous transplantation produces good CD34+ mobilization and that this approach has cured some patients. Results in patients with APL are especially promising.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Envejecimiento , Antígenos CD34/análisis , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Terapia Combinada/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Peso Corporal Ideal , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Inducción de Remisión , Trasplante Autólogo , Resultado del Tratamiento , Negativa del Paciente al Tratamiento , Adulto JovenRESUMEN
The best method to mobilize PBSCs in patients with non-Hodgkin's Lymphoma (NHL) is uncertain. We hypothesized that PBSC mobilization using an intensive chemotherapy regimen would improve outcomes after autologous hematopoietic stem cell transplantation (ASCT) in NHL patients at high risk for relapse. Fifty NHL patients were prospectively allocated to intense mobilization with high-dose etoposide plus either high-dose cytarabine or CY if they were 'high risk' for relapse, whereas 30 patients were allocated to nonintense mobilization with CY if they were 'standard risk' (all patients, +/-rituximab). All intensely mobilized patients were hospitalized compared with one-third of nonintensely mobilized patients. The EFS after ASCT was the same between the two groups, but overall survival (OS) was better for intensely mobilized patients (<0.01), including the diffuse large B-cell subgroup (P<0.04). We conclude that the intense mobilization of PBSCs in patients with NHL is more efficient than nonintense mobilization, but with greater toxicity. The equalization of EFS and superiority of OS in patients intensely mobilized to those nonintensely mobilized suggests that a treatment strategy using intensive chemotherapy for mobilization may be improving NHL outcomes after ASCT.
Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Linfoma no Hodgkin/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales , Anticuerpos Monoclonales de Origen Murino , Citarabina , Etopósido , Movilización de Célula Madre Hematopoyética/mortalidad , Humanos , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/mortalidad , Rituximab , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Although relocation is often indicated as a necessary therapeutic intervention, the stress of relocation on elderly persons can prove detrimental to their life satisfaction and longevity. If a move is involuntary or involves extreme change--for example, a move from a private home to an institution--the loss of environment control and predictability can pose a threat to the person's well-being. Yet there are cases in which the outcome is good--for example, a voluntary move from one private home to another. The physician can use a patient's individual characteristics to help predict the probable outcome of relocation.