Ghyka G, Haraga L
Arch Roum Pathol Exp Microbiol. 1989 Jan-Mar;48(1):33-45.
An experimental model evaluating comparatively the antineoplastic and the immunosuppressive effects of some cytostatics (cyclophosphamide and vinblastine) is described in the present paper. Different cytostatic doses were intraperitoneally administered in mice which were 24 hours later grafted with a suspension of human tumoral KB cells. The xenograft acceptance was macroscopically and microscopically recorded 21 days later. By the Reed and Muench method and also by graphical extrapolation the LD50 (lethal dose for 50% animals) and the TD50 (the immunosuppressive dose enabling 50% animals to accept the xenografts) could thus be determined for both cyclophosphamide and vinblastine. The number (percent) of the tumour bearing animals three weeks after grafting was considered as an indicator of the cytostatic dose at which the immunosuppressive effect exceeded the antineoplastic effect. The in vitro effect of the same drugs on the KB cells was tested by inoculating different cytostatic doses in the cell cultures and counting at different time intervals the adherent as well as the nonadherent cells. The in vitro drug toxicity on the KB cell cultures was also determined by the trypan blue exclusion test. Both cyclophosphamide and vinblastine proved to be in vitro highly potent cytostatics i.e. when directly acting on the KB cells. This effect was dose correlated for both the considered drugs. However our in vivo experiments have shown that none of the observed effects when considering the direct action of the cytostatic on the cultured cells could not safely be extrapolated in vivo. Our results have an obvious practical importance when considering the therapeutical approaches in the neoplastic diseases. They demonstrate that the increase in cytostatic dose is not directly correlated to the antineoplastic effect since it reaches a limit at which the immunosuppressive effect highly exceed the tumour growth inhibition effect. The described experimental model could also be used in comparative estimations of the biological effects of different cytostatic drugs possibly referred to a standard immunosuppressive reagent as an antilymphocyte antiserum.
本文描述了一个实验模型，用于比较某些细胞抑制剂（环磷酰胺和长春碱）的抗肿瘤和免疫抑制作用。向小鼠腹腔注射不同剂量的细胞抑制剂，24小时后给小鼠接种人肿瘤KB细胞悬液。21天后，通过宏观和微观观察记录异种移植的接受情况。通过里德-孟奇法以及图形外推法，可以确定环磷酰胺和长春碱的半数致死剂量（LD50，即导致50%动物死亡的剂量）和半数治疗剂量（TD50，即使50%动物能够接受异种移植的免疫抑制剂量）。将移植三周后携带肿瘤的动物数量（百分比）作为细胞抑制剂剂量的指标，此时免疫抑制作用超过抗肿瘤作用。通过在细胞培养物中接种不同剂量的细胞抑制剂，并在不同时间间隔对贴壁和未贴壁细胞进行计数，测试相同药物对KB细胞的体外作用。还通过台盼蓝排斥试验测定了KB细胞培养物中药物的体外毒性。环磷酰胺和长春碱在体外均被证明是高效的细胞抑制剂，即直接作用于KB细胞时。这种作用与所考虑的两种药物的剂量相关。然而，我们的体内实验表明，当考虑细胞抑制剂对培养细胞的直接作用时，所观察到的任何效应都不能安全地外推到体内。当考虑肿瘤疾病的治疗方法时我们的结果具有明显的实际重要性。结果表明，细胞抑制剂剂量的增加与抗肿瘤作用并不直接相关，因为它达到了一个极限，此时免疫抑制作用远远超过肿瘤生长抑制作用。所描述的实验模型也可用于比较评估不同细胞抑制剂药物的生物学效应，可能以抗淋巴细胞抗血清等标准免疫抑制试剂作为参照。
