Enhanced transformation of mouse 10T1/2 cells by 12-O-tetradecanoylphorbol-13-acetate following exposure to X-rays or to fission-spectrum neutrons.

Addition of the tumor promoter of 12-O-tetradecanoylphorbol-13-acetate (TPA) to C3H/10T1/2 cells after exposure to either X-rays or to fission-spectrum neutrons increases significantly the frequency of transformation without any effect on cell survival. However, treatment of unirradiated cells with 0.1 micrograms of TPA per ml alone results in a small increase in transformation frequency above background (i.e., from 1.1 x 10(-5) to 1.0 x 10(-4). Thus, besides being a promoter, TPA is also a weak initiator. Enhancement of radiation-induced transformation by TPA was relatively greater after low compared to high doses of either radiation. In addition, TPA causes the relative biological effectiveness of neutrons compared to X-rays to increase with increasing dose or with increasing frequency of transformation rather than to decrease, when TPA is not used. For X-ray doses from zero to approximately 120 rads, TPA raises transformation to frequencies approximately equal to those due to neutrons alone. Analysis of TPA enhancement in the context of the combined effect of two inducing agents, i.e., TPA plus a radiation, indicates that with either radiation TPA acts synergistically. Lastly, TPA was found to alter the dependence of transformation frequency on the density of viable cells. As opposed to a constant frequency of transformants per surviving (or viable) cell, which we observed after a fixed dose of X-rays or neutrons for a range of cell inocula, the addition of TPA increased the frequency of transformation for cell inocula (i.e., from approximately 20 to 6000 viable cells per 90-mm Petri dish). However, the frequency of transformation decreases with increasing size of the inoculum, a result that we interpret to indicate the combined effect of an interference with cell-to-cell communication by TPA plus the fading of initiation events due to the radiation.