Chemoprevention of Prostate Cancer with the Polyamine Synthesis Inhibitor Difluoromethylornithine

Abstract

In vitro and in vivo preclinical results suggest that inhibition of polyamine synthesis inhibits the progression of prostate cancer. These findings has led to two clinical trials in patients at risk for invasive prostate cancer with difluoromethylornithine which specifically and irreversibly inhibits ornithine decarboxylase which catalyses the conversion of ornithine to putrescine the rate limiting step in polyamines synthesis. We have conducted a phase IIa one month and placebo randomized phase IIb 12 months trials in patients at increased risk for invasive prostate cancer. Favorable reduction in prostate polyamine levels and prostate volume was documented with no difference in clinical hearing changes. Patients with Gleason's VI lesions in a surveillance cohort would be appropriate candidates for a definitive risk reduction trial although the unavailability of validated biomarkers for invasive progression would require a large and lengthy study.

Methionine Restriction and Cancer Biology

“…While the mechanism by which MR inhibits prostate cancer development is not known, evidence suggests that MR may work by inhibiting prostate cancer cell proliferation, inhibiting the insulin/IGF-1 axis, or by reducing polyamine synthesis [82]. The cells of the prostate produce high levels of polyamines and inhibition of polyamine synthesis is effective at suppressing tumor growth in prostate cancer [91]. Given the dependence of polyamine synthesis on methionine, the polyamine biosynthetic pathway may be a primary target of MR in prevention and/or treatment of prostate cancer.…”

Surface spermidine functionalized PEGylated poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery

“…By contrary, the mean uorescent intensity of A549 cells incubated with SPD-DOX-NPs was increased signicantly (P < 0.05) aer DFMO preconditioning for 24 h. In fact, DFMO was as a suicide inhibitor of ornithine decarboxylase (ODC), one of the key enzymes involved in polyamine biosynthesis. 35,36 The PTS activity of cancer cells was usually upregulated to replenish depleted intracellular polyamine pools, 37,38 leading more SPD-DOX-NPs transported into cells. However, the internalization efficiency reduced slightly due to the affection of cell viability when the amount of DFMO over 50 mM (Fig.…”

One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

“…All together these observations validate the polyamine pathway as chemopreventive and chemotherapeutic for PCa. Several trials have focused on targeting the polyamine pathway as a strategy for chemoprevention in patients at risk for aggressive PCa using difluoromethylornithine (DFMO), an inhibitor of ODC [238,239]. The results of those trials indicated that DMFO treatment results in decreased levels of putrescine, decreased rate of prostate growth, and a trend towards decreased PSA doubling time.…”