Modulation of biologic endpoints by topical difluoromethylornithine (DFMO), in subjects at high-risk for nonmelanoma skin cancer.
More than one million new skin cancers are diagnosed yearly in the United States creating the need for effective primary and chemopreventive strategies to reduce the incidence, morbidity, and mortality associated with skin cancer. Skin chemoprevention trials often focus on subjects at high risk of nonmelanoma skin cancers and include biological endpoints like number of actinic keratoses (AK) and measures of cell proliferation, apoptosis, and p53 expression and/or mutation. Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses increased polyamine synthesis and inhibits tumors in models of skin carcinogenesis. Thus, DFMO is a good candidate chemopreventive agent in humans at increased risk of NMSC. We reported previously results of a randomized, placebo-controlled trial of topical DFMO in 48 participants with AK. In this study there was a significant reduction in the number of AK (23.5%; P = 0.001) and the polyamine, spermidine (26%, P = 0.04; Alberts, D. S. et al. Cancer Epidemiol. Biomark. Prev., 9: 1281-2186, 2000). In skin biopsies from the same study, we demonstrate that topical DFMO significantly reduces the percentage of p53-positive cells (22%; P = 0.04); however, there were no significant changes in proliferating cell nuclear antigen or apoptotic indices, or in the frequency of p53 mutations (25% at baseline, 21% after placebo, and 26% after DFMO). We conclude that inhibition of the premalignant AK lesions as well as a reduction in the expression of p53 and in spermidine concentrations may serve as surrogate endpoint biomarkers of DFMO and possibly other topically administered skin cancer chemopreventive agents.
Einspahr
Janine G
JG
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA. jeinspahr@azcc.arizona.edu
Nelson
Mark A
MA
Saboda
Kathylynn
K
Warneke
James
J
Bowden
G Timothy
GT
Alberts
David S
DS
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D002455:Cell Division / Q000187:drug effects; D000518:Eflornithine / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007642:Keratosis / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009154:Mutation; D065108:Ornithine Decarboxylase Inhibitors; D010787:Photosensitivity Disorders / Q000378:metabolism / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012307:Risk Factors; D012878:Skin Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D013095:Spermidine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D013095:Spermidine; D000518:Eflornithine