Complexes of the platinum(II) tetrachlorodianion with positively charged nuclear dyes have been prepared in an effort to produce neutral molecules which could gain ready access to the nuclear DNA where the platinum(II) tetrachlorodianion could function as a radiosensitizing and a bifunctional alkylating agent. The thiazin dyes Thionin, Azure B, and Methylene Blue, the aminoxanthene dye Pyronin Y, and the thiazole dye Thioflavin have each been complexed to the platinum(II) tetrachlorodianion ( PtCl4) in a ratio of 2:1 ($\text{dye}\colon {\rm PtCl}_{4}$). Studies of the interaction of these complexes and of the dyes with the pBR322 plasmid superhelical DNA demonstrated that while each complex and dye readily associated with the DNA in a dose-dependent manner, only${\rm Pt}(\text{Thioflavin)}_{2}$ and Thioflavin produced irreversible DNA changes (single-strand breaks). In exponentially growing EMT6 cells the cytotoxicity of these drugs was assessed in normally oxygenated and hypoxic cells at both pH 7.4 and 6.45. At concentrations ranging from 1 to 500 μM,${\rm Pt}(\text{Methylene Blue})_{2}$ was significantly more cytotoxic than the other thiazin dye complexes${\rm Pt}(\text{Thionin)}_{2}$ and${\rm Pt}(\text{Azure B)}_{2}$. The cytotoxicity of${\rm Pt}(\text{Thionin)}_{2}$ and${\rm Pt}(\text{Methylene Blue)}_{2}$ was increased in normally oxygenated and hypoxic cells at low pH. Both${\rm Pt}(\text{Pyronin Y)}_{2}$ and${\rm Pt}(\text{Thioflavin)}_{2}$ were more toxic than the thiazin complexes.${\rm Pt}(\text{Pyronin Y)}_{2}$ was most cytotoxic to normally oxygenated cells at normal pH and hypoxic cells at low pH, while${\rm Pt}(\text{Thioflavin)}_{2}$ was most cytotoxic to cells at low pH under both oxygenation conditions. In vitro studies of the radiosensitizing properties of these agents in EMT6 cells demonstrated that exposure to 100 μM for 1 h before and during irradiation (except for${\rm Pt}[\text{Thioflavin]}_{2}$, which was assayed at 25 μM) resulted in enhancement rations of 2.5, 1.9, 1.5 for${\rm Pt}(\text{Azure B)}_{2},{\rm Pt}(\text{Thionin)}_{2},{\rm Pt}(\text{Pyronin Y)}_{2}$, and${\rm Pt}(\text{Thioflavin)}_{2}$, respectively, in hypoxic cells. In contrast,${\rm Pt}(\text{Methylene Blue)}_{2}$ (and Methylene Blue) proved to be a radioprotector of normally oxygenated cells and did not sensitize hypoxic cells to the cytotoxic effects of radiation. In the FSaIIC fibrosarcoma in vivo administration of each drug at 100 mg/kg intraperitoneally (ip) 15 min prior to irradiation (except for${\rm Pt}[\text{Thioflavin]}_{2}$, which was given at 1 mg/kg ip) showed that, with single radiation fractions of 10 and 20 Gy, dose-modifying factors of 2.1, 1.8, 1.5, and 1.2 were produced by${\rm Pt}(\text{Azure B)}_{2},{\rm Pt}(\text{Thionin)}_{2}$, Pt(Pyronin Y), and${\rm Pt}(\text{Methylene Blue)}_{2}$, respectively, after correcting for growth delays induced by the drug alone. In comparison, misonidazole at 1 g/kg ip produced a dose-modifying factor of 1.4. These results indicate that several of these new complexes seem to fulfill expectations in that they appear capable of direct cytotoxicity and radiosensitization.

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