Platinum complexes of triaminotriphenylmethanes: interaction with DNA and radiosensitization.
Complexes of the negatively charged tetrachloroplatinum (II) dianion and the positively charged triaminotriphenylmethane nuclear dyes, Basic Fuchsin and Methyl Green have been prepared. Elemental analysis indicated that the complexes associate as PtCl4(Basic Fuchsin)2 and PtCl4(Methyl Green) in neutral, tight ion pairs. Studies with pBR322 DNA indicated that Pt(Basic Fuchsin)2 and Basic Fuchsin produced no irreversible DNA changes, but that Pt(Methyl Green) readily and Methyl Green less efficiently produced single strand breaks in the DNA. Cytotoxicity studies in exponentially, growing asynchronous EMT6 cells in vitro showed that Pt(Basic Fuchsin)2 was more cytotoxic than Pt(Methyl Green) and that both complexes were more toxic to normally oxygenated than hypoxic cells and to cells at normal vs. acidotic pH (6.45). Radiation studies, also in EMT6 cells, demonstrated that Pt(Methyl Green) was an effective radiosensitizing drug in hypoxic cells (dose modifying factor [DMF] 1.9), but that neither the free dyes nor Pt(Basic Fuchsin)2 had significant radiosensitizing activity. In vivo studies in the FSallC fibrosarcoma confirmed the radiosensitizing properties of Pt(Methyl Green) (DMF 2.7), and indicated that Pt(Basic Fuchsin)2 also had some activity (DMF 1.4) which was equivalent to that of mizonidazole (DMF 1.4). These investigations suggest that these or similar platinum-dye complexes may have important antitumor applications in the human clinic.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, MA 02115.
Herman
T S
TS
Kaufmann
M
M
D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D008739:Methyl Green / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000378:metabolism; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents; D012394:Rosaniline Dyes / Q000138:chemical synthesis / Q000378:metabolism* / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D009944:Organoplatinum Compounds; D011838:Radiation-Sensitizing Agents; D012394:Rosaniline Dyes; C064121:tetrachloroplatinate dianion-methyl green complex; C064120:tetrachloroplatinate dianion-basic fuchsin complex; D008739:Methyl Green; D008920:Misonidazole; D004247:DNA