The sphingoid base backbones of
sphingolipids are highly bioactive compounds that affect cell growth, differentiation, diverse cell behaviors, and programmed cell death. Therefore, the efficacy of
sphingosine (SPH) and the analogs
N-acetylsphingosine (
NAS),
N-methylsphingosine (NMS),
octylamine (OCT), and
sterylamine (STR) in the prevention of
skin cancer was assessed in female Sencar mice by measuring effects on the induction of epidermal
ornithine decarboxylase (ODC) activity and
hyperplasia by 12-O-tetradecanoylphorbol-13-acetate (TPA) and effects on the induction of skin
tumors by 7, 12-dimethylbenz[a]
anthracene (DMBA) and TPA. ODC was measured in the shaved dorsal skin of mice treated topically with 0.05-20 mumol of these compounds 30 minutes before application of 8.5 nmol of TPA in 0.2 ml of
acetone. ODC activity was inhibited by > or = 5 mumol of SPH and STR, > or = 10 mumol of
NAS and NMS, and 20 mumol of OCT. In contrast, the induction of
hyperplasia was not inhibited by application of these compounds 30 minutes before TPA. Two
carcinogenesis studies were conducted with 10 nmol of DMBA as the initiator and 3.2 nmol of TPA (2x/wk for 15 wk) as the promoter. In the first study,
NAS, NMS, OCT, and STR (0.05 and 0.5 mumol) were applied before each TPA application.
Papilloma incidence and multiplicity were not inhibited, but
NAS (0.05 mumol) and NMS (0.05 and 0.50 mumol) increased
cancer-free survival. In the second experiment, SPH,
NAS, and NMS (0.05 and 0.5 mumol) were applied 30 minutes before each TPA treatment and twice weekly for 10 weeks after the final TPA treatment.
Papilloma incidence and multiplicity were not inhibited; however, the proportion of mice without
carcinoma was increased by both doses of SPH and by 0.5 mumol of
NAS. Thus low doses of
sphingolipids that were not effective in inhibiting ODC activity, reducing
hyperplasia, or preventing epidermal
papilloma development were, nonetheless, effective in inhibiting
carcinoma development.