Efeitos tóxicos da quimioterapia metronômica a base de ciclofosfamida ou metotrexato em ratos Wistar
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Data
2017-01-27
Autores
Correal Suárez, María Lucía [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A quimioterapia metronômica é uma estratégia de uso crescente em Medicina Veterinária, que emprega fármacos em baixas doses e por longos períodos de tempo para controlar o crescimento tumoral. Objetivou-se avaliar os efeitos tóxicos de dois quimioterápicos antineoplásicos em animais livres de tumores seguindo esquemas metronômicos, assim como os efeitos residuais uma vez que a terapia foi suspensa. Para tanto, foram empregados 54 ratos Wistar, divididos em 3 grupos de tratamento de 18 animais cada, que receberam doses baixas de ciclofosfamida (CPX), metotrexato (MTX) ou placebo (grupo controle, CTR), via oral, por meio de gavage, durante 45 dias. Os animais tiveram acompanhamento periódico para pesagem e monitoramento clínico e do consumo de alimento e água. Realizou-se eutanásia em seis animais de cada grupo aos 30 (M1), 45 (M2) e 60 dias (M3), para coleta de amostras para hemograma, bioquímica sérica, citologia de medula óssea e análise histopatológica de baço, fígado, rim, intestino, pulmão, coração, cérebro e artéria. Empregou-se o teste de Qui-quadrado para análise estatística das variáveis não paramêtricas e o teste T-student para amostras não pareadas ou uma ANOVA seguida de uma comparação múltipla de Tukey para as variáveis paramêtricas. Seis animais do grupo CPX morreram, portanto a terapia foi suspensa aos 30 dias de tratamento, mantendo o período de observação até 45 dias. Os animais tratados com CPX exibiram significativa redução de peso e do consumo de alimento e água (p<0,05), assim como múltiplas alterações clínicas com comprometimento respiratório e neuromuscular, principalmente, que persistiram após a suspensão do fármaco. Em M1, houve aumento significativo de neutrófilos e redução de leucócitos, linfócitos e albumina no sangue, assim como diminuição de linfócitos, plasmócitos e das populações eritroides maduras na medula óssea (p<0,05). Em M2, somente a redução de linfócitos e o aumento de neutrófilos persistiram de forma significativa, junto com a depleção de populações eritroides maduras (p<0,05). Os animais tratados com MTX mostraram sinais clínicos inespecíficos de leves a moderados. Estes animais em M1 exibiram aumento significativo de leucócitos no sangue e das populações mieloides imaturas na medula óssea (p<0,05), e para M3, significativo aumento de neutrófilos no sangue, e depleção das populações mieloides imaturas e linfócitos, com aumento das mieloides maduras (p<0,05). Na avaliação histopatológica, para ambos os fármacos, observou-se significativa hipocelularidade esplênica (p<0,05), alterações pulmonares, degeneração hidrópica hepatocelular, principalmente. As doses metronômicas de MTX e CPX causaram leve a moderada mielotoxicidade, junto com as consequências clínicas decorrentes da imunossupressão. Diferenças mínimas nas doses destes esquemas podem causar efeitos biológicos opostos, sugerindo uma estreita margem de segurança da quimioterapia metronômica, assim como possíveis efeitos residuais uma vez a terapia é suspensa. Sugere-se realizar novas pesquisas para estabelecer as doses metronômicas biologicamente ótimas conciliando efetividade e tolerância, de preferência na espécie alvo.
Metronomic chemotherapy is a growing strategy in veterinary medicine that uses low doses of antineoplastic drugs for sustained periods of time to control tumor growth. This work aimed to evaluate toxic effects of metronomic chemotherapy schemes in tumor-free animals, and residual toxicity once treatment was suspended. There were used 54 healthy Wistar rats, divided in 3 groups (18 animals each), that received low-doses of cyclophosphamide (CPX), methotrexate (MTX) or placebo (control group, CTR) by oral gavage during 45 days. Clinical alterations, body weight, water and food intake were monitored periodically. Euthanasia was practiced within 6 animals from each group at 30 (M1), 45 (M2) and 60 days (M3) to perform hematological, biochemical and histopathologic analysis (spleen, liver, kidney, gut, lung, heart, brain and artery), and bone marrow cytology. An unpaired T-student test or a one-way ANOVA in conjunction with a Tukey multiple comparison test were done to analyze parametrical data, as a Chi-square test for semi-quantitative parameters. Six animals treated with CPX died and therapy was suspended at 30 days, within 15 days of observation after withdrawal. CPX treated animals exhibited significant reduction of weight gain, water and food intake (p<0.05), and clinical alterations related to respiratory and neuromuscular involvement, which even persisted after CPX withdrawal. At M1, significant neutrophil augmentation and reduction of leukocytes, lymphocytes and albumin was predominant in blood, as bone marrow reduction of lymphocytes, plasmatic cells and mature erythroid populations were significantly prevalent (p<0.05). At M2, only higher neutrophils count and reduction of lymphocytes persisted, as depletion of mature erythroid populations (p<0.05). MTX treated animals only evidenced mild to moderate unspecific clinical signs. At M1, MTX treated showed significant leukocytosis and augmentation of immature myeloid populations from bone marrow (p<0.05), as well as, significant neutrophils augment in blood, depletion of lymphocytes and immature myeloid cells, with high mature myeloid populations in bone marrow (p<0.05) at M3. At histopathological level, both treatment groups mainly evidenced significant reduction of splenic cellularity (p<0.05); pulmonary compromise; and hepatocellular hydropic degeneration. Metronomic doses of CPX and MTX caused mild to moderate myelotoxicity, with immune suppression and associated clinical signs. Slight differences within metronomic doses can result in opposite biological effects, which suggest that metronomic chemotherapy has narrow margins of safety, and that residual effects may even persist after treatment withdrawal. More research is encouraged to establish optimal biological doses, effective and tolerable, for metronomic schedules and within target species.
Metronomic chemotherapy is a growing strategy in veterinary medicine that uses low doses of antineoplastic drugs for sustained periods of time to control tumor growth. This work aimed to evaluate toxic effects of metronomic chemotherapy schemes in tumor-free animals, and residual toxicity once treatment was suspended. There were used 54 healthy Wistar rats, divided in 3 groups (18 animals each), that received low-doses of cyclophosphamide (CPX), methotrexate (MTX) or placebo (control group, CTR) by oral gavage during 45 days. Clinical alterations, body weight, water and food intake were monitored periodically. Euthanasia was practiced within 6 animals from each group at 30 (M1), 45 (M2) and 60 days (M3) to perform hematological, biochemical and histopathologic analysis (spleen, liver, kidney, gut, lung, heart, brain and artery), and bone marrow cytology. An unpaired T-student test or a one-way ANOVA in conjunction with a Tukey multiple comparison test were done to analyze parametrical data, as a Chi-square test for semi-quantitative parameters. Six animals treated with CPX died and therapy was suspended at 30 days, within 15 days of observation after withdrawal. CPX treated animals exhibited significant reduction of weight gain, water and food intake (p<0.05), and clinical alterations related to respiratory and neuromuscular involvement, which even persisted after CPX withdrawal. At M1, significant neutrophil augmentation and reduction of leukocytes, lymphocytes and albumin was predominant in blood, as bone marrow reduction of lymphocytes, plasmatic cells and mature erythroid populations were significantly prevalent (p<0.05). At M2, only higher neutrophils count and reduction of lymphocytes persisted, as depletion of mature erythroid populations (p<0.05). MTX treated animals only evidenced mild to moderate unspecific clinical signs. At M1, MTX treated showed significant leukocytosis and augmentation of immature myeloid populations from bone marrow (p<0.05), as well as, significant neutrophils augment in blood, depletion of lymphocytes and immature myeloid cells, with high mature myeloid populations in bone marrow (p<0.05) at M3. At histopathological level, both treatment groups mainly evidenced significant reduction of splenic cellularity (p<0.05); pulmonary compromise; and hepatocellular hydropic degeneration. Metronomic doses of CPX and MTX caused mild to moderate myelotoxicity, with immune suppression and associated clinical signs. Slight differences within metronomic doses can result in opposite biological effects, which suggest that metronomic chemotherapy has narrow margins of safety, and that residual effects may even persist after treatment withdrawal. More research is encouraged to establish optimal biological doses, effective and tolerable, for metronomic schedules and within target species.
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Palavras-chave
Baixa dose, Câncer, Imunossupressão, Quimioterápico, Toxicidade, Cancer, Chemotherapeutical, Immune suppression, Low-dose, Toxicity, Cáncer, Quimioterapéutico, Inmunosupresión, Dosis baja