Bleehen N M, Newman H F, Maughan T S, Workman P
University Department, Unit of Clinical Oncology and Radiotherapeutics, Cambridge, U.K.
Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1093-6. doi: 10.1016/0360-3016(89)90924-3.
The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.
乏氧细胞放射增敏剂Ro 03-8799和SR 2508具有不同的临床毒性。前者会引发急性但短暂的中枢神经系统综合征，而后者会导致累积性周围神经病变。在单剂量研究之后，使用这两种药物联合的递增多剂量方案在较低剂量时未显示出意外的不良反应。本研究确定了对26例每周接受3次0.75 g/m² Ro 03-8799和2 g/m² SR 2508静脉输注的患者给予最大耐受剂量区域内的剂量时的临床耐受性和药代动力学。在15次给药时，3/4的患者出现世界卫生组织2级周围神经病变，而在12次给药时，1/9的患者出现2级病变，6/9的患者出现1级神经病变。这表明SR 2508的剂量低于单独给药时的剂量，提示在慢性周围神经毒性方面两种药物之间确实存在某种相互作用。药代动力学研究表明两种药物之间无不良相互作用，且患者间差异极小。从双变量分析来看，Ro 03-8799的累积曲线下面积（AUC）与周围神经病变的发生具有最显著的相关性。输注后30分钟，以给药剂量标准化的肿瘤药物浓度显示Ro 03-8799的平均值为34微克/克，SR 2508为76微克/克。预计这些浓度可产生1.5的单剂量增敏剂增强率。两种增敏剂在最大耐受剂量下联合使用可能会比单独使用任何一种药物具有更高的治疗效果。
