Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
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
2.
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
3.
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.

4.
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.

5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
Ann Hematol ; 95(7): 1137-43, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27118540

RESUMO

Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104.


Assuntos
Antineoplásicos/uso terapêutico , Flavonoides/uso terapêutico , Imunoterapia/tendências , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Cancer Immunol Res ; 4(4): 323-336, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26865456

RESUMO

Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor-expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P< 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P< 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P =0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.


Assuntos
Citocinas/metabolismo , Citotoxicidade Imunológica , Ácido Fólico/administração & dosagem , Imunoconjugados/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Expressão Gênica , Humanos , Imunoglobulina G/imunologia , Imunomodulação , Interleucina-12/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias/genética , Neoplasias/patologia , Carga Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Br J Haematol ; 169(5): 701-10, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847298

RESUMO

As a result of the anti-tumour activity observed in vitro and in vivo with combined anti-CD20 and anti-CD74 antibodies, we initiated a phase I/II trial of veltuzumab and milatuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Patients received an induction of veltuzumab 200 mg/m(2) weekly combined with escalating doses of milatuzumab at 8, 16 and 20 mg/kg weekly for 4 weeks. Patients without disease progression could receive an extended induction with treatment on weeks 12, 20, 28 and 36. A total of 35 patients enrolled on the study. Median age was 63 years, median number of prior therapies was 3, and 63% of patients were rituximab refractory. No dose-limiting toxicities were observed in the phase I study. Related grade 3-4 toxicities included lymphopenia, leucopenia, neutropenia, anaemia, infusion reactions, hyperglycaemia, fatigue and atrial tachycardia. Median weeks of therapy was 12 and 29% of patients completed all 36 weeks of therapy. The overall response rate was 24%, median duration of response was 12 months, and responses were observed at all dose levels and in 50% of patients refractory to rituximab. Combination therapy with veltuzumab and milatuzumab demonstrated activity in a population of heavily pre-treated patients with relapsed or refractory indolent NHL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Resultado do Tratamento
20.
Mol Carcinog ; 54(7): 532-42, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24302590

RESUMO

The presence of RD(INK4/ARF) (RD) enhancer in the INK4-ARF locus provides a novel mechanism to simultaneously increase the transcription of p15(INK4b) (p15), p14ARF (p14), and p16(INK4a) (p16). While such upregulation can be repressed through interactions between RD and oncoproteins CDC6 and BMI1, little is known about the involvement of RD in cancer. In this study we investigated RD deletions in 30 squamous cell carcinoma of the head and neck (SCCHN) and the patient-matched High At-Risk Mucosa specimens (HARM, "phenotypically normal" tissues neighboring SCCHN foci but beyond the surgical resection margin). RD was deleted (homozygously/heterozygously) in SCCHN and HARM at the incidence of 36.7% (11/30) and 13.3% (4/30), respectively. In comparison, no RD deletion was detected in 26 oral buccal brush biopsy specimens from healthy donors. Both p16 and p14 were lowly expressed in SCCHN and HARM, and their mRNA expression levels were positively associated with each other (P < 0.01). Moreover, BMI1 was highly expressed in both SCCHN and HARM, and BMI1 overexpression was associated with p16 downregulation in SCCHN (P < 0.05). These results indicate that RD deletion and BMI1 overexpression frequently occur in the early stage of oral carcinogenesis and BMI1 overexpression may downregulate the transcription of p16 and p14 through interfering with RD.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Neoplasias de Cabeça e Pescoço/genética , Proteína Supressora de Tumor p14ARF/genética , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 1/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA