RESUMO
Hemorrhagic cystitis (HC) is the major dose-limiting adverse effect of the clinical use ifosfamide (IFOS). The incidence of this side effect can be as high as 75%. Mesna has been used to reduce the risk of HC, although 5% of patients who get IFOS treatment may still suffer from HC. In previous studies, our group demonstrated that α-phellandrene (α-PHE) possesses anti-inflammatory activity, which opens the door for its study in the attenuation of HC. The objective of this study was to investigate the potential uroprotective effect of the α-PHE in the mouse model of IFOS-induced HC. In order to analyze the reduction of the urothelial damage, the bladder wet weight, hemoglobin content, and the Evans blue dye extravasation from the bladder matrix were evaluated. To investigate the involvement of neutrophil migration and lipid peroxidation and involvement of enzymatic and endogenous non-enzymatic antioxidants, the tissue markers myeloperoxidase (MPO), malondialdehyde, nitrite/nitrate (NOx), superoxide dismutase (SOD), and reduced glutathione (GSH) were evaluated. TNF-α and IL-1ß were measured by ELISA immunoassay technique. The results show that pretreatment with α-PHE significantly reduced urothelial damage that was accompanied by a decrease in the activity of MPO, MDA, and NOx levels and prevention of the depletion of SOD and GSH in bladder tissues. In the assessment of cytokines, α-PHE was able to significantly reduce TNF-α level. However, it does not affect the activities of IL-1ß. These data confirm that α-PHE exerts potent anti-inflammatory properties and demonstrates that α-PHE represents a promising therapeutic option for this pathological condition.
Assuntos
Monoterpenos Cicloexânicos/uso terapêutico , Cistite/prevenção & controle , Hemorragia/prevenção & controle , Ifosfamida/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Alquilantes/toxicidade , Monoterpenos Cicloexânicos/farmacologia , Cistite/induzido quimicamente , Cistite/metabolismo , Relação Dose-Resposta a Droga , Hemorragia/induzido quimicamente , Hemorragia/metabolismo , Masculino , Camundongos , Estresse Oxidativo/fisiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy-induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma-bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1-transfected HEK293 (hTRPA1-HEK293) cells were used to evaluate the TRPA1-mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16-F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1-HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine-induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine-induced nociception in a tumor-associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy-induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Dacarbazina/toxicidade , Hiperalgesia/induzido quimicamente , Melanoma Experimental , Canal de Cátion TRPA1/efeitos dos fármacos , Animais , Células HEK293 , Humanos , Hiperalgesia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Canal de Cátion TRPA1/metabolismoRESUMO
Bendamustine, an anticancer drug with alkylating properties, is widely used to treat hematological malignancies. Since the nitrogen mustard family alkylators induce DNA damages and have been associated with an elevated risk of second malignancy, current study evaluates the cytotoxic, mutagenic, and recombinogenic effects of bendamustine by using, respectively the mitotic index assay, the in vitro mammalian cell micronucleus test (Mnvit) and the chromosome aberration (CA) test in human peripheral lymphocytes, and the in vivo homozygotization assay in Aspergillus nidulans, which detects the loss of heterozygosity (LOH) due to somatic recombination. Bendamustine (6.0 µg/ml, 9.0 µg/ml, and 12.0 µg/ml) induced a statistically significant concentration-related increase in the frequencies of micronuclei and a significant reduction in the cytokinesis block proliferation index (CBPI) rates when compared to negative control. In the CA test, bendamustine significantly increased the frequencies of structural aberrations at the three tested concentrations when compared to the negative control. Aspergillus nidulans diploids, obtained after bendamustine treatment (6.0 µg/ml, 12.0 µg/ml, and 24.0 µg/ml), produced, after haploidization, homozygotization index (HI) rates higher than 2.0 and significantly different from the negative control. Since bendamustine showed genotoxic effects in all tested concentrations, two of them corresponding to the peak plasma concentrations observed in cancer patients treated with bendamustine, data provided in the current research work may be useful to identify the most appropriate dosage regimen to achieve the efficacy and safety of this anticancer medication.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Aspergillus nidulans/efeitos dos fármacos , Cloridrato de Bendamustina/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Perda de Heterozigosidade/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Adolescente , Adulto , Aspergillus nidulans/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Linfócitos/patologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Adulto JovemRESUMO
Several different strategies have been adopted in attempt to recover from chemotherapy-damaged spermatogenesis that is often seen in oncologic patients. In this study, we have evaluated the impact of short period of exposure to busulphan on the haemogram and seminiferous epithelium of adult rats, focusing on spermatogonial depletion and Sertoli cell (SC) integrity. We then examined whether vitamin B12 supplementation improves the haematological parameters and spermatogonia number. The animals received 10 mg/kg of busulphan (BuG) or busulfan+vitamin B12 (Bu/B12 G) on the first and fourth days of treatment. In H.E.-stained testicular sections, the areas of the seminiferous tubule (ST) and seminiferous epithelium were measured. The number of spermatogonia in H.E-stained and PCNA-immunolabelled testicular sections was quantified. The frequency of tubules with abnormal SC nuclei or TUNEL-positive SC was evaluated. Vimentin immunofluorescence in ST was also evaluated. In BuG and Bu/B12 G, the animals showed leukopenia and thrombocytopenia, but the body weight reduced only in BuG. The areas of ST and seminiferous epithelium decreased in Bu/B12 G and BuG. In BuG, the number of H.E.-stained and PCNA-immunolabelled spermatogonia reduced significantly. The frequency of tubules containing abnormal SC nuclei and TUNEL-positive SC increased and the vimentin immunoexpression pattern changed. In Bu/B12 G, the number of H.E.-stained or PCNA-immunolabelled spermatogonia increased fourfold in comparison with BuG. The structural changes in ST after 6 days of busulphan exposure may be associated with the potential effect of this anti-neoplastic agent on SC. The increased number of spermatogonia in the busulphan-treated animals receiving vitamin B12 indicates that this vitamin can be an adjuvant therapy to improve the fertility in male cancer patients.
Assuntos
Células-Tronco Germinativas Adultas/efeitos dos fármacos , Antineoplásicos Alquilantes/toxicidade , Bussulfano/toxicidade , Epitélio Seminífero/efeitos dos fármacos , Vitamina B 12/farmacologia , Células-Tronco Germinativas Adultas/patologia , Animais , Peso Corporal/efeitos dos fármacos , Leucopenia/induzido quimicamente , Leucopenia/prevenção & controle , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Epitélio Seminífero/patologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/patologia , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/prevenção & controle , Vimentina/metabolismoRESUMO
BACKGROUND: Uterine carcinosarcoma is well known for its aggressive behavior. There is little evidence regarding the gold standard combination chemotherapy in metastatic or locally advanced carcinosarcoma, due to poor survival outcomes obtained with conventional scheduled chemotherapy. This case report represents the first-ever reported objective response to a metronomic chemotherapy regimen and adds to the current literature. CASE PRESENTATION: We describe a case of a Caucasian woman diagnosed with metastatic carcinosarcoma that had already been treated with multiple lines of conventional chemotherapy, with progressive disease. This patient had a surprising clinical and imaging response when treated with oral metronomic cyclophosphamide. CONCLUSIONS: We reviewed the mechanism of action implicated in metronomic chemotherapy, and correlated it with the biology of disease in carcinosarcoma. This information may add to the current literature, providing important insights to future clinical trials in this patient population.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinossarcoma/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Sarcoma do Estroma Endometrial/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Administração Metronômica , Antineoplásicos Alquilantes/toxicidade , Carcinossarcoma/patologia , Ciclofosfamida/toxicidade , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Peritoneais/secundário , Sarcoma do Estroma Endometrial/patologia , Resultado do Tratamento , Neoplasias Uterinas/psicologiaRESUMO
Busulfan is a chemotherapy drug that has side effects on spermatogonial stem cells (SSC). The effects of bulsufan treatment on male germ cells and fertility vary significantly between individuals. In this study, we have used molecular, cellular and histopathology approaches to investigate the effects of a single intraperitoneal dose of busulfan (40mgkg(-1)) in two mice strains, Balb/C and Swiss, at two different periods after treatment, 30 and 90 days. Testicular degeneration was observed in both Balb/C and Swiss mice after busulfan injection. Interestingly, testicular functions and fertility recovered spontaneously post busulfan treatment in Swiss mice, but not in Balb/C mice. Abnormal fertility induced by busulfan in Balb/C mice was associated with altered seminiferous tubules, sperm morphology and transcript levels of Nanos2, Nanos3, Gdnf and Plzf genes. These findings revealed that SSC of Balb/C mice are more sensitive to the toxic effects of busulfan then those of Swiss mice.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Bussulfano/toxicidade , Fertilidade/efeitos dos fármacos , Infertilidade Masculina/induzido quimicamente , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Forma Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Nascido Vivo , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Proteína com Dedos de Zinco da Leucemia Promielocítica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Especificidade da Espécie , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologiaRESUMO
La cardiotoxicidad por fármacos quimioterápicos es un efecto adverso frecuente y esperado. En este sentido se ha creado una especialización, la cardiooncología, que tiene como principal objetivo la prevención de estos efectos. La forma de expresión de este fenómeno es muy variada, pudiendo manifestarse como: insuficiencia cardíaca, hipertensión arterial, eventos coronarios agudos y/o trastornos del ritmo. La clave en la prevención está en la idividualización del riesgo cardiotóxico de cada paciente (en base a factores reconocidos como edad, sexo, irradiación mediastinal previa, tipo de fármaco, dosis acumulada, cardiopatía asociada previamente) y el riesgo potencial cardiotóxico de cada quimioterápico. En este sentido se han creado algoritmos de actuación fundamentados en la monitorización y el inicio de tratamiento precoz y oportuno de cada efecto, previniendo el mal mayor en cada paciente.
Assuntos
Humanos , Masculino , Feminino , Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Doenças Cardiovasculares/etiologia , Alquilantes , Anticorpos Monoclonais , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/toxicidade , Antineoplásicos/efeitos adversos , Antraciclinas/efeitos adversos , Antraciclinas/toxicidade , Fluoruracila/efeitos adversos , Fluoruracila/toxicidade , Inibidores de Proteínas Quinases , Toxoides/efeitos adversos , Toxoides/toxicidadeRESUMO
La cardiotoxicidad por fármacos quimioterápicos es un efecto adverso frecuente y esperado. En este sentido se ha creado una especialización, la cardiooncología, que tiene como principal objetivo la prevención de estos efectos. La forma de expresión de este fenómeno es muy variada, pudiendo manifestarse como: insuficiencia cardíaca, hipertensión arterial, eventos coronarios agudos y/o trastornos del ritmo. La clave en la prevención está en la idividualización del riesgo cardiotóxico de cada paciente (en base a factores reconocidos como edad, sexo, irradiación mediastinal previa, tipo de fármaco, dosis acumulada, cardiopatía asociada previamente) y el riesgo potencial cardiotóxico de cada quimioterápico. En este sentido se han creado algoritmos de actuación fundamentados en la monitorización y el inicio de tratamiento precoz y oportuno de cada efecto, previniendo el mal mayor en cada paciente.
Assuntos
Humanos , Masculino , Feminino , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Doenças Cardiovasculares/etiologia , Antineoplásicos/toxicidade , Anticorpos Monoclonais , Alquilantes , Inibidores de Proteínas Quinases , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/toxicidade , Antineoplásicos/efeitos adversos , Antraciclinas/efeitos adversos , Antraciclinas/toxicidade , Fluoruracila/efeitos adversos , Fluoruracila/toxicidade , Toxoides/efeitos adversos , Toxoides/toxicidadeRESUMO
Baccharin (3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid) is an important chemical compound isolated from the aerial parts of Baccharis dracunculifolia DC (Asteraceae), a native plant of South America, and the most important plant source of Brazilian green propolis. The present study was designed to investigate the ability of baccharin to modulate the genotoxic effects induced by doxorubicin and methyl methanesulphonate in male Swiss mice using the micronucleus and comet assays, respectively. The different doses of baccharin [0.12, 0.24 and 0.48 mg/kg body-weight (b.w.)] were administered simultaneously to doxorubicin (micronucleus test; 15 mg/kg b.w.) and to methyl methanesulphonate (comet assay; 40 mg/kg b.w.). The results showed a significant decrease in the frequency of micronucleated polychromatic erythrocytes in animals treated with baccharin and doxorubicin compared to animals that received only doxorubicin. This reduction ranged from 39.8% to 50.7% in the micronucleus test. The extent of DNA damage in liver cells was significantly lower in animals treated with different concentrations of baccharin combined with methyl methanesulphonate in comparison with the damage observed for animals treated only with methyl methanesulphonate. These differences resulted in a significant reduction in the extent of DNA damage, which ranged from 47.8% to 60.6%.
Assuntos
Antimutagênicos/farmacologia , Doxorrubicina/toxicidade , Metanossulfonato de Metila/toxicidade , Tricotecenos/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Antimutagênicos/administração & dosagem , Antimutagênicos/isolamento & purificação , Antineoplásicos Alquilantes/toxicidade , Baccharis/química , Brasil , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Testes para Micronúcleos , Mutagênicos/toxicidade , Componentes Aéreos da Planta , Tricotecenos/administração & dosagem , Tricotecenos/isolamento & purificaçãoRESUMO
PURPOSE: Ifosfamide (IFS) is often involved in the occurrence of hemorrhagic cystitis due to direct contact of its metabolite acrolein with uroepithelium. It has been shown that COX-2 is involved in this pathogenesis. Thus, we aimed to study the functional changes on the urinary bladder in the putative modifications induced by IFS, as well as the COX-2 role in this process. MATERIALS AND METHODS: IFS-treated rats were evaluated by cystometrography in absence or presence of COX inhibitors indomethacin or etoricoxib or in the presence of mesna. Experiments with isolated strips of urinary bladder obtained from animals with IFS-induced cystitis, either treated or not treated with COX inhibitors or mesna, were performed. Histological analyses, immunohistochemistry for COX-2, and measurement of plasma PGE(2) were also performed. RESULTS: IFS treatment caused severe inflammation of the bladder tissue. Cystometrography recordings of IFS-treated rats revealed bladder with increased micturition frequency and enhanced filling intravesical pressure. Contractility of the isolated smooth muscle from the rat's bladder with IFS-induced cystitis showed decreased force development in response to KCl and CCh. Almost all effects induced by IFS were ameliorated by the use of COX inhibitors or mesna. Enzyme expression in the urinary bladder tissue was positive, and plasma concentration of PGE(2) was increased in IFS-treated animals and decreased significantly in etoricoxib-treated animals. CONCLUSIONS: IFS causes important changes in the micturition physiology in rats, and the inhibition of the isoenzyme COX-2 could be an important event that could prevent the detrimental effects elicited by IFS-induced hemorrhagic cystitis.