Inhibition of Metastatic Squamous Cell Carcinoma Development in Protein Kinase C Epsilon Transgenic Mice by Alpha-Difluoromethylornithine with Hair Follicle Degeneration and Hair Loss

June 2003 in “ PubMed ”

Deric L. Wheeler, Kristin J. Ness, Terry D. Oberley, Ajit Kumar Verma

The study investigated the effects of TPA-stimulated polyamine biosynthesis on metastatic squamous cell carcinoma (mSCC) development in protein kinase C epsilon (PKC epsilon) transgenic mice. It was found that TPA treatment significantly increased epidermal ornithine decarboxylase (ODC) activity and putrescine levels in these mice compared to wild-type littermates. The development of mSCC was completely prevented by administering alpha-difluoromethylornithine (DFMO), an ODC inhibitor, in the drinking water during TPA promotion. However, this treatment resulted in marked hair loss and a decrease in intact hair follicles in the transgenic mice. The findings suggested a link between TPA-induced ODC activity, putrescine accumulation, hair follicle maintenance, and mSCC development, with the observed hair loss being a novel side effect not previously reported in other cancer prevention models.

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Research cited in this study

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research Involvement of Follicular Stem Cells in Forming Not Only the Follicle but Also the Epidermis

1010 citations, August 2000 in “Cell”

Hair follicle stem cells can form both hair follicles and skin.

research Dynamic Expression of Ornithine Decarboxylase in Hair Growth

24 citations, June 1999 in “Mechanisms of Development”

The study demonstrated that ornithine decarboxylase (ODC) played a significant role in hair follicle development and hair growth by being associated with cell proliferation and commitment. ODC was expressed in embryonic epidermis at sites of follicle development and persisted in proliferating bulb cells of anagen follicles, except at the base of the bulb. Its expression decreased as follicles entered catagen and resumed with new follicle initiation. In vibrissae, ODC showed a complex expression pattern, being present in both the bulb and hair shaft, and in outer root sheath cells near the follicle bulge, suggesting a link to hair follicle stem cells.

research Modulation of Murine Hair Follicle Function by Alterations in Ornithine Decarboxylase Activity

71 citations, May 1996 in “Journal of Investigative Dermatology”

The study investigated the role of ornithine decarboxylase (ODC) in hair follicle function using transgenic mice that overexpressed a mutated ODC transgene in hair follicle keratinocytes. These mice experienced normal initial hair growth but lost their hair completely 2-3 weeks after birth, coinciding with the onset of ODC overexpression and the development of follicular cysts. The study found that the ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially restore normal skin histology if administered early, and it could also reactivate hair growth in mice with complete hair loss. The results suggested that ODC played a crucial regulatory role in mouse hair follicles.

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research Inhibition of Metastatic Squamous Cell Carcinoma Development in Protein Kinase C Epsilon Transgenic Mice by Alpha-Difluoromethylornithine with Hair Follicle Degeneration and Hair Loss

26 citations, June 2003 in “PubMed”

research Overexpression of Spermidine/Spermine N1-Acetyltransferase Under the Control of Mouse Metallothionein I Promoter in Transgenic Mice: Evidence for a Striking Post-Transcriptional Regulation of Transgene Expression by a Polyamine Analogue

43 citations, February 1999 in “Biochemical Journal”

The study involved generating a transgenic mouse line overexpressing the SSAT gene under a mouse metallothionein I promoter, leading to significant changes in tissue polyamine pools and delayed permanent hair loss compared to previous models. The liver was notably affected, with altered polyamine levels. Despite high SSAT mRNA levels, enzyme activity was only moderately increased unless induced by ZnSO4 or the polyamine analogue DENSPM, which caused a dramatic increase in enzyme activity and depletion of liver polyamines, resulting in high mortality and liver damage. The findings suggested that SSAT overexpression made the mice highly sensitive to polyamine analogues, indicating a post-transcriptional regulation mechanism.