Feldman N B, Kiselev S M, Gukasova N V, Posypanova G A, Lutsenko S V, Severin S E
Moscow Research Institute of Medical Ecology, Moscow, 113149, Russia.
Biochemistry (Mosc). 2000 Aug;65(8):967-71.
alpha-Fetoprotein (AFP) was conjugated with doxorubicin (DR) using glutaraldehyde as a cross-linking agent. The protein/DR molar ratio in the conjugate is 1 : 2. Cytotoxic activities (CTA) of the AFP-DR conjugate and of the free DR were compared using human mammary gland carcinoma cells, both DR-sensitive (MCF-7Wt) and DR-resistant (MCF-7AdrR). The CTA of the AFP-DR conjugate was fivefold higher than the CTA of the free DR for sensitive cells of the MCF-7Wt line and sevenfold higher for resistant cells of the MCF-7AdrR line. The CTA of the AFP-DR conjugate was also studied in vitro using the proliferating endothelium taken for a model of endothelial cell lining of blood vessels that supply the tumor. The AFP-DR conjugate was shown to have a high CTA for the endothelial cells (IC50 = 2.5 nM); thus, the conjugate is suggested to manifest an anti-angiogenic effect in vivo. The antitumor activity of the AFP-DR conjugate was studied using mice with inoculated melanoma B16 tumors. The treatment of animals significantly inhibited the tumor growth (>97%) and increased by 60% the mean life span of the animals compared to the control. The high antitumor efficiency of the AFP-DR conjugate and the possibility to significantly decrease the tumor cell resistance to DR make this conjugate a promising chemotherapeutic agent.
使用戊二醛作为交联剂，将甲胎蛋白（AFP）与阿霉素（DR）偶联。偶联物中蛋白质/DR的摩尔比为1:2。使用人乳腺癌细胞，包括对DR敏感的（MCF-7Wt）和对DR耐药的（MCF-7AdrR），比较了AFP-DR偶联物和游离DR的细胞毒性活性（CTA）。对于MCF-7Wt系的敏感细胞，AFP-DR偶联物的CTA比游离DR的CTA高5倍；对于MCF-7AdrR系的耐药细胞，高7倍。还使用取自供应肿瘤的血管内皮细胞衬里模型的增殖内皮细胞，在体外研究了AFP-DR偶联物的CTA。结果表明，AFP-DR偶联物对内皮细胞具有高CTA（IC50 = 2.5 nM）；因此，提示该偶联物在体内表现出抗血管生成作用。使用接种了黑色素瘤B16肿瘤的小鼠研究了AFP-DR偶联物的抗肿瘤活性。与对照组相比，动物治疗显著抑制了肿瘤生长（>97%），并使动物的平均寿命延长了60%。AFP-DR偶联物的高抗肿瘤效率以及显著降低肿瘤细胞对DR耐药性的可能性，使该偶联物成为一种有前景的化疗药物。
