Inhibitory effects of anti‐tumor platinum compounds on DNA, RNA and protein syntheses in mammalian cells in vitro

The inhibitory effects of anti‐tumor, bacterial filament forming platinum compounds, Cis‐Pt(II) (NH 3 ) 2 Cl 2 (A), Cis‐Pt(IV) (NH 3 ) 2 Cl 4 (B), and Pt(II) (NH 2 ) 2 (CH 2 ) 2 Cl 2 (C) on DNA, RNA and protein syntheses was measured by the incorporation of 3 H‐thymidine, 3 H‐uridine, and 3 H‐L‐leucine, respectively, into an acid‐insoluble polymer in human amnion AV 3 cells. Compound A, the most effective tumor‐inhibiting platinum compound, was shown to selectively inhibit DNA synthesis below 5μM and to inhibit 3 H‐thymidine incorporation more rapidly than 3 H‐uridine or 3 H‐leucine incorporation at 25μM. Like A, compounds B and C were also shown to inhibit all three processes after a 24‐hour period of treatment at 25μM. A correlation was established between the relative anti‐tumor effectiveness of compounds A, B, and C and the extent of their inhibitory effects. On the other hand, two non‐tumor‐inhibiting platinum compounds, [Pt(II) (NH 3 ) 4 ]Cl 2 (D) and Trans‐Pt(IV) (NH 3 ) 2 Cl 4 (E) had no inhibitory effects, except compound E, which exhibited a rapid initial inhibition of 3 H‐L‐leucine incorporation at 100μM. The inhibition of 3 H‐thymidine incorporation into cells pretreated 4 h with 5μM of compounds A, B, and C was shown to be irreversible. Finally the inhibition of the incorporation of 3 H‐thymidine into DNA by A was shown not to be caused by the inhibition of the uptake of the tracer into the acid‐soluble pool. A number of possible explanations for the greater sensitivity of DNA synthesis and the sequential inhibition of DNA, RNA and protein synthesis at higher concentrations are suggested.