Nevozhay Dmitry, Budzynska Renata, Kanska Urszula, Jagiello Monika, Omar Mohamed Salah, Boratynski Janusz, Opolski Adam
Laboratory of Experimental Anticancer Therapy, Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla st., 12, 53-114 Wroclaw, Poland.
Anticancer Res. 2006 Mar-Apr;26(2A):1135-43.
Methotrexate (MTX) is widely utilized in the clinical treatment of many forms of cancer. However, the drug has a short plasma half-life and causes toxic effects on normal proliferating cells. Conjugation with carriers is a possible way to alter these disadvantageous pharmacokinetics. Our aim was to synthesize dextran-MTX (D-MTX) conjugates, using carriers with molecular weights (Mw) ranging from 10 kDa to 500 kDa. Their in vitro and in vivo properties were compared with free MTX. The in vitro studies revealed that D-MTX conjugates had 4- to 10-fold lower antiproliferative effects against neoplastic cell lines compared to free MTX. There was a negative relationship between the Mw of the carrier and the antiproliferative effect of the respective conjugate. The data obtained in a mouse leukemia P388 in vivo model suggested that a lower in vitro antiproliferative effect of the conjugates does not result in diminished antileukemic activity in vivo. The toxicity of the conjugates was greater in comparison with the parent drug and tended to rise with increasing Mw. However, no superiority over free MTX in terms of an antileukemic effect was demonstrated. In particular, the D-MTX conjugate based on the dextran with Mw 10 kDa showed a comparable antileukemic effect with an even lower toxicity than that of free MTX. The data suggest that at least the toxicity of conjugates is dependent on the Mw of the carrier. This fact should be taken into account when designing new anticancer polymer-drug compounds.
甲氨蝶呤（MTX）广泛应用于多种癌症的临床治疗。然而，该药物的血浆半衰期较短，且会对正常增殖细胞产生毒性作用。与载体结合是改变这些不利药代动力学的一种可能方法。我们的目标是合成分子量（Mw）在10 kDa至500 kDa范围内的载体的葡聚糖-MTX（D-MTX）缀合物。将它们的体外和体内特性与游离MTX进行比较。体外研究表明，与游离MTX相比，D-MTX缀合物对肿瘤细胞系的抗增殖作用低4至10倍。载体的Mw与相应缀合物的抗增殖作用之间存在负相关关系。在小鼠白血病P388体内模型中获得的数据表明，缀合物较低的体外抗增殖作用并不会导致其体内抗白血病活性降低。与母体药物相比，缀合物的毒性更大，并且倾向于随着Mw的增加而升高。然而，在抗白血病作用方面未显示出优于游离MTX的效果。特别是，基于Mw为10 kDa的葡聚糖的D-MTX缀合物显示出相当的抗白血病作用，其毒性甚至比游离MTX更低。数据表明，至少缀合物的毒性取决于载体的Mw。在设计新的抗癌聚合物-药物化合物时应考虑这一事实。
