The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: results of a year-long phase IIb randomized placebo-controlled chemoprevention trial

Abstract

Background: Prostate cancer is a major health issue, and prevention of prostate cancer and/or its progression will yield benefits for men. Difluoromethylornithine (DFMO) is an antiproliferative agent, inhibiting ornithine decarboxylase, the first enzyme in the polyamine pathway, and has been studied as a therapeutic and chemopreventive agent. The prostate has high levels of tissue polyamines and has shown sensitivity to DFMO both in vitro and in vivo.

Methods: Eighty-one men participated in a 1-year randomized trial of placebo or DFMO. Prostate volume determination and biopsy of the prostate for histology and polyamine content were done at baseline and after 12 months. Other biomarker variables were assessed, including total and free prostate-specific antigen and prostate-specific antigen doubling time.

Results: Compared with baseline, men receiving DFMO had a smaller increase in prostate volume (0.14 cm(3)) than those on placebo (2.95 cm(3); P = 0.0301) at 1 year. In addition, DFMO caused a 60.8% reduction of prostate putrescine levels compared with a 139.5% increase in the placebo arm (P = 0.0014). Stratification by ornithine decarboxylase genotype showed that DFMO reduced prostate volume (P = 0.029) and putrescine levels (P = 0.0053) in the AA + GA group but not in the GG group. There were no grade 3 or 4 toxicities. There was no clinical ototoxicity, with one subclinical grade 2 hearing decline on audiogram.

Conclusion: In this randomized placebo-controlled trial, DFMO induced a decrease of prostate putrescine levels and rate of prostate growth. The potential of this compound for prostate cancer or hyperplasia should be further studied.

Figure 1

A. Median relative percent difference of putrescine, spermidine, and spermine for placebo or DFMO. The relative percent difference refers to the ratio of the absolute difference divided by the baseline multiplied by 100%. Statistical tests are based on nonparametric Wilcoxon two-sample tests. DFMO lowered putrescine levels (P = 0.0014); however, the other polyamines did not show significant differences between treatment groups. B. Median relative percent difference of putrescine, spermidine, and spermine for placebo or DFMO stratified by ODC polymorphism, GG versus GA and AA. Percent relative difference is calculated as the ratio of the absolute difference divided by the baseline value multiplied by 100%. Statistical tests for differences between treatment groups include nonparametric Wilcoxon two-sample tests for putrescine and spermidine and independent sample t tests for the log transform of spermine. DFMO treatment lowered putrescine levels in the GA and AA group (P = 0.0053) but not in the GG group (P = 0.11). The other polyamine levels did not show statistical differences by treatment within polymorphism subgroup, although trends may be seen in the GA and AA group for spermine (P = 0.06) and spermidine (P = 0.09) levels for treatment with DFMO.

Figure 2

A. Absolute 12-mo difference in prostate and transition zone volume. Columns, mean difference of prostate volume (cm³) and transitional zone volume (cm³); bars, SE. Comparisons between treatment groups are based on an independent sample t test for prostate volume and a nonparametric Wilcoxon two-sample test for transition zone volume. Prostate volume showed a treatment effect (P = 0.03). There was no significant difference between treatment groups in mean transitional zone change (P = 0.35). B. Absolute 12-mo difference in prostate and transition zone volume stratified by ODC genotype. Columns, mean absolute difference of 12 mo to baseline of prostate volume (cm³) and transitional zone volume (cm³) stratified by ODC allele, GG versus GA and AA; bars, SE. For analysis of transition zone volume within the GG allele, a nonparametric Wilcoxon two-sample test was applied. Independent sample t tests were used for all other comparisons within allele subgroups. Prostate volume showed a treatment effect in the GA and AA grouping (P = 0.029) but not in the GG group (P = 0.33). Mean transitional zone changes were not significantly different.