Takagaki M, Ono K, Oda Y, Kikuchi H, Nemoto H, Iwamoto S, Cai J, Yamamoto Y
Radiation Oncology Research Laboratory, Kyoto University, Osaka, Japan.
Cancer Res. 1996 May 1;56(9):2017-20.
Hydroxylforms of boronophenylalanine (BPA) were synthesized by conjugation with a cascade of polyols to decrease the BPA uptake of normal parenchyma without affecting uptake into the tumor. We determined their tumor cell killing effect on boron neutron capture therapy (BNCT) against BPA using the human glioma cell line T98G. The thermal neutron doses yielding the D37 (dose used to inhibit 63% colony formation) values of dl-p-BPA(OH)n were 1.45 x 10(12)nvt (n = 1), 1.33 x 10(12)nvt (n = 2), 3.37 x 10(12)nvt (n = 4), and 1.72 x 10(12)nvt (n = 0). The relative tumor cell killing effect on BNCT of dl-p-BPA(OH)n against dl-p-BPA, which was defined as the ratio of D37-BPA to D37-BPA(OH)n, was 1.18 (n = 1) 1.29 (n = 2), and 0.51 (n = 4). The tumor:normal brain ratio of dl-p-BPA(OH)n in 9L rat brain tumor models was improved 1.2- (n = 1) and 1.4-fold (n = 2) against that of dl-p-BPA without a decrease of its uptake into the tumor. The water solubility of BPA(OH)n increased against BPA, and the toxicity represented as the IC50 value of dl-p-BPA(OH)2 was nearly one half that of dl-p-BPA, being established in our previous works. Hydroxylforms of BPA, especially dl-p-BPA(OH)2, might be more suitable boron carriers of BNCT to malignant brain tumors since the radiation injury to the normal parenchyma surrounding the tumor is reduced.
通过与一系列多元醇共轭合成硼代苯丙氨酸（BPA）的羟基形式，以降低正常实质组织对BPA的摄取，同时不影响肿瘤对其的摄取。我们使用人胶质瘤细胞系T98G确定了它们在硼中子俘获疗法（BNCT）中对BPA的肿瘤细胞杀伤作用。产生dl-p-BPA(OH)n的D37（用于抑制63%集落形成的剂量）值的热中子剂量分别为1.45×10(12)nvt（n = 1）、1.33×10(12)nvt（n = 2）、3.37×10(12)nvt（n = 4）和1.72×10(12)nvt（n = 0）。dl-p-BPA(OH)n对dl-p-BPA在BNCT中的相对肿瘤细胞杀伤作用，定义为D37-BPA与D37-BPA(OH)n的比值，分别为1.18（n = 1）、1.29（n = 2）和0.51（n = 4）。在9L大鼠脑肿瘤模型中，dl-p-BPA(OH)n与dl-p-BPA相比，肿瘤与正常脑的比值提高了1.2倍（n = 1）和1.4倍（n = 2），且其在肿瘤中的摄取没有减少。BPA(OH)n的水溶性相对于BPA有所增加，如我们之前的研究所示，以dl-p-BPA(OH)2的IC50值表示的毒性几乎是dl-p-BPA的一半。BPA的羟基形式，尤其是dl-p-BPA(OH)2，可能是更适合用于恶性脑肿瘤BNCT的硼载体，因为它减少了对肿瘤周围正常实质组织的辐射损伤。
