Departamento do Farmacologia, Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM), Rua 3 de maio 100, Ed. INFAR, 3rd Floor, São Paulo, CEP 04044-020, Brazil.
Departamento de Patologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil.
Amino Acids. 2018 Feb;50(2):267-278. doi: 10.1007/s00726-017-2513-3. Epub 2017 Dec 12.
The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions, herein, we evaluated the antitumor effect of this native polypeptide employing the oral route. The efficacy of crotamine in inhibiting the melanoma growth in vivo, even after passing through the gastrointestinal tract of the animal, was confirmed here. In addition, biochemical biomarkers and also histopathological analysis showed both the absence of any potential toxic effects in tissues or organs of the animal in which the highest accumulation of crotamine is expected. Interestingly, a reduction of weight gain was observed mainly in animals with tumor treated with crotamine by IP route, but not by oral administration. Albeit, oral administered crotamine was able to significantly decrease the body weight gain of healthy animals without tumor. Taking advantage of this same experimental animal models receiving crotamine by oral route, it was possible to show metabolic changes as the increased capacity of glucose clearance, which was accompanied by a reduction of the total cholesterol, and by increased high-density lipoprotein levels, both observed mainly in the absence of tumor. Triglycerides and low-density lipoprotein were also significantly decreased, but only in the absence of tumor. Taken together, these data suggest a clear trend for metabolic positive effects and mischaracterize unhealthy condition of animals, with or without tumors, treated with crotamine for 21 days. In addition, this study confirmed the efficacy of crotamine administered by oral route as antitumor agent, which besides the additional advantage of administration convenience and decreased risk of toxic effects, allowed the serendipitous observation of several positive metabolic effects on treated animals.
蛇毒肽的抗肿瘤功效最初是通过在患有黑色素瘤肿瘤的动物模型中每天腹腔内（IP）注射低剂量的这种毒素来证明的。在连续 21 天每天 IP 给予蛇毒肽后，还注意到肿瘤生长的显著抑制和荷瘤小鼠的寿命延长。然而，由于 IP 途径在临床条件下对治疗的接受程度有限，在此，我们评估了这种天然多肽通过口服途径的抗肿瘤作用。 在此证实了蛇毒肽即使在穿过动物的胃肠道后，在体内抑制黑色素瘤生长的功效。此外，生化生物标志物和组织病理学分析也表明，在预期蛇毒肽积累最高的动物的组织或器官中，不存在任何潜在的毒性作用。有趣的是，主要在接受 IP 途径给予蛇毒肽的荷瘤动物中观察到体重增加减少，但口服给予时则没有。尽管如此，口服给予的蛇毒肽能够显著降低无肿瘤的健康动物的体重增加。利用相同的经口给予蛇毒肽的实验动物模型，有可能显示出代谢变化，如葡萄糖清除能力增加，同时伴随着总胆固醇降低，高密度脂蛋白水平升高，这些变化主要在没有肿瘤的情况下观察到。甘油三酯和低密度脂蛋白也显著降低，但仅在没有肿瘤的情况下。总之，这些数据表明，在接受蛇毒肽治疗 21 天的动物中，存在明显的代谢积极影响的趋势，并使患有或不患有肿瘤的动物的不健康状况特征复杂化。此外，这项研究证实了口服给予蛇毒肽作为抗肿瘤剂的功效，除了给药方便和降低毒性作用风险的额外优势外，还允许对治疗动物进行一些积极代谢作用的偶然观察。
