RESUMEN
Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.
Asunto(s)
Antineoplásicos/administración & dosificación , Proteínas Bacterianas/metabolismo , Neoplasias/tratamiento farmacológico , Probióticos , Profármacos/administración & dosificación , Animales , Antraquinonas/administración & dosificación , Antraquinonas/uso terapéutico , Antineoplásicos/uso terapéutico , Aziridinas/administración & dosificación , Aziridinas/uso terapéutico , Bifidobacterium/enzimología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Enzimas , Escherichia coli/enzimología , Femenino , Lactobacillus/enzimología , Lactococcus/enzimología , Ratones Endogámicos BALB C , Neoplasias/patología , Profármacos/uso terapéutico , Carga Tumoral/efectos de los fármacos , Fosfato de Vidarabina/administración & dosificación , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapéuticoRESUMEN
PURPOSE: Quantitative relationships between 9-ß-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m², Protocol 1519) or with fludarabine (total dose 250 mg/m²) with rabbit antithymocyte globulin (rATG, Protocol 2041). METHODS: Individual pharmacokinetic parameters were fixed to post hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the 3 weeks prior to graft infusion. A semi-physiological cell-kill model with three lymphocyte transit compartments was applied and aptly characterized the time course of suppression of circulating ALC by fludarabine administration. Drug- and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check. RESULTS: The final model successfully characterized the time course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9-211 %). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC. CONCLUSIONS: This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/farmacocinética , Linfopoyesis/efectos de los fármacos , Modelos Biológicos , Acondicionamiento Pretrasplante/efectos adversos , Fosfato de Vidarabina/análogos & derivados , Adolescente , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/uso terapéutico , Niño , Estudios de Cohortes , Semivida , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Leucemia Mieloide/sangre , Leucemia Mieloide/inmunología , Leucemia Mieloide/metabolismo , Leucemia Mieloide/terapia , Recuento de Linfocitos , Persona de Mediana Edad , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/inmunología , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/terapia , Reproducibilidad de los Resultados , Estudios Retrospectivos , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/sangre , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: Systemically administered fludarabine phosphate (F-araAMP) slows growth of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (PNP). However, this treatment has been limited by the amount of F-araAMP that can be administered in vivo. The current study was designed to (1) determine whether efficacy of this overall strategy could be improved by intratumoral administration of F-araAMP, (2) test enhancement of the approach with external beam radiation, and (3) optimize recombinant adenovirus as a means to augment PNP delivery and bystander killing in vivo. METHODS: The effects of systemic or intratumoral F-araAMP in mice were investigated with human tumor xenografts (300 mg), in which 10 % of the cells expressed E. coli PNP from a lentiviral promoter. Tumors injected with an adenoviral vector expressing E. coli PNP (Ad/PNP; 2 × 10(11) viral particles, 2 times per day × 3 days) and the impact of radiotherapy on tumors treated by this approach were also studied. Radiolabeled F-araAMP was used to monitor prodrug activation in vivo. RESULTS: Intratumoral administration of F-araAMP in human tumor xenografts expressing E. coli PNP resulted in complete regressions and/or prolonged tumor inhibition. External beam radiation significantly augmented this effect. Injection of large human tumor xenografts (human glioma, nonsmall cell lung cancer, or malignant prostate tumors) with Ad/PNP followed by intratumoral F-araAMP resulted in excellent antitumor activity superior to that observed following systemic administration of prodrug. CONCLUSION: Activation of F-araAMP by E. coli PNP results in destruction of large tumor xenografts in vivo, augments radiotherapy, and promotes robust bystander killing. Our results indicate that intratumoral injection of F-araAMP leads to ablation of tumors in vivo with minimal toxicity.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Genética , Profármacos/uso terapéutico , Purina-Nucleósido Fosforilasa/genética , Fosfato de Vidarabina/análogos & derivados , Adenoviridae/genética , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Efecto Espectador/efectos de los fármacos , Efecto Espectador/genética , Efecto Espectador/efectos de la radiación , Línea Celular Tumoral , Terapia Combinada , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de la radiación , Escherichia coli/genética , Vectores Genéticos , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/radioterapia , Humanos , Inyecciones Intralesiones , Ratones , Ratones Desnudos , Profármacos/administración & dosificación , Profármacos/farmacocinética , Purina-Nucleósido Fosforilasa/metabolismo , Transfección , Trasplante Heterólogo , Fosfato de Vidarabina/administración & dosificación , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: Previous studies have shown that Herpes Simplex Virus thymidine kinase (HSV-tk)/ganciclovir (GCV) comprised the most commonly used suicide gene therapy for prostate cancer, with modest results being obtained. However, novel suicide genes, such as Escherichia coli purine nucleoside phosphorylase (PNP), have been utilized to demonstrate more potent tumor killing and an enhanced bystander effect on local, non-expressing cells compared to HSV-tk. METHODS: PNP/fludarabine (Fludara®; fludarabine phosphate; Berlex Labs, Richmond, CA, USA) was deliveried by prostate-specific, rat probasin-based promoter, ARR2PB. After infection of various cell lines with ADV.ARR(2) PB-PNP and administration of androgen analog, R1881, expression of PNP mRNA was detected; in vivo, the antitumor effect of the ARR(2) PB-PNP/Fludara system was monitored and analyzed, as well as animal survival. RESULTS: After in vitro infection with ADV.ARR(2) PB-PNP (multiplicity of infection = 10), LNCaP cells were more sensitive to a lower concentration Fludara (LD(50) , approximately 0.1 µg/ml) in the presence of R1881. Furthermore, robust bystander effects after R1881/Fludara treatment were observed in LNCaP cells after infection with bicistronic vector ADV.ARR2PB/PNP-IRES-EGFP in contrast to a much weaker effect in cells treated with ADV.CMV-HSV-tk/GCV. In vivo, tumor size in the ADV.ARR2PB-PNP/Fludara treatment group was dramatically smaller than in the control groups, and the mice treated with our system had a significantly prolonged survival, with three of eight mice surviving up to the 160-day termination point, as well as no systemic toxicity. CONCLUSIONS: The ARR(2) PB-PNP/Fludara system induced massive tumor cell death and a prolonged life span without systemic cytotoxicity; therefore, it might be a more attractive strategy for suicide gene therapy of prostate cancer.
Asunto(s)
Genes Transgénicos Suicidas , Terapia Genética , Neoplasias de la Próstata , Purina-Nucleósido Fosforilasa/genética , Fosfato de Vidarabina/análogos & derivados , Animales , Arrestinas/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Escherichia coli , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Genes Transgénicos Suicidas/genética , Vectores Genéticos , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Masculino , Metribolona/administración & dosificación , Ratones , Regiones Promotoras Genéticas , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Purina-Nucleósido Fosforilasa/uso terapéutico , Ratas , Fosfato de Vidarabina/uso terapéutico , beta-ArrestinasRESUMEN
This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 2-6. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.
Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Estaurosporina/análogos & derivados , Fosfato de Vidarabina/análogos & derivados , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Femenino , Humanos , Linfocitosis/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estaurosporina/administración & dosificación , Estaurosporina/efectos adversos , Estaurosporina/uso terapéutico , Resultado del Tratamiento , Fosfato de Vidarabina/administración & dosificación , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/uso terapéuticoRESUMEN
Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.
Asunto(s)
Antineoplásicos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia de Células B/terapia , Linfoma de Células B/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Ciclofosfamida/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia de Células B/mortalidad , Linfoma de Células B/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapéuticoRESUMEN
Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 µg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 µg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/mortalidad , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Profármacos/farmacocinética , Fosfato de Vidarabina/análogos & derivados , Vidarabina/análogos & derivados , Adulto , Anciano , Monitoreo de Drogas , Femenino , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Incidencia , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Infiltración Neutrófila/efectos de los fármacos , Profármacos/efectos adversos , Profármacos/uso terapéutico , Insuficiencia Renal/complicaciones , Insuficiencia Renal/metabolismo , Factores de Riesgo , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Vidarabina/sangre , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/uso terapéutico , Adulto JovenRESUMEN
A selective delivery of drugs to liver can be obtained by conjugation with galactosyl terminating macromolecules. The conjugates selectively enter hepatocytes after interaction of the carrier galactose residues with the asialoglycoprotein receptor (ASGP-R) present only on these cells. Within hepatocytes the conjugates are transported to lysosomes where the drug is set free from the carrier, becoming concentrated in liver cells. The present article reviews the liver targeting of drugs obtained with lactosaminated albumin (L-SA), a neoglycoprotein exposing galactosyl residues. We report: (1) experiments which demonstrate the antiviral efficacy of the L-H(human)SA-ara-AMP conjugate in laboratory animals and in humans with viral hepatitis; (2) the property of a L-HSA conjugate with fluorodeoxyuridine to produce concentrations of the drug higher in hepatic sinusoids than in systemic circulation, with the potential of accomplishing a loco-regional, noninvasive treatment of liver micrometastases; (3) the increased anticancer activity of doxorubicin (DOXO) when coupled to L-HSA on all the forms of chemically induced rat hepatocellular carcinomas including those which do not express the ASGP-R.
Asunto(s)
Portadores de Fármacos/farmacocinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Albúmina Sérica/farmacocinética , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antivirales/farmacocinética , Antivirales/uso terapéutico , Receptor de Asialoglicoproteína/metabolismo , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapéutico , Portadores de Fármacos/uso terapéutico , Floxuridina/farmacocinética , Floxuridina/uso terapéutico , Glicoproteínas , Humanos , Albúmina Sérica/uso terapéutico , Albúmina Sérica Humana , Distribución Tisular , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/uso terapéuticoAsunto(s)
Inmunosupresores/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Vasculares/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Biopsia , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Persona de Mediana Edad , Piel/patología , Neoplasias Cutáneas/diagnóstico , Tomografía Computarizada por Rayos X , Neoplasias Vasculares/diagnóstico , Fosfato de Vidarabina/uso terapéuticoRESUMEN
The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Antineoplásicos/farmacología , Enfermedad Injerto contra Huésped/prevención & control , Leucemia Mieloide Aguda/terapia , Melfalán/uso terapéutico , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Fosfato de Vidarabina/análogos & derivados , Adolescente , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/uso terapéutico , Niño , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/mortalidad , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Resultado del Tratamiento , Fosfato de Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 microM, and for human CFU-GM were 8 and 0.11 microM, giving mouse to human differentials of >3.8- and 8.5-fold. Clofarabine produced IC90s of 1.7 microM in mouse and 0.51 microM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
Asunto(s)
Nucleótidos de Adenina/uso terapéutico , Arabinonucleósidos/uso terapéutico , Cladribina/uso terapéutico , Células Progenitoras de Granulocitos y Macrófagos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosfato de Vidarabina/análogos & derivados , Nucleótidos de Adenina/antagonistas & inhibidores , Nucleótidos de Adenina/farmacología , Animales , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Arabinonucleósidos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/fisiología , Células Cultivadas , Cladribina/farmacología , Clofarabina , Células Progenitoras de Granulocitos y Macrófagos/fisiología , Células HT29 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Modelos Biológicos , Resultado del Tratamiento , Fosfato de Vidarabina/farmacología , Fosfato de Vidarabina/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A multicentre single-arm study testing the efficacy and toxicity of the oral combination of fludarabine and cyclophosphamide (FC) over 5 d in 75 patients with untreated B cell-chronic lymphocytic leukaemia. Oral FC demonstrated high efficacy with overall (OR) and complete response (CR) rates of 80% and 53%, respectively. Out of the 30 CR patients studied for Minimal Residual Disease (MRD) using 4-colour flow-cytometry and the 22 using Clonospecific polymerase chain reaction, 22 (66%) and 16 (68%), respectively, were MRD negative. Median survival and median treatment-free interval had not been reached at 7 years of follow-up. Median progression-free survival (PFS) was 5 years. Toxicity was acceptable, with 52% and 16% of National Cancer Institute grade 3/4 neutropenia and infections, respectively. Gastrointestinal toxicity was mild. Oral FC demonstrated a high efficacy and an acceptable safety profile and may be considered as the standard first line treatment in chronic lymphocytic leukaemia.
Asunto(s)
Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Adulto , Anciano , Biomarcadores/orina , Creatinina/orina , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasia Residual , Inducción de Remisión , Tasa de Supervivencia , Resultado del Tratamiento , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/uso terapéuticoRESUMEN
OBJECTIVES: Extranodal marginal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) accounts for about 7% to 8% of all B-cell lymphomas and 50% of all gastric lymphomas. Long-term localized growth is typical of MALT lymphoma. Multifocal manifestations are possible in advanced stages. MALT lymphoma of the larynx is a very rare disease; only 15 cases have been reported in the literature. METHODS: We report a case of multifocal MALT lymphoma affecting the larynx associated with extraesophageal reflux, chronic laryngitis, and gastric Helicobacter pylori infection. The staging revealed a recurrent tumor of MALT lymphoma in the stomach and an involvement of the right conjunctiva. RESULTS: Following recent reports on successful treatment of MALT lymphoma with antibiotics, initial empirical therapy with doxycycline calcium led to a subjective clinical symptom improvement but no objective response as assessed by laryngoscopy, magnetic resonance imaging of the larynx, and esophagogastroduodenal endoscopy. Because of the advanced stage and multiple extranodal manifestations of the MALT lymphoma, the patient received 3 cycles of chemoimmunotherapy according to the FCR protocol (fludarabine phosphate-cyclophosphamide-rituximab). No evidence of disease was observed after a 6-month follow-up. CONCLUSIONS: In the rare diagnosis of MALT lymphoma of the larynx, comprehensive staging is indispensable to exclude multifocal involvement. In contrast to the treatment of primarily localized MALT lymphoma, multifocal disease warrants systemic therapy.
Asunto(s)
Neoplasias Laríngeas/diagnóstico , Linfoma de Células B de la Zona Marginal/diagnóstico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/uso terapéutico , Ciclofosfamida/uso terapéutico , Diagnóstico Diferencial , Quimioterapia Combinada , Endoscopía Gastrointestinal , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Laríngeas/tratamiento farmacológico , Neoplasias Laríngeas/cirugía , Laringoscopía , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/cirugía , Imagen por Resonancia Magnética , Rituximab , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapéuticoRESUMEN
We report a high incidence of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) in patients entered into the preceding Medical Research Council Chronic Lymphocytic Leukaemia Pilot study of autografting [corrected] Of 115 newly diagnosed patients treated with fludarabine, 65 patients proceeded to autologous transplant. Conditioning was cyclophosphamide and total body irradiation in 49 (75%) patients and chemotherapy in 12 (18%). Ten patients have developed MDS/AML; eight had undergone an autograft. Five-year actuarial risk of developing MDS/AML postautograft was 12.4% (95% confidence interval, 2.5-24%). No analysed potential risk factor was predictive for MDS/AML development. We hypothesise that potential causative factors are fludarabine, low cell dose and transplant conditioning.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Linfocítica Crónica de Células B/etiología , Leucemia Mieloide/terapia , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias/etiología , Enfermedad Aguda , Adulto , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapéuticoRESUMEN
PURPOSE: To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. PATIENTS AND METHODS: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. CONCLUSION: Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Estudios Prospectivos , Fosfato de Vidarabina/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). PATIENTS AND METHODS: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. RESULTS: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0-24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). CONCLUSIONS: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfoma de Células B/prevención & control , Linfoma no Hodgkin/prevención & control , Masculino , Persona de Mediana Edad , Recurrencia , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/uso terapéuticoRESUMEN
PURPOSE: Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study. PATIENTS AND METHODS: Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR). RESULTS: Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild. CONCLUSION: Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Administración Oral , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/uso terapéuticoRESUMEN
Lung involvement is rare in Waldenström macroglobulinemia (WM). We encountered a male patient with WM who complained of breathlessness. Chest X-ray revealed diffuse infiltrative shadow throughout the both lungs. Transbronchial biopsy showed infiltration of atypical plasmacytoid lymphocytes and non-caseating granuloma. We treated the patients with fludarabine phosphate, and both his symptom and X-ray findings were then improved. To our knowledge, this is the first case showing non-caseating granuloma with lung involvement of WM. We discuss a mechanism of non-caseating granuloma formation in this case.
Asunto(s)
Granuloma de Células Plasmáticas del Pulmón/etiología , Macroglobulinemia de Waldenström/complicaciones , Antimetabolitos Antineoplásicos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Granuloma de Células Plasmáticas del Pulmón/diagnóstico por imagen , Granuloma de Células Plasmáticas del Pulmón/tratamiento farmacológico , Radiografía , Resultado del Tratamiento , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapéutico , Macroglobulinemia de Waldenström/diagnóstico por imagen , Macroglobulinemia de Waldenström/tratamiento farmacológicoRESUMEN
The increasing number of allogeneic stem cell transplantations has made the management of graft-versus-host disease (GVHD) a continuing problem for transplantation professionals. GVHD is a complicated disease the treatment of which requires an equally multifaceted approach. Despite therapeutic efforts to decrease its distressing and potentially lethal clinical manifestations, treatment is still not optimal. Fludarabine phosphate is a purine analogue, which is known to cause immunosuppression and long-lasting T-cell lymphopenia it is commonly employed in the therapy of hematological malignancies and non-myeloablative stem cell transplantation conditioning regimens. Myelosuppression, especially leuko- and lymphopenia is the major dose-limiting toxicity of fludarabine. However, a prolonged reduction in CD4+ T-cell count may be a desired effect for the treatment of GVHD. Clinical observations, preclinical data on the management of GVHD and well-known immunosuppressive properties suggest that fludarabine should be tested in clinical grounds for GVHD prophylaxis and treatment.