Newman H F, Bleehen N M, Workman P
Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1113-6. doi: 10.1016/0360-3016(86)90238-5.
The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m2, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m2, but causes peripheral neuropathy at cumulative doses of 30 g/m2. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m2 of each agent, and proceeding to a fixed dose of 0.75 g/m2 Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m2 SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m2 Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone. The overall advantage will be determined by the maximum dose levels and number of doses possible; the escalation of both parameters is now in progress.
低氧细胞放射增敏剂Ro 03-8799会产生急性中枢神经系统毒性，这限制了该药物的重复给药剂量至0.75 g/m²，但不会发生周围神经病变。SR-2508在剂量大于3.0 g/m²时不会产生急性影响，但在累积剂量达到30 g/m²时会导致周围神经病变。通过联合使用每种药物的最大耐受剂量，有可能提高疗效，但不会增加毒性。对10名患者给予递增剂量的Ro 03-8799和SR-2508。两种药物在50 ml 0.9%生理盐水中混合，在10分钟内输注，每种药物起始剂量为0.5 g/m²，然后Ro 03-8799固定剂量为0.75 g/m²，SR-2508分别为0.5、1.0、2.0和3.0 g/m²。4名患者出现了与Ro 03-8799相关的预期急性综合征，但SR-2508剂量递增并未增加其发生率，且未观察到周围神经病变。血浆和尿液药代动力学研究表明未发生药物相互作用。6名患者在3周内接受了9次给药方案，使用0.75 g/m²的Ro 03-8799和递增剂量的0.5、1.0和1.5 g/m²的SR-2508。所有患者均出现了与Ro 03-8799相关的预期急性副作用，但SR-2508高剂量时并未增加。未观察到其他毒性。在给药方案开始和结束时进行的血浆药代动力学相似。联合使用放射增敏剂后，从6个浅表肿瘤中取活检。输注结束后30分钟内，Ro 03-8799和SR-2508的平均肿瘤浓度分别为30和72微克/克。这些值预计将转化为约1.5至1.6的单剂量增敏剂增强比，与单独使用药物相比有显著提高。总体优势将取决于最大剂量水平和可能的给药次数；目前这两个参数都在递增。
