Furthermore, hypoxia has been shown in vitro to increase the invasiveness of cancer cells in an NO-mediated manner, which can be blocked by NO-donors.[10] An interesting study in this respect is a non-randomized phase 2 trial by Siemens et al, in which a very low dose of nitroglycerin (Minitran 5 patch (18 mg) cut in 6 pieces, delivering 0.033 mg/h in stead of 0.2 mg/h normally) was given to patients with biochemical recurrence (PSA-failure) after primary therapy. After 24 months the PSA doubling time was more than 31 months versus 12.8 months before the start of therapy, demonstrating the inhibitory effect of nitroglycerin on prostate cancer cells. [11]