Xeroderma pigmentosum (XP) patients are deficient in nucleotide excision repair (NER) because of mutations in one of the genes coding for NER
enzymes. This results predominantly in high frequency of UV-induced skin
tumors at an early age; the most severe phenotype is found in patients of complementation group A (XPA). However, in a subset of these XPA patients no skin
tumors appear, even at advanced age. Fibroblasts of this subset of patients are not capable of raising UV-induced enhanced reactivation (ER) of viruses and up-regulation of
ornithine decarboxylase (ODC). We hypothesized that prevention of ODC induction would protect NER-deficient patients from
cancer. To simulate the situation in XPA patients, we used a hairless Xpa knockout mouse model and down-regulated the ODC activity by
difluoromethylornithine (DFMO) administered in the
drinking water. The DFMO treatment significantly suppressed UV-induced
carcinogenesis. In a crossover study, we additionally found that discontinuation of the DFMO treatment resulted in a rapid appearance of skin
tumors, up to levels found in mice not treated with DFMO. Late-stage DFMO treatment significantly reduced the number of
carcinomas by
a factor of 2-3, and it appeared to select for
carcinomas with high ODC activity. These results indicate that DFMO suppresses the outgrowth but not the initiation of UV-induced
tumors. The DFMO treatment reduced the
tumor load but did not offer the Xpa knockout mice full protection against UV
carcinogenesis.