RESUMO
BACKGROUND: In a previous study, we found that amifostine provides some protection to the seminiferous epithelium of prepubertal doxorubicin-treated male rats but does not improve their fertility status as adults. Based on these results, a long-term study was undertaken to evaluate the DNA damage caused to spermatogonia and the consequences for embryo development. METHODS: Twenty-four male prepubertal rats (30-day-old) were divided into four equal groups and treated with: doxorubicin (D--5 mg/kg), amifostine (A--400 mg/kg), amifostine/doxorubicin (AD--amifostine 15 min before doxorubicin) and control (C--0.9% saline solution). Sixty-four days after the treatment, animals were euthanized and the testes and epididymides were excised. The testes were fixed in Bouin's solution and historesin-embedded for histopathological analysis. Spermatozoa from the cauda epididymides were collected for chromatin structure analyses (Comet Assay and SCSA™). Adult rats (100-day-old) were mated with fertile females for embryo analyses on 2.5, 4.5 and 20 days post-coitum (d.p.c.). RESULTS: The seminiferous epithelium histopathology of AD group was better preserved compared with the D group. On the other hand, rats from the D and AD groups presented an increased percentage of sperm DNA strand breaks, as assessed by the comet assay, as well as an increased level of sperm chromatin denaturation, as assessed by the SCSA™ assay. In amifostine-treated groups (A and AD) there was a significant increase in the number of arrested embryos, as observed by the number of oocytes/zygotes on 2.5 d.p.c., when compared with control and doxorubicin groups; however, this number was increased when the AD group was compared with the A group. CONCLUSIONS: These results raise a concern about the effects of the association of these two drugs on the germ cell genome. Amifostine-doxorubicin-exposed rat spermatogonia produced long-term damage on sperm DNA, compromised conceptus development and reduced pregnancy outcome.
Assuntos
Amifostina/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Espermatogônias/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/efeitos adversos , Cromatina/metabolismo , Ensaio Cometa , Implantação do Embrião/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Feminino , Masculino , Tamanho do Órgão , Gravidez , Prenhez , Protetores contra Radiação/efeitos adversos , Ratos , Ratos Wistar , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Fatores de TempoRESUMO
PURPOSE OF REVIEW: As part of the multidisciplinary approach to head and neck cancer patients, radiation therapy plays an essential role, improving locoregional control. Radiation therapy-induced xerostomia is a late side-effect that increases the risk for developing dental caries and compromises oral mucosal integrity, resulting in oral pain, loss of taste, difficulties with swallowing and chewing, sleep disorders and worse quality of life. This review focuses on evaluation, prevention and management of radiation therapy-induced xerostomia. RECENT FINDINGS: In terms of xerostomia prevention, some clinical trials evaluating amifostine and intensity-modulated radiation therapy have shown positive results. Pilocarpine is a useful agent as a treatment of radiation-induced xerostomia in head and neck cancer patients. SUMMARY: Despite some advances in radiation therapy-induced xerostomia prevention, its treatment is an area in which advances are urgently needed.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Lesões por Radiação/etiologia , Glândulas Salivares/efeitos da radiação , Xerostomia/etiologia , Amifostina/efeitos adversos , Amifostina/economia , Amifostina/uso terapêutico , Ensaios Clínicos como Assunto , Grânulos Citoplasmáticos/enzimologia , Grânulos Citoplasmáticos/metabolismo , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/economia , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Peroxidação de Lipídeos/efeitos da radiação , Parassimpatomiméticos/uso terapêutico , Pilocarpina/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/fisiopatologia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/efeitos adversos , Protetores contra Radiação/economia , Protetores contra Radiação/uso terapêutico , Radioterapia/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Glândulas Salivares/metabolismo , Xerostomia/tratamento farmacológico , Xerostomia/fisiopatologia , Xerostomia/prevenção & controleRESUMO
Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and to reduce tumor burden. We enrolled 29 patients, 22 (75. 9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin's lymphoma (NHL), who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients) affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0. 04). None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage) colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively). Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.