DNA interaction, cytotoxicity, and radiosensitization with PtCl4(Nile Blue)2 and PtCl4(Neutral Red)2.
Complexes of the positively charged, nuclear staining, quinone-imine dyes Nile Blue and Neutral Red with negatively charged tetrachloroplatinum (II) have been prepared in an effort to form neutral drugs which could gain ready access to the cellular nucleus and deliver significant quantities of the reactive tetrachloroplatinum anion to the vicinity of the DNA. Elemental analysis showed that both the Nile Blue and Neutral Red complexes with tetrachloroplatinum (II) comprised 2 mol of dye and 1 mol of tetrachloroplatinum, forming Pt(Nile Blue)2 and Pt(Neutral Red)2. Exposure of superhelical pBR322 DNA to the complexes or the dyes for 24 h followed by agarose gel electrophoresis showed that Neutral Red and Pt(Neutral Red)2 had little effect on DNA conformation, but that both Nile Blue and Pt(Nile Blue)2 could produce single-strand DNA breaks in a dose-dependent fashion. Studies in exponentially growing asynchronous, hypoxic, and normally oxygenated EMT6 cells at normal pH (7.40) and pH 6.45 demonstrated that neither dye was highly toxic, but that both complexes were capable of producing significant cytotoxicity. Both complexes killed normally oxygenated cells more efficiently than hypoxic cells, but Pt(Neutral Red)2 was more cytotoxic at pH 6.45, while Pt(Nile Blue)2 killed significantly more cells at normal pH. Both complexes decreased the survival of hypoxic EMT6 cells as indicated by the slope of the radiation survival curve [dose modifying factor (DMF) 2.90 for Pt(Nile Blue)2 and 1.45 for Pt(Neutral Red)2]. Studies with the FSaIIC murine tumor showed that both complexes were active radiosensitizing agents in vivo [DMF 1.76 for Pt(Nile Blue)2 and 1.25 for Pt(Neutral Red)2]. These results indicate that these new platinum complexes have characteristics which may make them and similar complexes effective radiosensitizing agents in humans.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Herman
T S
TS
Kaufmann
M E
ME
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000528:radiation effects; D004278:DNA, Superhelical / Q000187:drug effects*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D009499:Neutral Red / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010078:Oxazines / Q000494:pharmacology*; D010619:Phenazines / Q000494:pharmacology*; D010984:Platinum / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use
D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D010078:Oxazines; D010619:Phenazines; D011838:Radiation-Sensitizing Agents; C061288:Neutral Red-platinum tetrachloride complex; C061287:Nile Blue-platinum tetrachloride complex; D009499:Neutral Red; D010984:Platinum