O'Hara J A, Douple E B, Abrams M J, Giandomenico C M, Bradley F C, McElligott M A, Caruso F S
Norris Cotton Cancer Center, Department of Medicine, Hanover NH 03756.
Int J Radiat Oncol Biol Phys. 1992;22(3):607-12. doi: 10.1016/0360-3016(92)90887-n.
Ternary Cu(II) complexes with bidentate malonato- and heterocyclic amine ligands were tested with regard to cytotoxicity and potentiation of x-ray induced cell killing in V79 cells. Two lead complexes were also tested in a tumor assay using the MTG-B murine adenocarcinoma model growing in the flanks of female C3H/HeJ mice. One complex, [2,2'-bipyridyl malonatoCu(II)] (RL-5077), produced sensitizer enhancement ratios (SER's) of 1.8 (hypoxic conditions) and 1.0 (oxic conditions) in vitro when irradiation followed 1 hr exposure to the drug at 100 microM. When RL-5077 was administered at doses of 1/2 (11.65 mg/kg) or 1/4 (5.25 mg/kg) the maximum tolerated dose (MTD), 15 min prior to a locally delivered dose of 20 Gy, enhancement ratios (ER's) of 1.6 and 2, respectively, resulted. The second lead complex, [1,10 phenanthroline (malonato)Cu(II)hydrate] (RL-5027), produced SER's of 1.8 and 1.2 under hypoxic and oxic conditions, respectively, at a concentration of 25 microM. Injection of RL-5027 (5 mg/kg) resulted in toxicity without enhancement in combination with radiation. Analogues of these two complexes have been synthesized in an effort to optimize the potentiation of radiation effects while minimizing toxicity to drug alone and increasing water solubility of the drug. Further studies of the structure-activity relationship of Cu(II) ternary complexes using in vitro radiosensitization as the endpoint have identified four classes of ligands with varying biological activity and have supplied information about the effects of group substitution on solubility, toxicity, and radiation potentiation. This group of complexes represents a new class of radiopotentiators that deserves further investigation into its potential for clinical use.
对具有双齿丙二酸酯和杂环胺配体的三元铜（II）配合物进行了细胞毒性测试，以及在V79细胞中增强X射线诱导细胞杀伤作用的测试。还使用在雌性C3H/HeJ小鼠胁腹生长的MTG-B小鼠腺癌模型对两种先导配合物进行了肿瘤试验。一种配合物，[2,2'-联吡啶丙二酸铜（II）]（RL-5077），在体外，当在100 microM下将药物暴露1小时后进行照射时，在低氧条件下敏化增强比（SER）为1.8，在有氧条件下为1.0。当在局部给予20 Gy剂量前15分钟以最大耐受剂量（MTD）的1/2（11.65 mg/kg）或1/4（5.25 mg/kg）给予RL-5077时，增强比（ER）分别为1.6和2。第二种先导配合物，[1,10菲咯啉（丙二酸）铜（II）水合物]（RL-5027），在25 microM浓度下，在低氧和有氧条件下的SER分别为1.8和1.2。注射RL-5027（5 mg/kg）导致毒性增加，且与辐射联合使用时无增强作用。已合成这两种配合物的类似物，以优化辐射效应的增强作用，同时将单独药物的毒性降至最低并提高药物的水溶性。以体外放射增敏为终点对铜（II）三元配合物的构效关系进行的进一步研究已确定了具有不同生物活性的四类配体，并提供了有关基团取代对溶解度、毒性和辐射增强作用影响的信息。这组配合物代表了一类新型的放射增敏剂，值得进一步研究其临床应用潜力。
