Inhibition of the development of metastatic squamous cell carcinoma in protein kinase C epsilon transgenic mice by alpha-difluoromethylornithine accompanied by marked hair follicle degeneration and hair loss.
The role of 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated polyamine biosynthesis in the development of metastatic squamous cell carcinoma (mSCC) in protein kinase C epsilon (PKC epsilon) transgenic mice was determined. TPA treatment induced epidermal ornithine decarboxylase (ODC) activity and putrescine levels approximately 3-4-fold more in PKC epsilon transgenic mice than their wild-type littermates. Development of mSCC by the 7,12-dimethylbenz(a)anthracene (100 nmol)-TPA (5 nmol) protocol in PKC epsilon transgenic mice was completely prevented by administration of the suicide inhibitor of ODC alpha-difluoromethylornithine (DFMO, 0.5% w/v) in the drinking water during TPA promotion. However, DFMO treatment led to marked hair loss in PKC epsilon transgenic mice. DFMO treatment-associated hair loss in PKC epsilon transgenic mice was accompanied by a decrease in the number of intact hair follicles. These results indicate that TPA-induced ODC activity and the resultant accumulation of putrescine in PKC epsilon transgenic mice are linked to growth and maintenance of hair follicles, and the development of mSCC. Severe hair loss observed in PKC epsilon transgenic mice on DFMO during skin tumor promotion has not been reported before in the prevention of cancer in other animal models or in human cancer prevention trials.
Wheeler
Deric L
DL
Department of Human Oncology, Medical School, University of Wisconsin, Madison, Wisconsin 53762, USA.
Ness
Kristin J
KJ
Oberley
Terry D
TD
Verma
Ajit K
AK
D000284:Administration, Oral; D000505:Alopecia / Q000139:chemically induced* / Q000201:enzymology; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control / Q000556:secondary*; D003043:Cocarcinogenesis; D000518:Eflornithine / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology; D018859:Hair Follicle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000502:physiology*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D011700:Putrescine / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control; D012883:Skin Ulcer / Q000139:chemically induced; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology / Q000633:toxicity*
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011993:Recombinant Fusion Proteins; C046810:7,12-dihydroxymethylbenz(a)anthracene; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D011700:Putrescine; D000518:Eflornithine