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1.
J Cell Sci ; 137(12)2024 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-38940347

RESUMEN

Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.


Asunto(s)
Proteína 1 de la Respuesta de Crecimiento Precoz , Lomustina , ARN Mensajero , Humanos , ARN Mensajero/metabolismo , ARN Mensajero/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Lomustina/farmacología , Gránulos de Estrés/metabolismo , Gránulos de Estrés/genética , Apoptosis/efectos de los fármacos , Antineoplásicos Alquilantes/farmacología
2.
Pharmacol Res ; 185: 106510, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36252775

RESUMEN

Glioblastoma multiforme (GBM) is the most common malignant brain tumor with limited therapeutic options. Besides surgery, chemotherapy using temozolomide, carmustine or lomustine is the main pillar of therapy. However, therapy success is limited and prognosis still is very poor. One restraining factor is drug resistance caused by drug transporters of the ATP-binding cassette family, e.g. ABCB1 and ABCG2, located at the blood-brain barrier and on tumor cells. The active efflux of xenobiotics including drugs, e.g. temozolomide, leads to low intracellular drug concentrations and subsequently insufficient anti-tumor effects. Nevertheless, the role of efflux transporters in GBM is controversially discussed. In the present study, we analyzed the role of ABCB1 and ABCG2 in GBM cells showing that ABCB1, but marginally ABCG2, is relevant. Applying a CRISPR/Cas9-derived ABCB1 knockout, the response to temozolomide was significantly augmented demonstrated by decreased cell number (p < 0.001) and proliferation rate (p = 0.04), while apoptosis was increased (p = 0.04). For carmustine, a decrease of cells in G1-phase was detected pointing to cell cycle arrest in the ABCB1 knockout (p = 0.006). For lomustine, however, loss of ABCB1 did not alter the response to the treatment. Overall, this study shows that ABCB1 is involved in the active transport of temozolomide out of the tumor cells diminishing the response to temozolomide. Interestingly, loss of ABCB1 also affected the response to the lipophilic drug carmustine. These findings show that ABCB1 is not only relevant at the blood-brain barrier, but also in the tumor cells diminishing success of chemotherapy.


Asunto(s)
Glioblastoma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Carmustina/farmacología , Carmustina/uso terapéutico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Lomustina/uso terapéutico , Lomustina/farmacología , Sistemas CRISPR-Cas , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo
3.
Sci Rep ; 14(1): 17639, 2024 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085346

RESUMEN

Glioblastoma is the most common primary brain tumor in adults, characterized by an inherent aggressivity and resistance to treatment leading to poor prognoses. While some resistance mechanisms have been elucidated, a deeper understanding of these mechanisms is needed to increase therapeutic efficacy. In this study we first discovered glial-cell derived neurotrophic factor (GDNF) to be upregulated in patient-derived glioblastoma spheroid cultures after chemotherapeutic temozolomide treatment, through RNA-Seq experiments. Therefore, we investigated the role of the GDNF/GDNF receptor alpha 1 (GFRA1) signaling pathway as a resistance mechanism to chemotherapy with temozolomide and lomustine, as well as irradiation using patient-derived glioblastoma spheroid cultures. With qPCR experiments we showed a consistent upregulation of GDNF and its primary receptor GFRA1 following all three lines of treatment. Moreover, CRISPR/Cas9 knock-outs of GDNF in two patient-derived models sensitized these cells to chemotherapy treatment, but not radiotherapy. The increased sensitivity was completely reversed by the addition of exogeneous GDNF, confirming the key role of this factor in chemoresistance. Finally, a CRISPR KO of GFRA1 demonstrated a similar increased sensitivity to temozolomide and lomustine treatment, as well as radiotherapy. Together, our findings support the role of the GDNF/GFRA1 signaling pathway in glioblastoma chemo and radioresistance.


Asunto(s)
Resistencia a Antineoplásicos , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Factor Neurotrófico Derivado de la Línea Celular Glial , Glioblastoma , Tolerancia a Radiación , Transducción de Señal , Temozolomida , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/radioterapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Resistencia a Antineoplásicos/genética , Temozolomida/farmacología , Tolerancia a Radiación/genética , Tolerancia a Radiación/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Lomustina/farmacología , Esferoides Celulares/metabolismo , Esferoides Celulares/efectos de los fármacos
4.
Br J Neurosurg ; 27(4): 516-8, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23391098

RESUMEN

A 15-year-old female presented with a middle cranial fossa anaplastic astrocytoma that was completely excised. She received local radiotherapy (54 Gy) and oral temozolomide. Five months after therapy, MRI showed local relapse. She underwent resection of the tumour with implantation of seven carmustine-impregnated wafers (Gliadel). She then received six cycles of procarbazine and lomustine therapy. Three years later, she is well and disease free. This case supports the further investigation of Gliadel in children and young people with relapsed high-grade glioma, particularly in the setting of a second complete resection.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos/farmacología , Astrocitoma , Carmustina/farmacología , Lomustina/farmacología , Recurrencia Local de Neoplasia , Procarbazina/farmacología , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Astrocitoma/tratamiento farmacológico , Astrocitoma/cirugía , Carmustina/administración & dosificación , Terapia Combinada , Implantes de Medicamentos , Femenino , Humanos , Lomustina/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Procarbazina/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento
5.
Vet Med Sci ; 9(4): 1573-1583, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37365849

RESUMEN

BACKGROUND: Combined chemoradiation offers a promising therapeutic strategy for dogs with glioma. The alkylating agents temozolomide (TMZ) and lomustine (CCNU) penetrate the blood-brain barrier, and doses for dogs are established. Whether such combinations are clinically advantageous remains to be explored together with tumour-specific markers. OBJECTIVE: To investigate if triple combination of lomustine, temozolomide and irradiation reduces canine glioma cell survival in vitro. METHODS: We evaluated the sensitising effect of CCNU alone and in combination with TMZ-irradiation in canine glioma J3T-BG cells and long-term drug-exposed subclones by using clonogenic survival and proliferation assays. Bisulphite-SEQ and Western Blot were used to investigate molecular alterations. RESULTS: TMZ (200 µM) or CCNU alone (5 µM) reduced the irradiated survival fraction (4 Gy) from 60% to 38% (p = 0.0074) and 26% (p = 0.0002), respectively. The double-drug combination reduced the irradiated survival fraction (4 Gy) more potently to 12% (p < 0.0001). After long-term drug exposure, both subclones show higher IC50 values against CCNU and TMZ. For CCNU-resistant cells, both, single-drug CCNU (p = 0.0006) and TMZ (p = 0.0326) treatment combined with irradiation (4 Gy) remained effective. The double-drug-irradiation combination reduced the cell survival by 86% (p < 0.0001), compared to 92% in the parental (nonresistant) cell line. For TMZ-resistant cells, only the double-drug combination with irradiation (4 Gy) reduced the cell survival by 88% (p = 0.0057) while single-drug treatment lost efficacy. Chemoresistant cell lines demonstrated higher P-gp expression while MGMT-methylation profile analysis showed a general high methylation level in the parental and long-term treated cell lines. CONCLUSIONS: Our findings indicate that combining CCNU with TMZ-irradiation significantly reduces canine glioma cell survival. Such a combination could overcome current challenges of therapeutic resistance to improve overall patient survival.


Asunto(s)
Enfermedades de los Perros , Glioma , Animales , Perros , Temozolomida/farmacología , Temozolomida/uso terapéutico , Lomustina/uso terapéutico , Lomustina/farmacología , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Supervivencia Celular , Glioma/veterinaria , Glioma/tratamiento farmacológico , Enfermedades de los Perros/tratamiento farmacológico
6.
Curr Opin Oncol ; 24(6): 694-701, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22913972

RESUMEN

PURPOSE OF REVIEW: This review summarizes the recent studies in adults' diffuse low-grade gliomas (LGGs) chemotherapy, including response assessment and potential predictive biomarkers of chemosensitivity. RECENT FINDINGS: Recent studies have confirmed that chemotherapy is an interesting treatment option in LGGs. About 25-50% of LGGs achieve radiological responses with temozolomide or a procarbazine-CCNU-vincristine (PCV) regimen. Clinical and quality-of-life improvements are commonly observed with more than half of the patients with epilepsy, demonstrating a significant reduction of seizure frequency. Dynamic volumetric studies have provided a better description of LGGs evolution after chemotherapy. They have shown that an ongoing volume decrease can be observed many months after chemotherapy discontinuation, particularly after PCV, raising the question of how and for how long should LGGs be treated. New response criteria have been defined by the Response Assessment in Neuro-Oncology group. In addition to 1p/19q codeletion and MGMT promoter methylation, IDH1 mutation might also be a potential predictive biomarker of chemosensitivity. SUMMARY: It has now been widely accepted that chemotherapy is an interesting treatment option in LGGs. However, several questions remain unanswered regarding its optimal use. Ongoing phase III studies will allow a better delineation of the role of chemotherapy in LGGs and will also help to better determine the potential predictive value of a 1p/19q codeletion, a MGMT promoter methylation and an IDH1 mutation.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Quimioradioterapia , Ensayos Clínicos como Asunto , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Glioma/mortalidad , Glioma/radioterapia , Humanos , Lomustina/farmacología , Lomustina/uso terapéutico , Procarbazina/farmacología , Procarbazina/uso terapéutico , Temozolomida , Resultado del Tratamiento , Vincristina/farmacología , Vincristina/uso terapéutico
7.
Vopr Onkol ; 58(3): 394-7, 2012.
Artículo en Ruso | MEDLINE | ID: mdl-22888657

RESUMEN

SHR mice with intracranial transplanted lymphosarcoma LIO-1 received a single intraperitoneal gemcitabine injection in maximal tolerated dose of 25 mg/kg or single maximal tolerated oral dose of lomustine, 50 mg/kg. Compared to control group gemcitabine injection increased the mice lifespan 1.4-fold (p < 0,01) and oral lomustine 1.6-fold (p < 0,01). The median lifespan of the mice receiving both gemcitabine and lomustine in maximal dose underwent a significant 3.3-fold increase (p < 0,01) compared to controls (2.4-fold compared to gemcitabine and 2.1-fold compared to lomustine group). Combined therapy didn't cause an increase of toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Linfoma no Hodgkin/tratamiento farmacológico , Administración Oral , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Sinergismo Farmacológico , Inyecciones Intraperitoneales , Lomustina/administración & dosificación , Lomustina/farmacología , Masculino , Dosis Máxima Tolerada , Ratones , Análisis de Supervivencia , Gemcitabina
8.
Cells ; 11(16)2022 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-36010664

RESUMEN

A first-line therapeutic for high-grade glioma, notably glioblastoma (GBM), is the DNA methylating drug temozolomide (TMZ). Previously, we showed that TMZ induces not only apoptosis and autophagy, but also cellular senescence (CSEN). We presented the hypothesis that GBM cells may escape from CSEN, giving rise to recurrent tumors. Furthermore, the inflammatory phenotype associated with CSEN may attenuate chemotherapy and drive tumor progression. Therefore, treatments that specifically target senescent cells, i.e., senolytic drugs, may lead to a better outcome of GBM therapy by preventing recurrences and tumor inflammation. Here, we tested Bcl-2 targeting drugs including ABT-737, ABT-263 (navitoclax), several natural substances such as artesunate, fisetin and curcumin as well as lomustine (CCNU) and ionizing radiation (IR) for their senolytic capacity in GBM cells. Additionally, several proteins involved in the DNA damage response (DDR), ATM, ATR, Chk1/2, p53, p21, NF-kB, Rad51, PARP, IAPs and autophagy, a pathway involved in CSEN induction, were tested for their impact in maintaining CSEN. Treatment of GBM cells with a low dose of TMZ for 8-10 days resulted in >80% CSEN, confirming CSEN to be the major trait induced by TMZ. To identify senolytics, we treated the senescent population with the compounds of interest and found that ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866 and the natural compounds fisetin and artesunate exhibit senolytic activity, inducing death in senescent cells more efficiently than in proliferating cells. Curcumin showed the opposite effect. No specific effect on CSEN cells was observed by inhibition of Chk1/Chk2, p21, NF-kB, Rad51 and PARP. We conclude that these factors neither play a critical role in maintaining TMZ-induced CSEN nor can their inhibitors be considered as senolytics. Since IR and CCNU did not exhibit senolytic activity, radio- and chemotherapy with alkylating drugs is not designed to eliminate TMZ-induced senescent cancer cells.


Asunto(s)
Curcumina , Glioblastoma , Artesunato/farmacología , Senescencia Celular , Curcumina/farmacología , Glioblastoma/metabolismo , Humanos , Lomustina/farmacología , Lomustina/uso terapéutico , FN-kappa B , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Senoterapéuticos , Temozolomida/farmacología , Temozolomida/uso terapéutico
9.
Eur J Cancer ; 155: 179-190, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34388515

RESUMEN

BACKGROUND: The REGOMA trial showed that regorafenib significantly improved overall survival in patients with recurrent glioblastoma compared with lomustine. Patients treated with regorafenib experienced a higher occurrence of grade 3-4 drug-related adverse events than those receiving the standard treatment. Because this safety profile was expected, it was considered of great importance to assess the patient point of view regarding the disease and treatment impact on different aspects of life and patient well-being. We here report the final results of the health-related quality of life (HRQoL) assessment, a secondary end-point of the study. This trial is registered with ClinicalTrials.gov, NCT02926222. METHODS: Patient-reported outcomes were assessed, within a prospective, randomised, multicentre, open-label phase II trial, by the European Organisation for Research and Treatment of Cancer core questionnaire and brain module at baseline and every 8-weekly neuroradiological assessment till disease progression. Mixed-effect linear models were fitted for each of the HRQoL domain to examine the change over progression-free time within and between arms. Furthermore, differences were also classified as clinically meaningful changes. To correct for multiple comparisons and avoid type I errors, the level of significance was set at P = 0.01 (2-sided). RESULTS: Of 119 enrolled patients, 56/59 (95%) patients and 58/60 (97%) patients treated with regorafenib and lomustime completed questionnaires at baseline, respectively. No significant differences were observed in any generic or cancer-specific domain during treatment in both arms, or between the two arms, except for the appetite loss and diarrhoea scales which were significantly worse in patients treated with regorafenib. The rate of patients with a clinically meaningful worsening for appetite loss, diarrhoea and for any other domain was not statistically different between the two arms. CONCLUSIONS: Regorafenib did not negatively affect HRQoL in patients with recurrent glioblastoma. These data combined with the survival benefit shown in the REGOMA trial support the use of regorafenib as a treatment option for these patients.


Asunto(s)
Glioblastoma/tratamiento farmacológico , Lomustina/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Piridinas/uso terapéutico , Anciano , Femenino , Glioblastoma/patología , Humanos , Lomustina/farmacología , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Compuestos de Fenilurea/farmacología , Estudios Prospectivos , Piridinas/farmacología , Recurrencia , Encuestas y Cuestionarios
10.
Sci Rep ; 11(1): 20338, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-34645858

RESUMEN

Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC50 values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas , Ciclo Celular/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma , Azacitidina/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Lomustina/farmacología , Temozolomida/farmacología
11.
Int Immunopharmacol ; 97: 107826, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34091114

RESUMEN

PURPOSE: Treatment options for recurrent glioblastoma (rGBM) remain scarce, which may be due to the limited understanding of its molecular characteristics. METHODS: Based on gene expression profiling, the infiltration scores of 26 immune cell types were calculated using gene set variation analysis. The differences between rGBM and other cancer subtypes were estimated to characterize the specific immune characteristics of rGBM, and the prognostic value of immune cells in rGBM was estimated using univariate and multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were performed to identify whether CD8 T-cell infiltration could be useful in selecting treatment options for rGBM patients. RESULTS: We found that rGBM patients were associated with enrichment of activated CD8 T cells, and high CD8 T-cell infiltration was associated with superior overall survival. Patients exhibiting high CD8 T-cell infiltration who received treatment with bevacizumab and lomustine combination therapy experienced a significant benefit in overall survival and progression-free survival, whereas patients with low CD8 T-cell infiltration did not experience such a benefit. CD8 T cells remained an independent prognostic factor in multivariate analyses (cohort 1: hazard ratio [HR] = 0.546, 95% confidence interval [CI]: 0.316-0.945, P = 0.031; cohort 3: HR = 0.615, 95% CI: 0.387-0.978, P = 0.040) after adjusting for clinicopathological and molecular factors. CONCLUSIONS: Activated CD8 T-cells is a promising biomarker for predicting overall survival in rGBM patients and could be used for assisting treatment selection.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Linfocitos T CD8-positivos/inmunología , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Niño , Toma de Decisiones Clínicas , Estudios de Cohortes , Conjuntos de Datos como Asunto , Monitoreo de Drogas/métodos , Femenino , Glioblastoma/inmunología , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Lomustina/farmacología , Lomustina/uso terapéutico , Activación de Linfocitos/efectos de los fármacos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Selección de Paciente , Pronóstico , Supervivencia sin Progresión , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Adulto Joven
12.
Aust Vet J ; 97(9): 308-315, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31328256

RESUMEN

Multi-agent chemotherapy (vincristine, epirubicin and prednisolone) including either cyclophosphamide (CEOP) or lomustine (LEOP) was given as first-line chemotherapy to treatment-naïve canine lymphoma patients with measurable, high grade T-cell lymphoma (HGTCL). All patients responded to either CEOP or LEOP. Toxicity was typical of multi-agent chemotherapy protocols and 25% of dogs receiving lomustine exhibited mild-to-moderate ALT elevation and 29% grade 3 or 4 neutropenia. Median progression-free survival (100 versus 269 days) and overall survival (155 versus 327 days) were significantly higher in patients receiving LEOP compared to CEOP. Overall survival was improved for patients receiving LEOP compared to those receiving CEOP followed by lomustine-based rescue therapy. The results of this retrospective study support further evaluation of lomustine as part of first-line, multi-agent therapy for patients with HGTCL.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/farmacología , Enfermedades de los Perros/tratamiento farmacológico , Lomustina/farmacología , Linfoma de Células T/veterinaria , Animales , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Supervivencia sin Enfermedad , Perros , Epirrubicina/uso terapéutico , Femenino , Linfoma de Células T/tratamiento farmacológico , Masculino , Neutropenia/inducido químicamente , Prednisolona/uso terapéutico , Estudios Retrospectivos , Reino Unido , Vincristina/uso terapéutico
13.
J Pharm Biomed Anal ; 176: 112786, 2019 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-31398506

RESUMEN

Electrochemical techniques were used to investigate the behavior of lomustine (CCNU) and its degradation in aqueous solution at a glassy carbon electrode (GCE). The in situ interaction of CCNU and chemically degraded CCNU (cdCCNU) with dsDNA was then investigated in dsDNA incubated solutions, using dsDNA electrochemical biosensors and comet assays. CCNU undergoes electrochemical reduction in two irreversible, diffusion-controlled, and pH-dependent redox processes, each with transfer of two electrons and one proton. At pH ≥ 10.1, the peak potential for the two processes was essentially pH-independent and involved only one electron. A mechanism was proposed for the reduction of CCNU in a neutral medium. In addition, it was found that CCNU underwent spontaneous degradation during incubation in aqueous solution, without the formation of electroactive degradation products. The degradation process was faster in basic media. Moreover, this pro-drug interacted with the DNA. Its metabolite(s) initially caused condensation of the double helix chains, followed by the unwinding of these chains. In addition, free guanine (Gua) was released from the dsDNA and oxidative damage to the DNA by the CCNU metabolite(s) was evidenced from the detection of 8-oxoGua and 2,8-oxoAde. These results were confirmed by the poly(dA)- and poly(dG)-polyhomonucleotide biosensors, which revealed the oxidative damage caused to both bases (guanine and adenine) of the dsDNA by the CCNU metabolite(s). The comet assay indicated breaks in the single strand DNA, complementing the results of the studies using differential pulse voltammetry. Conformational changes of dsDNA caused by CCNU and cdCCNU were confirmed using comet assays.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Roturas del ADN de Cadena Simple/efectos de los fármacos , ADN/efectos de los fármacos , Lomustina/farmacología , Antineoplásicos Alquilantes/química , Técnicas Biosensibles , ADN/química , Difusión , Estabilidad de Medicamentos , Técnicas Electroquímicas , Electrodos , Lomustina/química , Conformación de Ácido Nucleico/efectos de los fármacos , Agua
14.
Biochem Biophys Res Commun ; 367(1): 7-13, 2008 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-18162179

RESUMEN

Chemical modification of proteins is often carried out to generate protein-small molecule conjugates for various applications. The high resolution and mass accuracy of a Fourier transform mass spectrometer is particularly useful for assessing the extent or sites of covalent modifications. As protein-small molecule reactions often produce products with variable numbers of the compound incorporated at different sites, a direct mass analysis of the reaction products at times yields mass spectra hard to interpret. Chromatographic separation at protein level could reduce the complexity of a sample, thus allowing more accurate mass spectrometric analysis. In this report, we demonstrate the utility of reversed-phase protein chromatography and FT-ICR mass spectrometry in analyzing CCNU (lomustine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitroso-urea, MW: 233.7Da) modification of stathmin. With this combined approach, we determined the stoichiometry as well as sites of CCNU incorporation into the protein, demonstrating differential reactivity of several lysyl residues to CCNU alkylation.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Lomustina/farmacología , Espectrometría de Masas/métodos , Péptidos/análisis , Estatmina/metabolismo , Tripsina/análisis , Alquilación , Secuencia de Bases , Sitios de Unión , Cromatografía Líquida de Alta Presión/métodos , Humanos , Lisina/química , Lisina/metabolismo , Péptidos/química , Péptidos/metabolismo , Estatmina/química , Tripsina/química , Tripsina/metabolismo
15.
J Mol Neurosci ; 66(3): 383-389, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30284228

RESUMEN

Glioblastoma (GBM) is an incurable disease ranked among the deadliest solid cancers worldwide. A better understanding on the molecular aspects of this malignancy could contribute to the development of new treatment strategies and help to improve survival rates. Previously, our group had shown that GBM patients expressing the cancer/testis antigen Opa Interacting Protein 5 (OIP5) present a longer survival period than the OIP5-negative group. The main goal of this study was to evaluate the OIP5 contribution to GBM tumorigenesis and assess the role of OIP5 in GBM cell response to lomustine, an alkylating agent used in the treatment of this malignancy. So, the effect of OIP5 knockdown was evaluated in A172 and T98G GBM cell lines. Our results demonstrated that downregulation of the OIP5 stimulates glioma cell viability and inhibits cell death-induced necrosis prompted by lomustine. In conclusion, our data shows that OIP5 expression in GBM cells seems to be able to enhance lomustine cytotoxic effects, reinforcing that this gene is a potential therapeutic target and putative molecular biomarker for treatment response in GBM.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Proteínas Cromosómicas no Histona/genética , Resistencia a Antineoplásicos/genética , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/metabolismo , Humanos , Lomustina/farmacología
16.
Clin Transl Oncol ; 20(4): 508-516, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28825189

RESUMEN

PURPOSE: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. While the alkylating agent temozolomide (TMZ) has prolonged overall survival, resistance evolution represents an important clinical problem. Therefore, we studied the effectiveness of radiotherapy and CCNU in an in vitro model of acquired TMZ resistance. METHODS: We studied the MGMT-methylated GBM cell line U251 and its in vitro derived TMZ-resistant subline, U251/TMZ-R. Cytotoxicity of TMZ, CCNU, and radiation was tested. Both cell lines were analyzed for MGMT promotor status and expression of mismatch repair genes (MMR). The influence of MMR inhibition by cadmium chloride (CdCl2) on the effects of both drugs was evaluated. RESULTS: During the resistance evolution process in vitro, U251/TMZ-R developed MMR deficiency, but MGMT status did not change. U251/TMZ-R cells were more resistant to TMZ than parental U251 cells (cell viability: 92.0% in U251/TMZ-R/69.2% in U251; p = 0.032) yet more sensitive to CCNU (56.4%/80.8%; p = 0.023). The effectiveness of radiotherapy was not reduced in the TMZ-resistant cell line. Combination of CCNU and TMZ showed promising results for both cell lines and overcame resistance. CdCl2-induced MMR deficiency increased cytotoxicity of CCNU. CONCLUSION: Our results confirm MMR deficiency as a crucial process for resistance evolution to TMZ. MMR-deficient TMZ-resistant GBM cells were particularly sensitive to CCNU and to combined CCNU/TMZ. Effectiveness of radiotherapy was preserved in TMZ-resistant cells. Consequently, CCNU might be preferentially considered as a treatment option for recurrent MGMT-methylated GBM and may even be suitable for prevention of resistance evolution in primary treatment.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Reparación de la Incompatibilidad de ADN/fisiología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Glioblastoma/patología , Lomustina/farmacología , Línea Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Glioblastoma/genética , Humanos , Temozolomida
17.
Biosci Rep ; 38(4)2018 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-29789400

RESUMEN

Carnosic acid (CA), a major polyphenolic diterpene present in Rosmarinus officinalis, has been reported to have multiple functions, including antitumor activity. The MTT assay, BrdU incorporation, wound healing, and colony formation were used to detect melanoma B16F10 cell growth and proliferation. Flow cytometry was used for cell cycle detection. p21 and p27 expression was detected by Western blotting. B16F10 cell xenograft model was established, and treated with CA, carmustine (BCNU), or lomustine (CCNU). The present study found that CA exhibits significant growth inhibition and cell cycle arrest in melanoma B16F10 cells. We also found that CA triggers cell cycle arrest at G0/G1 phase, and enhances p21 expression. Additionally, CA can enhance BCNU- and CCNU-mediated cytotoxicity and cell cycle arrest in B16F10 cells. Finally, we found that CA inhibits tumor growth, and reduces the values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in vivo The present study study concluded that CA may be safe and useful as a novel chemotherapeutic agent.


Asunto(s)
Abietanos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Antioxidantes/uso terapéutico , Carmustina/uso terapéutico , Lomustina/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Abietanos/farmacología , Animales , Antineoplásicos Alquilantes/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Carmustina/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Lomustina/farmacología , Masculino , Melanoma Experimental/patología , Ratones Endogámicos C57BL
18.
Acta Pol Pharm ; 64(1): 27-33, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17665847

RESUMEN

Four new ethylnitrosourea derivatives of substituted naphthalimides 3a-d have been synthesized from the respective N-(2-ethylamino) naphthalimides. Their chemical alkylating activity compared with the clinical drug CCNU and an experimental compound Mitonafide indicated that they possess lower alkylating activity than CCNU and comparable activity with the latter. Their anti-tumor efficacies were assessed in vivo in two murine ascites tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. CCNU and Mitonafide were used as positive controls for comparison. The representative compound 3a has displayed marginal anti-tumoral activity in these tumors. Three compounds were further screened in vitro in 4 different human tumor cell lines but no significant activity was observed in those lines. These compounds moderately inhibit the synthesis of DNA and RNA in S-180 tumor cells.


Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Carcinoma de Ehrlich/tratamiento farmacológico , Naftalimidas/síntesis química , Compuestos de Nitrosourea/síntesis química , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacología , Línea Celular Tumoral , ADN/biosíntesis , ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidas/farmacología , Isoquinolinas/farmacología , Lomustina/farmacología , Ratones , Naftalimidas/química , Naftalimidas/farmacología , Compuestos de Nitrosourea/administración & dosificación , Compuestos de Nitrosourea/química , Compuestos de Nitrosourea/farmacología , ARN/biosíntesis , ARN/efectos de los fármacos , Relación Estructura-Actividad
19.
J Natl Cancer Inst ; 60(6): 1495-7, 1978 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-349171

RESUMEN

The nitrosourea derivatives 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU; NSC-95441), and 1-methyl-1-nitrosourea (MNU; NSC-23909) were screened for mutagenic potential with Salmonella typhimurium strains G46 and TA1530 in vitro and in vivo. Alu were also mutagenic in the host-mediated assay. Four additional chemotherapeutic nitrosoureas were tested in vitro, three of which were mutagenic. The lack of activity of the fourth agent was probably a reflection of its stability in solution rather than a true indication of mutagenic potential. All eight agents were tested in a repair test with S. typhimurium strains TA1978 and TA1538. Results of this test were negative, reflecting the insensitivity of these strains to ethylating and methylating agents. The insensitivity of the host-mediated assay is also discussed.


Asunto(s)
Mutágenos , Compuestos de Nitrosourea/farmacología , Salmonella typhimurium/efectos de los fármacos , Carmustina/farmacología , Lomustina/farmacología , Métodos , Metilnitrosourea/farmacología , Semustina/farmacología
20.
J Natl Cancer Inst ; 81(2): 146-52, 1989 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-2909755

RESUMEN

Antineoplastic drugs can be effective in solid tumors only if they can penetrate several cell layers and retain their activity in the tumor microenvironment. The capacity of several common chemotherapeutic agents to meet these requirements was evaluated in an in vitro tumor model, V79 Chinese hamster cells grown as spheroids. The delivery and toxicity of radioactively labeled 5-fluorouracil, lomustine, tetraplatin, and chlorambucil were determined by use of cell-sorting techniques to select cells as a function of their position (depth) within these spheroids, and the delivery and toxicity of doxorubicin (DOX) were evaluated on the basis of fluorescence intensity. Simultaneous measurement of drug level and toxicity in cells at the time of recovery from different depths within the spheroids led to the conclusion that drug delivery was a problem only for DOX. In contrast, several of the other agents showed a dissociation between cellular drug levels and activity, implicating a major role of the cellular microenvironment in modulating drug toxicity.


Asunto(s)
Antineoplásicos/farmacocinética , Animales , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cricetinae , Doxorrubicina/farmacología , Fluorouracilo/farmacocinética , Fluorouracilo/farmacología , Lomustina/farmacocinética , Lomustina/farmacología , Modelos Biológicos , Compuestos Organoplatinos/farmacocinética , Compuestos Organoplatinos/farmacología
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