RESUMEN
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
Asunto(s)
Catepsina C/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Proteínas Recombinantes/química , Espectrometría de Fluorescencia , Relación Estructura-Actividad , Especificidad por Sustrato , Difracción de Rayos XRESUMEN
The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tioguanina/administración & dosificación , Tioguanina/efectos adversos , Niño , Preescolar , Femenino , Humanos , Hipertensión Portal/inducido químicamente , Lactante , Inyecciones Espinales , Masculino , Metotrexato/administración & dosificaciónAsunto(s)
Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/radioterapia , Sarcoma/cirugía , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/cirugíaRESUMEN
BACKGROUND: Although mercaptopurine (MP) is conventionally used to treat childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is a more potent thiopurine in vitro and, when administered orally to patients, achieves cytotoxic drug concentrations in the cerebrospinal fluid (CSF). We performed a pilot study incorporating oral and 24-hr continuous IV infusion (CIVI) TG in children with newly diagnosed standard-risk ALL. PROCEDURE: Children with newly diagnosed standard-risk ALL (age 1-10 years, WBC<50 k) were eligible. Multi-agent chemotherapy was patterned after the Children's Cancer Group (CCG) 105 trial, with the addition of CIVI-TG (480 mg/m2) during consolidation, interim maintenance and maintenance, and substitution of oral TG (60 mg/m2/day) for oral MP during maintenance. RESULTS: Fifty-eight patients (31 female), median age 4.3 years, were enrolled. At 8 years, the relapse-free and overall survival probabilities were 83% and 88%. There were no CNS relapses. Six patients (five males) experienced reversible veno-occlusive disease (VOD) while receiving oral TG, and the study was amended to discontinue TG, changing all patients to oral MP. Red cell TG nucleotide concentrations during oral TG averaged 95 ng (570 pmol)/8x10(8) RBC, greater than concentrations reported with oral MP. CONCLUSION: Although the absence of CNS relapses in this pilot study suggests that TG may contribute to the prevention of CNS recurrences, the development of VOD negatively impacts the risk:benefit ratio of substituting TG for MP.
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Antimetabolitos Antineoplásicos/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tioguanina/administración & dosificación , Administración Oral , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Humanos , Lactante , Infusiones Intravenosas , Masculino , Proyectos Piloto , Análisis de Supervivencia , Tioguanina/efectos adversosRESUMEN
PURPOSE: Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. PATIENTS AND METHODS: The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed. RESULTS: Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold). CONCLUSION: Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.
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Carcinoma Basocelular/mortalidad , Carcinoma de Células Escamosas/mortalidad , Neoplasias Cutáneas/mortalidad , Sobrevivientes , Adolescente , Adulto , Carcinoma Basocelular/patología , Carcinoma Basocelular/radioterapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Niño , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , América del Norte , Factores de Riesgo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/radioterapiaRESUMEN
BACKGROUND: The Childhood Cancer Survivor Study is a resource that was designed to investigate long-term effects among 5-year survivors of childhood and adolescent malignancies. Previous studies have shown that exposure to chemotherapy and/or radiation can compromise pulmonary function in these survivors of childhood cancer. METHODS: Using information obtained from questionnaires from 12,390 childhood cancer survivors and 3546 randomly selected siblings, the authors evaluated the rate of first occurrence of 15 selected pulmonary conditions in three periods: during therapy, from the end of therapy to 5 years postdiagnosis, and >/= 5 years postdiagnosis. Multivariate analyses were used to determine the relative risks with 95% confidence intervals of reported pulmonary conditions by exposure to the following treatment variables: radiation therapy to the chest, bleomycin, cyclophosphamide, busulfan, lomustine (CCNU), and/or carmustine (BCNU). RESULTS: Compared with siblings, survivors had a statistically significant increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen, abnormal chest wall, exercise-induced shortness of breath, bronchitis, recurrent sinus infection, and tonsillitis for all three periods. During the period of >or= 5 years postdiagnosis, statistically significant associations were present for lung fibrosis and chest radiation (RR, 4.3; P = 0 001); for supplemental oxygen use and chest radiation (RR, 1.8; P < 0.001), BCNU (RR, 1.4; P = 0.05), bleomycin (RR, 1.7; P = 0.001), busulfan (RR, 3.2; P = 0.002), CCNU (RR, 2.1; P < 0.001), and cyclophosphamide (RR, 1.5; P = 0.01); for recurrent pneumonia and chest radiation (RR, 2.2; P = 0.001) and cyclophosphamide (RR, 1.6; P = 0.04); for chronic cough and chest radiation (RR, 2.0; P < 0.001), bleomycin (RR, 1.9; P < 0.001), and cyclophosphamide (RR, 1.3; P = 0.004); and for pleurisy and chest radiation (RR, 1.4; P = 0.02) and busulfan (RR, 5.1; P = 0.02). Chest radiation was associated with a 3.5% cumulative incidence of lung fibrosis at 20 years after diagnosis. CONCLUSIONS: For self-report of pulmonary conditions, treatment-related factors that continue to manifest > 5 years after diagnosis and treatment are important determinants of risk. Continued follow-up of childhood cancer survivors is needed to evaluate the impact of pulmonary conditions on quality of life.