Asunto(s)
Imidazoles/uso terapéutico , Leucemia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Humanos , Imidazoles/efectos adversos , Imidazoles/química , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/efectos adversos , Piridazinas/química , Piridazinas/farmacología , Trombosis/inducido químicamente , Resultado del TratamientoRESUMEN
Busulfan (Bu)-containing regimens are commonly used in myeloablative conditioning regimens before allogeneic hematopoietic cell transplantation (HCT). Yet, there is considerable variability on how Bu is administered related to frequency (4 times a day [Q6] or daily [Q24]) and combinations with other chemotherapeutic agents (cyclophosphamide [Cy] or fludarabine [Flu]). We performed a prospective cohort study of recipients of Bu-based conditioning according to contemporary practices to compare different approaches (BuCy Q6, n = 495; BuFlu Q24, n = 331; BuCy Q24, n = 96; BuFlu Q6, n = 91) in patients with myeloid malignancies between 2009 and 2011. BuFlu Q24 recipients were more likely to be older and tended to have worse performance status and a higher comorbid burden. The cumulative incidences of hepatic veno-occlusive disease (P = .40), idiopathic pneumonia (P = .50), and seizures (P = .50) did not differ across groups. One-year HCT-related mortality ranged from 12% to 16% (P = .80), 3-year relapse incidence ranged from 32% to 36% (P = .80), and 3-year overall survival ranged from 51% to 58% (P = .20) across groups. This study demonstrates that HCT conditioning regimens using i.v. Bu Q6 or Q24 alone or in combination with Cy or Flu have similar outcomes in the myeloablative setting for treatment of myeloid malignancies.
Asunto(s)
Busulfano/administración & dosificación , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Ciclofosfamida/uso terapéutico , Esquema de Medicación , Femenino , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Neumonía/etiología , Estudios Prospectivos , Convulsiones/etiología , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 play a central role in angiogenesis, which is necessary for solid tumors to expand and metastasize. Specific inhibitors of VEGFR-2 tyrosine kinase are therefore thought to be useful for treating cancer. We showed that the quinazoline urea derivative KRN633 inhibited tyrosine phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant tyrosine kinases showed that KRN633 was highly selective for VEGFR-1, -2, and -3. KRN633 also blocked the activation of mitogen-activated protein kinases by VEGF, along with human umbilical vein endothelial cell proliferation and tube formation. The propagation of various cancer cell lines in vitro was not inhibited by KRN633. However, p.o. administration of KRN633 inhibited tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats. KRN633 also caused the regression of some well-established tumors and those that had regrown after the cessation of treatment. In these models, the trough serum concentration of KRN633 had a more significant effect than the maximum serum concentration on antitumor activity. KRN633 was well tolerated and had no significant effects on body weight or the general health of the animals. Histologic analysis of tumor xenografts treated with KRN633 revealed a reduction in the number of endothelial cells in non-necrotic areas and a decrease in vascular permeability. These data suggest that KRN633 might be useful in the treatment of solid tumors and other diseases that depend on pathologic angiogenesis.