Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants

Individuals who receive life saving organ transplants and the required immu nosuppression often develop secondary cancers. One of the most common secon dary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to p revent these cancers have not been successful. Difluoromethylornithine (DFM O), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experi mental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 orga n transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impac t of DFMO on two biological parameters, skin polyamines and 12-O-tetradecan oylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was signi ficantly lowered by 80 and 67% at the two dose levels. Polyamine levels wer e not affected significantly except for putrescine at the 0.5-g level. Bloo d levels of DFMO were about two times higher than expected, based on our pr ior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this popu lation as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.