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1.
Toxicol Pathol ; 34(3): 223-31, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16698718

RESUMO

Species and sex differences in susceptibility to vincristine sulphate (VCR)-induced olfactory epithelial lesions were investigated among the BALB/c mice, Crj: CD(SD) IGS rats and common marmoset monkeys following a single intravenous administration on day 1. As dosage levels, the 0.17-fold LD10, 0.6-fold LD10 and LD10 were used for mice and rats, and a maximum tolerated dose (MTD) was chosen only for monkeys. The order of strength of VCR action on peripheral neuropathic signs, body weight gain, and hematological parameters was mice > rats > monkeys, without clear sex differences. Histopathologically, on day 2, single cell death in the olfactory epithelium and vomeronasal organ was observed only in male mice at LD10, and in female mice at 0.6-fold LD10 or more. On day 5, the olfactory epithelium in these mice showed regenerative proliferation suggesting a sign of recovery. On day 10, axonopathy and demyelination in the sciatic and trigeminal nerves were noted in mice of both sexes at 0.6-fold LD10 or more. In rats and monkeys of either sex, however, no morphological changes were observed at any dose level. In conclusion, mice, particularly females, were shown to be more susceptible to VCR-induced apoptosis in the olfactory epithelium than rats and monkeys.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Mucosa Olfatória/efeitos dos fármacos , Vincristina/toxicidade , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Callithrix , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Relação Dose-Resposta a Droga , Feminino , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Queratinas/metabolismo , Dose Letal Mediana , Masculino , Dose Máxima Tolerável , Camundongos , Microscopia Eletrônica de Transmissão , Ratos , Neuropatia Ciática/induzido quimicamente , Neuropatia Ciática/patologia , Fatores Sexuais , Especificidade da Espécie , Doenças do Nervo Trigêmeo/induzido quimicamente , Doenças do Nervo Trigêmeo/patologia , Vincristina/administração & dosagem
2.
Toxicol Pathol ; 32(6): 701-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15580704

RESUMO

In order to examine and compare the potential toxicity in the olfactory epithelium, the antitumor drug vincristine sulfate (VCR), vinblastine sulfate(VBL), vindesine sulfate (VDS), paclitaxel (PTX), mitomycin C (MMC), 5-fluorouracil, (5-FU) or cisplatin (CDDP) was intravenously injected once(designated as day 1) at an estimated 10% lethal dose (LD(10)) to male BALB/c mice. The animals were necropsied on days 2, 5 and 15, and nasal tissues were examined by light-microscopy, counting of epithelial cells positive for terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL), immunohistochemical staining with keratin antibody, and electron microscopy. Further, to delineate the drug disposition in the target organ, whole-body radioluminography was performed 1 hour and 24 hours after treatment with the LD(10) of PTX or 5-FU. Of the antitumor drugs employed, only the antimicrotubule agents, VCR, VBL, VDS, and PTX, induced single cell death in the olfactory epithelium, especially sensory cells on day 2, atrophy of the olfactory epithelium on day 5, and myelin fragmentation in the trigeminal nerve on day 15. PTX induced the strongest changes among the 4 antimicrotubule agents. The cell death was confirmed to be apoptosis by TUNEL assay and electron microscopy, whereas the change in horizontal basal cells of the olfactory epithelium was shown not to be apoptosis by keratin staining. In quantitative radioluminography,radioactivity of PTX in the nasal tissues both 1 hour and 24 hours after administration was about 4- or 5-fold higher than those of 5-FU. These results suggest that tubulin-targeting antitumour drugs could induce apoptosis in the olfactory epithelial cells of mice and that high drug distribution may effect the onset of the olfactory lesions.


Assuntos
Antineoplásicos/toxicidade , Mucosa Olfatória/efeitos dos fármacos , Animais , Autorradiografia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Queratinas/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitomicina/toxicidade , Mucosa Olfatória/patologia , Mucosa Olfatória/ultraestrutura , Paclitaxel/toxicidade , Vimblastina/toxicidade , Vincristina/toxicidade , Vindesina/toxicidade
4.
Toxicol Pathol ; 30(3): 306-11, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12051547

RESUMO

To delineate morphological characteristics of olfactory lesions induced by vincristine (VCR), a vinca alkaloid derivative with antitumor activity, male BALB/c mice were given a single intravenous injection of 1.95 mg/kg, an estimated 10% lethal dose (designated as day 1). The animals were serially sacrificed on days 2, 3, 5, 10, 15 and 60, and the nasal mucosa was examined histopathologically. Cell death was noted in the olfactory epithelia adjacent to the respiratory epithelia from days 2 to 5. Inflammatory responses were not detected throughout the observation periods. Cell death was identified as apoptotic by the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay and electron microscopy. Mitotic figures and proliferating cell nuclear antigen (PCNA)-positive reactions were diffusely scattered in both the basal and sensory cells. On days 10 or after, no prominent histological abnormalities were noted in the olfactory epithelia, which suggests the aforementioned lesions were completely recovered. These results demonstrate that it is essential to perform histopathological evaluation of the nasal mucosa during an early preclinical stage for novel antitumor drugs, since olfactory lesions due to the certain compounds like VCR may not be detected by any other procedure.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Apoptose/efeitos dos fármacos , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/ultraestrutura , Vincristina/efeitos adversos , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Antígeno Nuclear de Célula em Proliferação/metabolismo , Vincristina/administração & dosagem
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