Radiotoxicity of Platinum-195m-Labeled trans-Platinum (II) in Mammalian Cells

The chemotoxicity and radiotoxicity of trans-dichlorodiammineplatinum (II) labeled with${}^{195{\rm m}}{\rm Pt}$ ($trans\text{-}{}^{195{\rm m}}{\rm Pt}$) 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$trans\text{-}{}^{195{\rm m}}{\rm Pt}$ is investigated using cells of the Chinese hamster V79 cell line. The cellular uptake of${}^{195{\rm m}}{\rm Pt}$ 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${}^{195{\rm m}}{\rm Pt}$ decay site is substantially greater than the density of species along the track of a 5.3 MeV α particle. This explains qualitatively the efficacy of${}^{195{\rm m}}{\rm Pt}$ in causing high-LET radiation type biological effects. The extreme radiotoxicity of intranuclearly localized${}^{195{\rm m}}{\rm Pt}$, 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.