Howell R W, Kassis A I, Adelstein S J, Rao D V, Wright H A, Hamm R N, Turner J E, Sastry K S
Department of Radiology, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark 07103.
Radiat Res. 1994 Oct;140(1):55-62.
The chemotoxicity and radiotoxicity of trans-dichlorodiammineplatinum (II) labeled with 195mPt (trans-195mPt) are investigated to ascertain the potential of radioplatinum coordination complexes as antineoplastic agents. Platinum-195m, with a half-life of about 4 days, is a prolific emitter of low-energy Auger electrons because of the high probability of internal conversion in its isomeric transitions. The kinetics of cellular uptake and retention after incubation and the radiotoxicity of this Auger electron emitter in the form of trans-195mPt is investigated using cells of the Chinese hamster V79 cell line. The cellular uptake of 195mPt reaches a plateau in about 3 to 5 h of incubation and varies nonlinearly with the extracellular concentration of radioactivity. The radioactivity is eliminated from the cells after incubation with an effective half-life of 24 h. Cell survival data, when corrected for the chemical toxicity of nonradiolabeled trans-platinum, give a cell survival curve typical for radiations with high linear energy transfer. At 37% survival, the mean lethal cellular uptake is about 1.0 mBq/cell. Dosimetric considerations, based on subcellular distribution of the radionuclide, yield a value of 4.8 for the relative biological effectiveness when compared with 250 kVp X rays. Theoretical Monte Carlo track-structure calculations indicate that the density of radical species produced in liquid water in the immediate vicinity of a 195mPt decay site is substantially greater than the density of species along the track of a 5.3 MeV alpha particle. This explains qualitatively the efficacy of 195mPt in causing high-LET radiation type biological effects. The extreme radiotoxicity of intranuclearly localized 195mPt, in conjunction with the proclivity of platinum chemotherapy agents to bind to DNA in the cell nucleus, suggests that the combination of chemical effects and the effects of Auger electrons that can be obtained with radioplatinum coordination complexes may have potential in the treatment of cancer.
研究了用¹⁹⁵mPt标记的反式二氯二氨铂（II）（反式¹⁹⁵mPt）的化学毒性和辐射毒性，以确定放射性铂配位络合物作为抗肿瘤药物的潜力。¹⁹⁵mPt的半衰期约为4天，由于其同质异能跃迁中内转换的高概率，它是低能俄歇电子的大量发射体。使用中国仓鼠V79细胞系的细胞研究了孵育后细胞摄取和保留的动力学以及这种以反式¹⁹⁵mPt形式存在的俄歇电子发射体的辐射毒性。¹⁹⁵mPt的细胞摄取在孵育约3至5小时后达到平台期，并随细胞外放射性浓度呈非线性变化。孵育后，放射性以24小时的有效半衰期从细胞中消除。校正未标记反式铂的化学毒性后的细胞存活数据给出了典型的高传能线密度辐射的细胞存活曲线。在37%存活时，平均致死细胞摄取量约为1.0 mBq/细胞。基于放射性核素亚细胞分布的剂量学考虑，与250 kVp X射线相比，相对生物效能值为4.8。理论蒙特卡罗径迹结构计算表明，¹⁹⁵mPt衰变位点紧邻处的液态水中产生的自由基种类密度远大于5.3 MeV α粒子径迹沿线的种类密度。这定性地解释了¹⁹⁵mPt在引起高传能线密度辐射型生物效应方面的功效。细胞核内定位的¹⁹⁵mPt的极端辐射毒性，与铂类化疗药物倾向于与细胞核中的DNA结合相结合，表明放射性铂配位络合物可获得的化学效应和俄歇电子效应的组合可能在癌症治疗中具有潜力。
