Rowland A J, Pietersz G A
Austin Research Institute, Austin Hospital, Heidelberg, Vic, Australia.
Cancer Immunol Immunother. 1994 Aug;39(2):135-9. doi: 10.1007/BF01525319.
Although aminopterin(AMN)-antibody drug conjugates have been demonstrated to have a greatly increased antitumor efficacy compared to the free drug, their use is limited by an increase in systemic toxicity manifested by weight loss and bone marrow suppression. Using a murine thymoma model (E3) in inbred mice, the toxicity of a sublethal dose of free AMN could be prevented by the administration of leucovorin 24 h following drug treatment, whilst maintaining the antitumour effect of the drug. The same rescue protocol completely abrogated the antitumour efficacy of AMN-antibody, although toxicity was also diminished. However, the later administration of leucovorin 48-72 h following a sublethal dose of AMN-antibody conjugates resulted in a maintenance of the anti-tumour efficacy of the immunoconjugates and a reduction in toxicity, with a mean percentage change in mouse weight not significantly different from that of the controls. These studies demonstrate that reversal of toxicity caused by AMN-antibody conjugates can be achieved by leucovorin while maintaining a powerful antitumour effect provided that the dose of leucovorin is administered 48-72 h after the conjugate.
尽管与游离药物相比，氨甲蝶呤（AMN）-抗体药物偶联物已被证明具有显著增强的抗肿瘤疗效，但其应用受到体重减轻和骨髓抑制所表现出的全身毒性增加的限制。在近交系小鼠中使用鼠胸腺瘤模型（E3），在药物治疗后24小时给予亚叶酸可以预防亚致死剂量游离AMN的毒性，同时维持药物的抗肿瘤效果。相同的挽救方案完全消除了AMN-抗体的抗肿瘤疗效，尽管毒性也有所降低。然而，在亚致死剂量的AMN-抗体偶联物给药后48-72小时给予亚叶酸，导致免疫偶联物的抗肿瘤疗效得以维持且毒性降低，小鼠体重的平均百分比变化与对照组无显著差异。这些研究表明，只要在偶联物给药后48-72小时给予亚叶酸剂量，亚叶酸就可以在维持强大抗肿瘤作用的同时实现AMN-抗体偶联物所致毒性的逆转。
