Cole S, Stratford I J, Fielden E M, Adams G E, Leopold W, Elliott W, Suto M, Sebolt-Leopold J
MRC Radiobiology Unit, Chilton, Didcot, U.K.
Int J Radiat Oncol Biol Phys. 1992;22(3):545-8. doi: 10.1016/0360-3016(92)90872-f.
Following the toxicity and synthetic difficulties encountered with the hypoxic cell radiosensitizer RSU 1069, efforts have focused on development of a superior analogue. Two compounds, RB 6145 and PD 130908, have emerged from this program which overcome the instability and synthetic problems associated with RSU 1069 while retaining favorable biological activity. Both agents show comparable radiosensitizing activity to RSU 1069 following oral or i.p. administration to mice bearing the KHT or RIF-1 tumors. Sensitizing efficiency is about 10 X greater than that observed for misonidazole or etanidazole. Toxicity toward hypoxic tumor cells in vivo is demonstrated by clamping tumors (for 60 min) following administration of PD 130908 or RB 6145. Both are effective hypoxic cytotoxins, but less potent than RSU 1069. Systemic toxicity is substantially reduced following oral drug administration. Further, doses achievable following fractionated drug treatments are sufficiently high to produce significant levels of radiosensitization.
鉴于低氧细胞放射增敏剂RSU 1069存在毒性和合成困难问题，研究工作集中在开发一种更优的类似物上。从该项目中已产生了两种化合物，即RB 6145和PD 130908，它们克服了与RSU 1069相关的不稳定性和合成问题，同时保留了良好的生物活性。对携带KHT或RIF - 1肿瘤的小鼠经口或腹腔注射后，这两种药物均显示出与RSU 1069相当的放射增敏活性。其增敏效率比甲硝唑或依他硝唑高约10倍。在给予PD 130908或RB 6145后通过钳夹肿瘤（60分钟）可证明其对体内低氧肿瘤细胞的毒性。二者均为有效的低氧细胞毒素，但效力低于RSU 1069。口服给药后全身毒性显著降低。此外，分次给药后可达到的剂量足够高，足以产生显著水平的放射增敏作用。
