CHARACTERIZATION OF THE TUMOR-PROMOTING ACTIVITY OF THAPSIGARGIN IN CF-1 MOUSE SKIN

Abstract

The ornithine decarboxylase (ODC), hydroperoxide (HPx) and DNA responses to 12-O-tetradecanoylphorbol-13-acetate (TPA) and mezerein (MEZ) are similar in vivo. Thapsigargin (TG) respectively mimics about 15, 75 and 75% of the ODC, HPx and DNA responses to TPA and these differences persist after chronic treatments. The peak of ODC induction 5 h after 2 TG treatments at 12 to 48-h intervals is twice that produced 16 h after a single TG treatment or 5 h after 2 TG treatments at a 72-h interval. The ODC-inducing activity of TG is dose dependent from 1 to 15 nmol and its magnitude is maximal after 2 applications. The biochemical effects of TG and TPA are neither synergistic nor additive. But the ODC response to TG is greater when this compound is applied 48 h after TPA than after another TG treatment. In initiated skins promoted 2x/week with 5 nmol of TPA, MEZ, or TG, the Ist papillomas (PAs) appear at 7, 12 and 17 weeks, the tumor incidences are 100, 40 and 24%, and there are 17, 1 and 0.6 PAs/mouse, respectively. The tumor-promoting activity of TG is increased at a higher dose (15 nmol), slightly accelerated at a higher frequency (1x/2 days) and decreased at a lower frequency (1x/week). TPA applied 1x/3 weeks is insufficient to promote tumors but slightly enhances the tumor-promoting activity of TG. MEZ applied 1x/4 weeks in stage 2 also accelerates the tumor-promoting activity of TG. TG is effective as a stage 1 promoter but its promoting activity is not enhanced by stage 1 treatments with TPA. In contrast to TPA or even MEZ, TG may be a very weak tumor promoter because it is a very weak ODC inducer and mobilizes enough intracellular free Ca2+ to impair tumor cell proliferation.