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1.
East Mediterr Health J ; 25(7): 481-494, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31612980

RESUMO

Background: For metastatic colorectal cancer a series of novel therapies has emerged during the last decade but their use in routine clinical practice and their costs are not well documented. Aims: This study evaluated the clinical effectiveness of metastatic colorectal cancer patients in Lebanese oncologic units and estimated the costs. Methods: A prospective cohort study was conducted on metastatic colorectal cancer patients during 2008-2013. The type of medical management, overall survival and total costs from diagnosis to death were described. Cost analysis was performed using tariffs from 2013 in US dollars. Results: One hundred and seventy-nine metastatic patients were selected among which 84.9% had colorectal cancer involvement. The average follow-up from diagnosis until death or the latest news was 34.8 months. Around 49.7% were still alive at last follow-up date. Three lines of treatment accounted for 4.5%, 39.6% and 55.9% with an average duration of 14.5, 11.4 and 14.6 months respectively. A 73.2% of patients benefited from targeted therapy. The median overall survival was 20.8 months. The mean total costs of drugs was $22 256 in patients with standard therapy alone whereas the cost increased to $80 396 after the addition of targeted therapy. The mean global total cost was estimated at $64 805 per patient (min $3703; max $304 086). Conclusions: Targeted therapy associated to standard therapy is highly prevalent in Lebanon in metastatic disease and the associated medical cost substantial. This study is the first to show the clinical effectiveness and costs of targeted therapy in patients with metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Produtos Biológicos/economia , Produtos Biológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Custos e Análise de Custo , Feminino , Humanos , Líbano , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Nitrosoureia , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
CNS Oncol ; 8(2): CNS32, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31290692

RESUMO

Aim: To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3-4 hematological toxicities occurred. Conclusion: The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/efeitos adversos , Medição de Risco , Taxa de Sobrevida
3.
DNA Repair (Amst) ; 78: 128-141, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31039537

RESUMO

Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged unselectively, they exert tumor-specific killing effects because of downregulation of some DNA repair activities in cancer cells. Agents exhibiting methylating properties (temozolomide, procarbazine, dacarbazine, streptozotocine) induce at least 12 different DNA lesions. These are repaired by damage reversal mechanisms involving the alkyltransferase MGMT and the alkB homologous protein ALKBH2, and through base excision repair (BER). There is a strong correlation between the MGMT expression level and therapeutic response in high-grade malignant glioma, supporting the notion that O6-methylguanine and, for nitrosoureas, O6-chloroethylguanine are the most relevant toxic damages at therapeutically relevant doses. Since MGMT has a significant impact on the outcome of anti-cancer therapy, it is a predictive marker of the effectiveness of methylating anticancer drugs, and clinical trials are underway aimed at assessing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair, DNA double-strand break (DSB) repair by homologous recombination (HR) and DSB signaling. Base excision repair and ALKBH2 might also contribute to alkylating drug resistance and their downregulation may have an impact on drug sensitivity notably in cells expressing a high amount of MGMT and at high doses of temozolomide, but the importance in a therapeutic setting remains to be shown. MGMT is frequently downregulated in cancer cells (up to 40% in glioblastomas), which is due to CpG promoter methylation. Astrocytoma (grade III) are frequently mutated in isocitrate dehydrogenase (IDH1). These tumors show a surprisingly good therapeutic response. IDH1 mutation has an impact on ALKBH2 activity thus influencing DNA repair. A master switch between survival and death is p53, which often retains transactivation activity (wildtype) in malignant glioma. The role of p53 in regulating survival via DNA repair and the routes of death are discussed and conclusions as to cancer therapeutic options were drawn.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Reparo do DNA/efeitos dos fármacos , Compostos de Nitrosoureia/farmacologia , Medicina de Precisão/métodos , Temozolomida/farmacologia , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Humanos , Compostos de Nitrosoureia/uso terapêutico , Temozolomida/uso terapêutico
4.
Nature ; 566(7742): 94-99, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728519

RESUMO

Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens1,2 and important cancer chemotherapeutics3,4. Despite the considerable importance of this functional group to human health, enzymes dedicated to the assembly of the N-nitroso unit have not been identified. Here we show that SznF, a metalloenzyme from the biosynthesis of streptozotocin, catalyses an oxidative rearrangement of the guanidine group of Nω-methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF reveal two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. This biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-haem-iron-dependent enzymes to include N-N bond formation. We find that biosynthetic gene clusters that encode SznF homologues are widely distributed among bacteria-including environmental organisms, plant symbionts and human pathogens-which suggests an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites.


Assuntos
Metaloproteínas/metabolismo , Estreptozocina/biossíntese , Estreptozocina/química , Arginina/análogos & derivados , Domínio Catalítico/genética , Coenzimas/metabolismo , Cristalografia por Raios X , Guanidina/metabolismo , Ferro/metabolismo , Metaloproteínas/química , Metaloproteínas/genética , Modelos Moleculares , Família Multigênica , Compostos de Nitrosoureia/metabolismo , Streptomyces/enzimologia , Streptomyces/genética
5.
Bull Exp Biol Med ; 166(4): 456-460, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30810868

RESUMO

We performed an in vivo comparative study of activity of three substances of the nitrosourea group produced in Russia. All substances demonstrated high antitumor activity against various solid and leukemic tumors. Aranosa significantly enhanced life duration in mice with leukemia (by 65-194%) and inhibited the growth of solid tumors (by 49-99.6%). Lisomustine and ormustine showed higher activity than aranose. Single administration of lisomustine increased life span of mice (by 22-114%) and resulted in cure of all animals in four models: lymphoblastic leukemia L-1210, lymphocytic leukemia P-388, Lewis lung carcinoma, and cervical cancer RShM-5. After ormustine treatment, full recovery was observed only in groups with lymphocytic leukemia P-388 and cervical cancer RShM-5. These findings attest to higher activity of lisomustine in the studied models.


Assuntos
Antineoplásicos/uso terapêutico , Compostos de Nitrosoureia/uso terapêutico , Animais , Feminino , Leucemia L1210/tratamento farmacológico , Leucemia P388/tratamento farmacológico , Masculino , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Federação Russa , Resultado do Tratamento , Neoplasias do Colo do Útero/tratamento farmacológico
6.
J Neurooncol ; 140(2): 427-434, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30109672

RESUMO

OBJECTIVE: This prospective, randomized, controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen (fotemustine, teniposide and dexamethasone) compared to HD-MA therapy (high-dose methotrexate plus cytarabine) and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma. METHODS: Participants were stratified by IELSG risk score (low versus intermediate versus high) and randomly assigned (1:1) to receive four cycles of FTD or HD-MA regimen. Both regimens were administered every 3 weeks and were followed by whole-brain radiotherapy. The primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Between June 2012, and June 2015, 52 patients were enrolled, of whom 49 patients were randomly assigned and analyzed. Of the 49 eligible patients, no significant difference was observed in terms of ORR between FTD (n = 24) and HD-MA (n = 25) groups (88% versus 84%, respectively, P = 0.628). Neither the 2-year PFS nor the 3-year OS rate differed significantly between FTD and HD-MA groups (37% versus 39% for 2-year PFS, P = 0.984; 51% versus 46% for 3-year OS, P = 0.509; respectively). The HD-MA group showed more serious neutropenia (P = 0.009) than the FTD group. High Bcl-6 expression correlated with longer OS (P = 0.038). CONCLUSIONS: FTD chemotherapy appeared to be safe and effective for PCNSL patients. High Bcl-6 expression correlated with longer survival.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Humanos , Linfoma/metabolismo , Linfoma/mortalidade , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Teniposídeo/administração & dosagem , Teniposídeo/efeitos adversos , Resultado do Tratamento , Adulto Jovem
7.
Medicine (Baltimore) ; 97(27): e11254, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29979390

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. METHODS: In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24). RESULTS: Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m dose level and in 3 of 31 patients treated at 120 mg/m. Median PFS and overall survival were 12.1 (1-40.2) weeks and 19.7 (1-102) weeks, respectively. CONCLUSION: We conclude that fotemustine can be safely administered at 120 mg/m biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg and the standard weekly schedule at 80 to 100 mg/m.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Trombocitopenia/induzido quimicamente , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Glioblastoma/epidemiologia , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Temozolomida , Trombocitopenia/classificação
8.
Int J Hematol ; 108(5): 510-515, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30043334

RESUMO

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.


Assuntos
Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Compostos de Nitrosoureia/administração & dosagem , Transplante de Células-Tronco , Adulto , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/efeitos adversos , Estudos Prospectivos , Taxa de Sobrevida
9.
Artigo em Inglês | MEDLINE | ID: mdl-29875078

RESUMO

The mutagenic potencies of 1,3-propane sultone (PS), N-propyl-N-nitrosourea (PNU), and mitomycin C (MMC) were investigated in three independent laboratories in Korea using the Pig-a assay in vivo. Sprague-Dawley rats were treated with vehicle or test substance on three consecutive days. Blood samples were collected for measuring Pig-a mutant phenotypes (CD59-deficient erythrocytes, RBCCD59-; CD59-deficient reticulocytes, RETCD59-) on days -1, 15, and 29 after the first treatment. In some studies, blood was collected for determining DNA damage (comet assay) on day 3 and measuring micronucleated reticulocytes (MN-RET) on day 4. Treatment with the alkylating agents PS and PNU induced dose-dependent increases in the frequency of RBCCD59- on days 15 and 29, and caused maximum elevations in the frequency of RETCD59- on day 15. Inter-laboratory comparison of the day 29 Pig-a assay data confirmed the mutagenic potencies of PS and PNU, and showed good agreement among the test sites. Treatment with the DNA cross-linker MMC induced increases in the frequencies of RBCCD59- and RETCD59- on days 15 and 29 (all three laboratories). MN-RETs increased significantly in animals treated with PS, PNU, or MMC, but biologically significant increases in DNA damage were observed only with PS and PNU, and not with MMC. The results of this study indicate that the Pig-a assay is a sensitive, reproducible method for evaluating the in vivo mutagenicity of various test substances, in particular, DNA cross-linkers and alkylating agents. Our limited data on integrating the Pig-a assay with the comet and micronucleus assays indicate that a short-term treatment protocol evaluating these three endpoints in a single set of animals may be a robust strategy for evaluating in vivo genotoxicity.


Assuntos
Laboratórios/normas , Proteínas de Membrana/genética , Mitomicina/toxicidade , Mutação , Compostos de Nitrosoureia/toxicidade , Reticulócitos/patologia , Tiofenos/toxicidade , Alquilantes/toxicidade , Animais , Reagentes para Ligações Cruzadas/toxicidade , Dano ao DNA , Masculino , Proteínas de Membrana/sangue , Testes de Mutagenicidade , Ratos , Ratos Sprague-Dawley , Reticulócitos/efeitos dos fármacos , Reticulócitos/metabolismo
10.
BMC Cancer ; 18(1): 552, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29747595

RESUMO

BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. METHODS: A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m2 on days 1 and 2 and FM iv 100 mg/m2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients. RESULTS: We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status. CONCLUSION: This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed. TRIAL REGISTRATION: EUDRACT 2009-016487-36l ; date of registration 23 June 2010.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Metilases de Modificação do DNA/antagonistas & inibidores , Enzimas Reparadoras do DNA/antagonistas & inibidores , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Compostos Organofosforados/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Temozolomida/administração & dosagem , Resultado do Tratamento , Proteínas Supressoras de Tumor/antagonistas & inibidores , Adulto Jovem
11.
Am J Clin Oncol ; 41(12): 1272-1275, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29782366

RESUMO

OBJECTIVES: Bevacizumab is an anti-vascular endothelial growth factor antibody used in the treatment of recurrent glioblastoma (GBM). Despite the large number of studies carried out in patients with recurrent GBM, little is known about the administration of this angiogenesis inhibitor after the failure of the second-line chemotherapy. MATERIALS AND METHODS: In this retrospective multicenter study, on behalf of the Italian Association of Neuro-Oncology, we reported the results obtained in 51 patients with recurrent GBM treated with single-agent bevacizumab after the failure of second-line chemotherapy with fotemustine. RESULTS: In March 2016, at the time of data analysis, 3 patients (14.4%) were still alive with stable disease, whereas 48 died due to disease progression. Kaplan-Meier estimated median survival from the diagnosis of GBM was 28 months (95% confidence interval [CI], 22.1-33.9 mo). Median survival measured from the beginning of fotemustine and bevacizumab therapy were 11.3 (95% CI, 8.4-13.6 mo) and 6 months (95% CI, 3.8-8.1 mo), respectively. The 6- and 12-month progression free survival rates from the beginning of bevacizumab treatment were 18% and 13%, respectively. CONCLUSIONS: On the basis of our data, in patients with recurrent GBM, the failure of a second-line chemotherapy with cytotoxic agents might not exclude the administration of bevacizumab as third-line chemotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Nitrosoureia/farmacologia , Compostos Organofosforados/farmacologia , Adolescente , Adulto , Idoso , Antineoplásicos/farmacologia , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Adulto Jovem
12.
Med Sci Monit Basic Res ; 24: 31-39, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29398693

RESUMO

BACKGROUND The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. MATERIAL AND METHODS We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. RESULTS Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=-0.73, P=0.003; r=-0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). CONCLUSIONS Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition-related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Fenômenos Fisiológicos da Nutrição , Transplante de Células-Tronco de Sangue Periférico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/uso terapêutico , Ciclofosfamida/uso terapêutico , Ingestão de Energia , Etoposídeo/uso terapêutico , Feminino , Humanos , Ifosfamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/uso terapêutico , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
13.
Mutat Res ; 773: 104-121, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28927522

RESUMO

Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects. Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved.


Assuntos
Efeito Espectador/efeitos dos fármacos , Efeito Espectador/efeitos da radiação , Animais , Linhagem Celular , Técnicas de Cocultura , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Humanos , Metais Pesados/toxicidade , Nanopartículas/toxicidade , Compostos de Nitrosoureia/toxicidade , Radiação Ionizante , Transdução de Sinais
14.
Bull Exp Biol Med ; 163(4): 469-474, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28853075

RESUMO

The toxic effects of combined cisplatin/docetaxel therapy cycles on erythroid and granulocytic hematopoietic lineages as well as their intercycle recovery were examined in patients with stage III-IV non-small-cell lung carcinoma. Responsiveness of the blood system to this therapy remained at a high level. Combined therapy pronouncedly activated the key elements of the erythroid and granulocytic hematopoietic lineages leading to accumulation of immature and mature myelokaryocytes in the bone marrow, enlargement of the medullary pool of mature neutrophils, and increase in the count of medullary erythroid and granulocytic precursor cells under conditions of their accelerated maturation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Granulócitos/metabolismo , Neoplasias Pulmonares/metabolismo , Antraciclinas/farmacologia , Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Cisplatino/farmacologia , Dissacarídeos/farmacologia , Docetaxel , Doxorrubicina/farmacologia , Eritropoese/efeitos dos fármacos , Granulócitos/citologia , Granulócitos/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Macrolídeos/farmacologia , Compostos de Nitrosoureia/farmacologia , Compostos Organoplatínicos/farmacologia , Taxoides/farmacologia
15.
Neuro Oncol ; 19(2): 145-146, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28391298
18.
Biochim Biophys Acta Rev Cancer ; 1868(1): 29-39, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28143714

RESUMO

Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O6-chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide.


Assuntos
Morte Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos de Nitrosoureia/farmacologia , Compostos de Nitrosoureia/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Replicação do DNA/efeitos dos fármacos , Humanos
19.
Redox Biol ; 11: 562-576, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28107677

RESUMO

Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKß inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKß inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKß inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKß inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKß inhibitors with nitrosoureas can be potentially exploited for melanoma therapy.


Assuntos
Morte Celular/efeitos dos fármacos , Quinase I-kappa B/genética , Melanoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Alquilantes/administração & dosagem , Animais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Humanos , Quinase I-kappa B/antagonistas & inibidores , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Metástase Neoplásica , Compostos de Nitrosoureia/administração & dosagem , Tiofenos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Neuro Oncol ; 19(2): 252-258, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27994066

RESUMO

Background: The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Methods: Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Results: Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). Conclusions: RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Dacarbazina/análogos & derivados , Compostos de Nitrosoureia/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/metabolismo , Astrocitoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Temozolomida , Adulto Jovem
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