Institute of Bioengineering, Universidad Miguel Hernández, Elche, Spain and Centre for Network Biomedical Research (CIBER-BBN), Avenida de la Universidad s/n, 03202 Elche, Spain.
Instituto de Tecnología Química, Universitat Politècnica de València-Consejo Superior de Investigaciones Científicas, Avenida de los Naranjos s/n, 46022 Valencia, Spain.
Mol Pharm. 2021 Apr 5;18(4):1558-1572. doi: 10.1021/acs.molpharmaceut.0c00968. Epub 2021 Mar 1.
A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through and testing by using the prodrug camptothecin-20--(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.
一项针对多形性胶质母细胞瘤 (GBM) 治疗的新治疗方法已经通过使用前药喜树碱-20--(5-氨基乙酰丙酸) (CPT-ALA) 进行 和 测试得以实施。ALA 与 CPT 的结合可能会促进细胞毒性分子被Glioblastoma 细胞摄取，因为这些细胞中的血红素合成途径是活跃的，从而提高治疗效果并减少对健康组织的副作用。CPT-ALA 的抗肿瘤特性已在不同的 GBM 细胞系（U87、U251 和 C6）以及大鼠的原位 GBM 模型中进行了测试，分析了对中枢神经系统细胞的潜在毒性。 结果表明，CPT 和 CPT-ALA 对不同 GBM 细胞系的细胞毒性作用没有显著差异，尽管 CPT 对正常细胞系的细胞死亡率明显高于 CPT-ALA。此外，CPT-ALA 治疗 2 周后，大鼠颅内 GBM 明显减少（体积减少 30%），且无明显副作用，也未改变受试动物的健康状况。5-ALA 部分通过提高溶解度和基于代谢的靶向作用来增强 CPT 向肿瘤的扩散，从而增加 CPT 对恶性细胞的细胞毒性作用，同时减少 CPT 向其他增殖性健康组织的扩散。我们证明 CPT-ALA 可以阻止 GBM 细胞的增殖，降低 GBM 的浸润能力，并促进手术切除的成功，从而通过减少肿瘤复发来提高预期寿命。
