title: Phase I chemoprevention study of difluoromethylornithine in subjects with organ transplants.
abstract: Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ 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 impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-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 significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53792, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Carbone
authors.forename: J D
authors.initials: JD
authors.lastname: Pirsch
authors.forename: J P
authors.initials: JP
authors.lastname: Thomas
authors.forename: J A
authors.initials: JA
authors.lastname: Douglas
authors.forename: A K
authors.initials: AK
authors.lastname: Verma
authors.forename: P O
authors.initials: PO
authors.lastname: Larson
authors.forename: S
authors.initials: S
authors.lastname: Snow
authors.forename: K D
authors.initials: KD
authors.lastname: Tutsch
authors.forename: D
authors.initials: D
authors.lastname: Pauk
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018890:Chemoprevention; D000518:Eflornithine / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation; D009955:Ornithine Decarboxylase / Q000032:analysis / Q000378:metabolism; D010919:Placebos; D012878:Skin Neoplasms / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D010919:Placebos; D009955:Ornithine Decarboxylase; D000518:Eflornithine