Martin R F, Broadhurst S, D'Abrew S, Budd R, Sephton R, Reum M, Kelly D P
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Australia.
Br J Cancer Suppl. 1996 Jul;27:S99-101.
Molecular studies on the mechanism of radioprotection by Hoechst 33342 have suggested that radioprotective activity might be improved by addition of electron-donating substituents to the ligand. This paper reports the results of experiments with proamine, in which the ethoxy group of Hoechst 33342 has been replaced with a dimethylamino group. Clonogenic survival studies with V79 cells confirmed the expectation of increased radioprotective activity of proamine. Also, proamine is less cytotoxic than Hoechst 33342, which further improves the extent of achievable radioprotection. The more general features of DNA-binding radioprotectors are also discussed in terms of their potential use in cancer radiotherapy. In particular it is proposed that the limited penetration of the compounds through cell layers might enable delivery to epithelial tissues by topical application, with limited access to the tumour via systemic uptake. In this context, the question of whether sufficient concentrations of such radioprotectors can be achieved in vivo has been addressed by experiments with the mouse lung model. In control animals, the ED50 for lethal loss of respiratory function at 16 weeks after irradiation was 19 Gy (single dose). Intravenous injection of Hoechst 33342 before irradiation extended the ED50 to 23 Gy.
关于Hoechst 33342辐射防护机制的分子研究表明，通过向配体添加供电子取代基，可能会提高辐射防护活性。本文报道了对丙胺的实验结果，其中Hoechst 33342的乙氧基已被二甲氨基取代。对V79细胞进行的克隆形成存活研究证实了丙胺辐射防护活性增强的预期。此外，丙胺的细胞毒性比Hoechst 33342小，这进一步提高了可实现的辐射防护程度。还根据DNA结合辐射防护剂在癌症放射治疗中的潜在用途讨论了其更一般的特征。特别是有人提出，这些化合物穿过细胞层的穿透能力有限，这可能使得通过局部应用将其递送至上皮组织，而通过全身摄取进入肿瘤的机会有限。在这种情况下，通过小鼠肺部模型实验解决了在体内能否达到足够浓度的此类辐射防护剂的问题。在对照动物中，照射后16周呼吸功能致死丧失的半数有效剂量（ED50）为19 Gy（单次剂量）。照射前静脉注射Hoechst 33342可将ED50延长至23 Gy。
