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1.
Artigo em Inglês | MEDLINE | ID: mdl-33492438

RESUMO

PURPOSE: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity. METHODS: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD. RESULTS: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached). CONCLUSION: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors. TRIAL REGISTRATION: NCT01129193, registered 5/24/2010.

2.
Anticancer Res ; 40(10): 5707-5713, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988896

RESUMO

BACKGROUND/AIM: Genetic variations of the non-coding RNA gene, ANRIL, have been associated with human diseases including cancer, type-2 diabetes, and atherosclerosis. In the present study, we investigated the potential associations of select ANRIL single nucleotide polymorphisms (SNPs) with overall survival and other clinical outcomes in adult patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: Genomic DNA was extracted from whole blood samples from 103 adult patients with hematologic malignancies who had received allo-HSCT followed by oral tacrolimus therapy. The genotypes of four select ANRIL SNPs, rs564398, rs1063192, rs2151280, and rs2157719 were determined using qRT-PCR-based genotyping assays. RESULTS: rs2151280 (C->T) in ANRIL was associated with worse overall survival in these patients (CT/CC vs. TT). Contrarily, rs2151280 and the other select ANRIL SNPs were not associated with death at Day-100 after transplantation, the incidence of graft-versus-host disease (GVHD), acute kidney injury (AKI), and neurotoxicity in the study cohort. CONCLUSION: rs2151280 represents a potential prognostic biomarker for overall survival in adult patients with hematologic malignancies after allo-HSCT.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , RNA Longo não Codificante/genética , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Idoso , Feminino , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos
3.
J Rural Health ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32633045

RESUMO

PURPOSE: Large-scale genomic sequencing studies are driving oncology drug development. However, rural populations, like those residing in Appalachian Kentucky, are underrepresented in these efforts. In this study, we determined the frequency of participation, reasons for nonparticipation, and factors predicting the decision to participate in the Total Cancer Care (TCC) prospective genomic cohort study. METHODS: A total of 1,188 patients were invited to enroll in the TCC prospective cohort from December 2018 to May 2019. Declining patients were queried for their rationale for nonparticipation and their patient data were obtained from the Kentucky Cancer Registry (KCR). Logistic regression was used to assess the association between characteristics and study participation. The association of study participation with survival was modeled with Cox proportional-hazards regression. RESULTS: 90.9% (1,081) patients consented to participate. In multivariate analysis, factors significantly associated with participation were age, gender, treatment status, and race. Though overall more women participated in the study, men were more likely to participate than women when invited (OR 1.57). Younger, Caucasian individuals who had received chemotherapy, but not surgery, were also more likely to participate. Patients in the Kentucky Appalachian cohort were primarily rural, had less educational attainment, and lower socioeconomic status. Kentucky Appalachian patients were no less likely to enroll in TCC than non-Appalachian patients. Consented individuals had higher overall survival compared to those who declined. CONCLUSION: Though minorities, those with low socioeconomic status, and rural populations are underrepresented in genomic studies, they were no less likely to participate when given the opportunity, and participation was associated with better clinical outcomes.

4.
Nat Commun ; 11(1): 1924, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317630

RESUMO

Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Células Epiteliais/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição SOX9/metabolismo , Animais , Morte Celular , Células Epiteliais/metabolismo , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Queratinócitos/metabolismo , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo
5.
Anticancer Res ; 40(1): 67-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892553

RESUMO

BACKGROUND/AIM: Aberrant expression of the SEI1 oncogene has been prevalently found in a variety of human cancers, including oral squamous cell carcinoma (OSCC). Recent studies have shown that cisplatin up-regulates the expression of SEI1 in breast and bladder cancer cells, thus inhibiting apoptosis and cell death in these cells. In the present study, we investigated the impact of cisplatin on the expression of SEI1 in OSCC cells. MATERIALS AND METHODS: Four OSCC cell lines, CAL27, SCC4, SCC15, and SCC22A were treated with cisplatin and 5-fluorouracil, and changes in SEI1 expression in these cells were evaluated using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. RESULTS: Cisplatin significantly induced SEI1 expression in the tested OSCC cells. Contrarily, cisplatin treatment did not affect the expression of gankyrin and BMI1, two oncogenes frequently overexpressed in a coordinate manner with SEI1 in OSCC. Additionally, 5-fluorouracil did not bring about any detectable changes in SEI1 expression in these cells. CONCLUSION: Cisplatin-induced up-regulation of SEI1 expression in OSCC is specific, and such induction could underlie the development of resistance to cisplatin in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Bucais/genética , Oncogenes , Fatores de Transcrição/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos
6.
Anticancer Res ; 40(1): 133-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892561

RESUMO

BACKGROUND/AIM: Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS: Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS: PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p<0.05). Moreover, PTC209 drove more cells into apoptosis (p<0.05). CONCLUSION: PTC209 (BMI1-targeting agents, in general) represents a novel chemotherapeutic agent with potential in cervical cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
7.
Cancer Control ; 26(1): 1073274819883287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736324

RESUMO

PURPOSE: This study tested the feasibility and efficacy of using a text-based intervention to increase initiation, decrease discontinuation, and improve adherence as prescribed to adjuvant hormone therapy (AHT) among hyphenate post-menopausal breast cancer survivors. METHODS: The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (eg, feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit. RESULTS: Of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and the exit surveys, both blood draws, and did not miss more than 2 weekly surveys). Significant improvements were observed pre- to postintervention for self-reported medication adherence (P = .015), mental health functioning (P = .007), and perceived stress (P = .04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit (P < .001), indicating the accuracy of self-reported AHT adherence. Participants (91.9%) and physicians (100%) agreed that participant participation in the intervention was beneficial. CONCLUSIONS: The results of this pilot study established the general feasibility and efficacy of an app-based intervention to support patient AHT adherence. Larger controlled, randomized trials are needed to examine the effectiveness of the app-based intervention in improving AHT and quality of life among breast cancer survivors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Qualidade de Vida/psicologia , Smartphone/normas , Feminino , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Projetos Piloto , Apoio Social
8.
Mol Carcinog ; 58(12): 2327-2339, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31544312

RESUMO

Autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan-induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single-strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan-induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression-free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan-induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.


Assuntos
Reparo do DNA , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/terapia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Interferência de RNA , Transplante Autólogo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
9.
Bioanalysis ; 11(6): 471-483, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30892061

RESUMO

Aim: To develop and validate a reliable, robust and efficient assay to detect and quantify biologic compounds in vitro and in vivo during early stage of a biotherapeutic agent discovery. Methodology & results: An enrichment-free immunoassay method was developed to quantify a polyhistidine N- and FLAG C-terminally-tagged recombinant protein of ∼55 kDa. The target proteins were purified by a nickel-based matrix via tag affinity, followed by probing with biotinylated antitag antibody and subsequently detected by streptavidin-horseradish peroxidase conjugate using an automated capillary-based western system. Conclusion: A simple, highly sensitive and efficient immunoassay protocol was established to assess the in vitro stability and pharmacokinetic properties of propitious recombinant proteins in vivo in mouse to support early stage development of a biotherapeutic lead.


Assuntos
Epitopos/química , Imunoensaio/métodos , Proteínas Recombinantes/sangue , Animais , Biotinilação , Western Blotting/métodos , Histidina/química , Indicadores e Reagentes/química , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Níquel/química , Oligopeptídeos/sangue , Oligopeptídeos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Estreptavidina/química
10.
Anticancer Res ; 39(1): 67-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591441

RESUMO

BACKGROUND/AIM: SLC7A5 is recognized as the major mediator of melphalan uptake into multiple myeloma (MM) cells; however, its contribution to the inter-patient variability of melphalan efficacy and toxicity is yet to be well elucidated. This study aimed to investigate the impact of a single nucleotide polymorphism (SNP) rs4240803 in SLC7A5 on the gene expression, ex vivo sensitivity to melphalan, and clinical outcomes in MM patients who were undergoing autologous stem cell transplantation with high-dose melphalan. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 108 MM patients prior to melphalan therapy. Clinical data were also collected from these patients following melphalan therapy. RESULTS: rs4240803 was associated with elevated expression of SLC7A5 mRNA, higher ex vivo sensitivity to melphalan in PBMCs, and positive 90-day response in these patients (p=0.047, 0.10, 0.049, respectively). CONCLUSION: rs4240803 impacted the expression of SLC7A5, thus contributing to the clinical response of MM patients to melphalan therapy.


Assuntos
Transportador 1 de Aminoácidos Neutros Grandes/genética , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único , Transplante Autólogo/efeitos adversos , Resultado do Tratamento
11.
CPT Pharmacometrics Syst Pharmacol ; 7(11): 748-758, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30343510

RESUMO

High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration. The aim of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model capable of predicting neutrophil kinetics in individual patients with MM undergoing ASCT with high-dose melphalan and G-CSF administration. The extended PK/PD model incorporated several covariates, including G-CSF regimen, stem cell dose, hematocrit, sex, creatinine clearance, p53 fold change, and race. The resulting model explained portions of interindividual variability in melphalan exposure, therapeutic effect, and feedback regulation of G-CSF on neutrophils, thus enabling simulation of various doses and prediction of neutropenia duration.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Neutropenia/induzido quimicamente , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/farmacologia , Área Sob a Curva , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Meia-Vida , Humanos , Masculino , Melfalan/efeitos adversos , Melfalan/farmacocinética , Melfalan/farmacologia , Pessoa de Meia-Idade , Modelos Biológicos , Neutropenia/terapia
12.
Methods Mol Biol ; 1680: 29-40, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29030839

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that trigger post-transcriptional gene silencing. These RNAs need to be associated with the Argonaute proteins to be functional. This assembly begins with loading of a miRNA duplex, followed by the ejection of one of the strands (passenger). The remaining strand (guide) together with the Argonaute protein forms a ribonucleoprotein effector complex (the RNA-induced silencing complex, RISC). Mutation on the Argonaute protein, if affecting either step of the RISC assembly, impacts the function of miRNAs. Therefore, any observation of decreased miRNA level of mutants will provide insights into the role of those amino acid residues in the mechanical function of the Argonaute protein. In this chapter, we introduce a method to relatively quantify a specific miRNA co-immunoprecipitated with wild type and mutant Argonaute proteins from HEK293T cells, using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). Spiking a synthetic exogenous miRNA as an internal control with RNA extraction prior to cDNA synthesis will normalize the C t values obtained from the qRT-PCR assays and enable us to quantify the relative level of Argonaute-bound miRNA.


Assuntos
Proteínas Argonauta/metabolismo , Imunoprecipitação , MicroRNAs/genética , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Anticorpos/imunologia , Anticorpos/metabolismo , Proteínas Argonauta/imunologia , Biologia Computacional/métodos , DNA Complementar , Interpretação Estatística de Dados , Expressão Gênica , Células HEK293 , Humanos , Imunoprecipitação/métodos , Mutação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Fluxo de Trabalho
13.
DNA Repair (Amst) ; 57: 50-55, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28688373

RESUMO

The presence of an enhancer element, RDINK4/ARF (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of the p15INK4B (p15), p16INK4A (p16), and p14ARF tumor suppressor genes. While genetic inactivation of p15, p16, and p14ARF in human cancers has been extensively studied, little is known about RD alteration and its potential contributions to cancer progression. In this review, we discuss recent developments in RD alteration and its association with p15, p16, and p14ARF alterations in human cancers, and demonstrate that RD deletion may represent a novel mechanism to simultaneously down-regulate p15, p16, and p14ARF, thus promoting carcinogenesis.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Elementos Facilitadores Genéticos/genética , Neoplasias/genética , Deleção de Sequência , Proteína Supressora de Tumor p14ARF/genética , Sequência de Bases , Carcinogênese , Feminino , Humanos , Masculino , Neoplasias/metabolismo , Neoplasias/patologia
14.
Am J Health Syst Pharm ; 74(11 Supplement 2): S35-S41, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506975

RESUMO

PURPOSE: Pharmacy services provided in clinical trials at National Cancer Institute (NCI)-designated centers were assessed. METHODS: This was a cross-sectional survey of 61 NCI-designated cancer centers. Directors of pharmacy were contacted and data were collected electronically via Qualtrics over 2 months. Trial participants were asked to estimate the frequency that their sites performed 26 services and the perceived importance of these services. Services were examined with respect to the difference between their reported performance and their reported importance. Eight of the 26 services showed a difference of at least 40% between the proportion of respondents performing the activities "often" or "almost always" and the proportion considering them "important" or "very important." Demographic information was collected, as well as perceived barriers. RESULTS: Survey response rate was 59% (36 out of 61). The majority of services for clinical trials (19 out of 26) were viewed as important for pharmacists to perform; however, less than half (10 out of 26) were performed more than 50% of the time. Eight services had a gap of more than 40% when comparing the importance versus extent of implementation. Some of the largest gaps were reported in investigator-initiated trials development, medication reconciliation, therapeutic drug monitoring, and oral chemotherapy adherence assessment. Future studies can assist with cost justification by demonstrating the regulatory, safety, and financial benefits of pharmacist involvement in cancer trials. CONCLUSION: A survey of pharmacy directors at cancer centers revealed gaps between what respondents considered important pharmacist services in the provision of cancer clinical trials and the actual performance of those services in their institution.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Serviço de Farmácia Hospitalar/estatística & dados numéricos , Ensaios Clínicos como Assunto/organização & administração , Estudos Transversais , Humanos , National Cancer Institute (U.S.) , Serviço de Farmácia Hospitalar/organização & administração , Papel Profissional , Inquéritos e Questionários , Estados Unidos
16.
Leuk Lymphoma ; 58(10): 2310-2318, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28270022

RESUMO

Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01129193.


Assuntos
Inibidores de Histona Desacetilases , Linfoma de Células B , Mieloma Múltiplo , Fenilbutiratos , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma de Células B/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Fenilbutiratos/efeitos adversos , Fenilbutiratos/uso terapêutico
17.
Mol Carcinog ; 56(7): 1722-1732, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28150872

RESUMO

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and overproduction of monoclonal immunoglobins. Treatment with melphalan is currently standard of care for younger and fit patients when followed by hematopoietic stem cell transplantation (HSCT), and in transplant ineligible patients when used in combination regimens. It has been previously shown that changes in the p53 pathway are associated with melphalan efficacy, but the regulatory role of the p14ARF-MDM2-p53 axis has yet to be fully explored. Recently, a non-coding RNA, ANRIL (antisense non-coding RNA in the INK4-ARF locus) has been shown to negatively regulate the transcription of the entire INK4-ARF locus and simultaneously modulate the p53 and pRb pathways. Moreover, some single nucleotide polymorphisms (SNPs) in ANRIL have previously been associated with susceptibility to several malignancies. Here we investigated select ANRIL SNPs in DNA from patient-derived peripheral blood mononuclear cells obtained from 108 MM patients treated with high-dose melphalan followed by HSCT. Our results show that the rs2151280 (CàT) SNP in ANRIL was associated with worse progression-free survival (TC/CC vs TT: HR = 0.53, 95%CI, [0.26, 1.07], P = 0.07; adjusted HR = 0.39, 95%CI, [0.18, 0.84], P = 0.016), and the TT variant had higher ANRIL expression and lower p15, p14ARF, and p16 expression compared to the TC/CC variants. Our results indicate that ANRIL may be involved in melphalan-mediated apoptosis via down-regulating p14ARF and subsequent p53, and that the rs2151280 polymorphism may be a potential prognostic biomarker for relapse in melphalan-treated MM patients.


Assuntos
Leucócitos Mononucleares/patologia , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Transplante de Células-Tronco/efeitos adversos , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Seguimentos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Transplante Autólogo , Proteína Supressora de Tumor p14ARF/metabolismo
18.
Drugs ; 76(13): 1245-1255, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27484675

RESUMO

Vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Vosaroxin has chemical and pharmacologic characteristics distinct from other topoisomerase II inhibitors due to its quinolone scaffold. The efficacy and safety of vosaroxin in combination with cytarabine were evaluated in patients with relapsed/refractory acute myeloid leukemia (AML) in a phase III, randomized, multicenter, double-blind, placebo-controlled study (VALOR). In this study, the addition of vosaroxin produced a 1.4-month improvement in median overall survival (OS; 7.5 months with vosaroxin/cytarabine vs. 6.1 months with placebo/cytarabine; hazard ratio [HR] 0.87, 95 % confidence interval [CI] 0.73-1.02; unstratified log-rank p [Formula: see text] 0.061; stratified log-rank p [Formula: see text]0.024), with the greatest OS benefit observed in patients ≥60 years of age (7.1 vs. 5.0 months; HR 0.75, 95 % CI 0.62-0.92; p [Formula: see text]0.003) and patients with early relapse (6.7 vs. 5.2 months; HR 0.77, 95 % CI 0.59-1.00; p [Formula: see text] 0.039), two AML patient groups that typically have poor prognosis. Here we review the chemical and pharmacologic properties of vosaroxin, how these properties are distinct from those of currently available topoisomerase II inhibitors, how they may contribute to the efficacy and safety profile observed in the VALOR trial, and the status of clinical development of vosaroxin for treatment of AML.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/uso terapêutico , Quinolonas/química , Tiazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Método Duplo-Cego , Haplorrinos , Humanos , Leucemia Mieloide Aguda/mortalidade , Camundongos , Pessoa de Meia-Idade , Naftiridinas/farmacologia , Ratos , Tiazóis/farmacologia
19.
Exp Toxicol Pathol ; 68(9): 505-515, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27555377

RESUMO

Minocycline is purported to have neuroprotective properties in experimental models of some human neurologic diseases, and has therefore been identified as a putative neuroprotectant for chemotherapy-induced cognitive impairment (CICI) in breast cancer patients. However, because its mechanism of action is believed to be mediated through anti-inflammatory, anti-apoptotic, and anti-oxidant pathways, co-administration of minocycline with chemotherapeutic agents has the potential to reduce the efficacy of anticancer drugs. The objective of this study is to evaluate the effect of minocycline on the activity of the AC chemotherapeutic regimen (Adriamycin [doxorubicin], Cytoxan [cyclophosphamide]) in in vitro and in vivo models of triple-negative breast cancer (TNBC). Clonogenic and methylthiazol tetrazolium (MTT) assays were used to assess survival and viability in two TNBC cell lines treated with increasing concentrations of AC in the presence or absence of minocycline. Biomarkers of apoptosis, cell stress, and DNA damage were evaluated by western blot. The in vivo effects of AC and minocycline, each alone and in combination, were assessed in a xenograft model of TNBC in female athymic nude mice by weekly tumor volume measurement, body and organ weight measurement, and histopathology. Apoptosis and proliferation were characterized by immunohistochemistry in the xenografts tumors. Brains from tumor-bearing mice were evaluated for microglial activation, glial scars, and the proportion of neural progenitor cells. Data from these in vitro and in vivo studies demonstrate that minocycline does not diminish the cytotoxic and tumor-suppressive effects of this chemotherapeutic drug combination in TNBC cells. Moreover, minocycline appeared to prevent the reduction in doublecortin-positive neural progenitor cells observed in AC-treated mice. We posit that minocycline may be useful clinically for its reported neuroprotective activity in breast cancer patients receiving AC without loss of chemotherapeutic efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Transtornos Cognitivos/induzido quimicamente , Minociclina/farmacologia , Fármacos Neuroprotetores/farmacologia , Neoplasias de Mama Triplo Negativas , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cognitivos/prevenção & controle , Ciclofosfamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/toxicidade , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Am J Health Syst Pharm ; 73(17): 1331-7, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27543577

RESUMO

PURPOSE: The stability of extemporaneously prepared erlotinib, lapatinib, and imatinib oral liquid dosage forms using two commercially available vehicles when stored at 4 and 25 °C was evaluated. METHODS: Three batches of extemporaneous oral suspensions were prepared for each drug. Erlotinib and lapatinib tablets were crushed and mixed in a 1:1 mixture of Ora-Plus:Ora-Sweet solution to yield 10- and 50-mg/mL suspensions, respectively. Imatinib tablets were crushed and mixed in Ora-Sweet solution to yield a 40-mg/mL suspension. Suspensions were stored in amber plastic bottles, and samples from each bottle were obtained on days 0, 1, 3, 7, 14, and 28. RESULTS: Erlotinib 10-mg/mL and lapatinib 50-mg/mL oral suspensions in a 1:1 mixture of Ora-Plus and Ora-Sweet retained at least 90% of their initial concentration throughout the 28-day study when stored at 25 °C. Visual inspection revealed notable viscosity changes in the erlotinib and lapatinib suspensions stored at 4 °C for 7 days and beyond. The viscosity of these preparations increased with time and was particularly evident with the erlotinib suspension, which exhibited a puddinglike texture. Imatinib 40-mg/mL oral suspension in Ora-Sweet appeared stable for up to 14 days when stored at both 25 and 4 °C. CONCLUSION: Erlotinib 10-mg/mL and lapatinib 50-mg/mL oral suspensions prepared from commercially available tablets were stable for at least 28 days when prepared in a 1:1 mixture of Ora-Plus:Ora-Sweet at 25 °C. Imatinib 40-mg/mL oral suspension prepared from commercially available tablets was stable for up to 14 days when prepared in Ora-Sweet and stored at 25 and 4 °C.


Assuntos
Química Farmacêutica/métodos , Cloridrato de Erlotinib/química , Mesilato de Imatinib/química , Quinazolinas/química , Administração Oral , Química Farmacêutica/normas , Formas de Dosagem , Estabilidade de Medicamentos , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/normas , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/normas , Lapatinib , Quinazolinas/administração & dosagem , Quinazolinas/normas , Suspensões
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