SAHA sails ahead

Encouraging results have been reported from Phase I clinical trials of suberoylanilide hydroxamic acid (SAHA) ?an inhibitor of histone deacetylase (HDAC). The drug was given orally or intravenously to 70 patients with solid and haematological tumours and shown to have excellent oral bioavailability, long duration of action and to inhibit HDAC at doses that were well tolerated. The studies, which were conducted at the Memorial Sloan?Kettering Cancer Center, were reported by Victoria Richon of Aton Pharma at the First International Congress on Targeted Therapies in Washington DC (16?18 August, 2002).

HDACs catalyse the removal of acetyl groups from core nucleosomal histones to alter chromatin structure and regulate the transcriptional activity. Hypoacetylated histones are generally associated with transcriptional repression, and aberrant recruitment of HDAC activity has been associated with the development of certain human cancers. SAHA inhibits HDAC activity by directly binding the catalytic pocket of the enzyme, leading to the accumulation of acetylated core nucleosomal histones.

The investigators are planning Phase II studies of SAHA, and a second HDAC inhibitor, pyroxamide, is already in Phase I trials that are sponsored by the National Cancer Institute.

Wait or act?

Radical prostatectomy is widely used for the treatment of early prostate cancer, but it has not been adequately assessed in a randomized trial until now. Holmberg et al., of the Scandinavian Prostatic Cancer Group, report that the outcomes of radical prostatectomy and watchful waiting are similar.

A total of 695 men with early prostate cancer were randomized to watchful waiting or radical prostatectomy. After a median follow-up of 6.2 years, there was no significant difference in overall survival between the two groups. However, death due to prostate cancer was higher in the group that was assigned to watchful waiting ? the relative risk of death due to prostate cancer after 8 years of follow-up was 0.5. The authors conclude that the absolute benefit associated with radical surgery is limited in men who have the same risk of dying from prostate cancer as the men in this study.

An accompanying article by Steineck et al. indicates that the effects on well-being and subjective quality of life in the men in the trial discussed above, evaluated 4 years after randomization, were similar in both groups.

This randomized trial was initiated before screening for prostate-specific antigen began, and Holmberg et al. suggest that, in men with cancer detected by screening ? which would be more representative of most patients today ? the base-line risk of death from prostate cancer might be even lower, and the benefit of radical treatment might therefore also be less. Longer follow-up is awaited, as metastases and death in patients with prostate cancer can occur up to 20 or 25 years after diagnosis. In addition, in the past decade, radiation-therapy techniques have been developed as an alternative treatment approach, and are soon to be evaluated in randomized trials.

ORIGINAL RESEARCH PAPER Holmberg, L. et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer N. Engl. J. Med. 347 781?789 (2002) Steinbeck, G. et al. Quality of life after radical prostatectomy or watchful waiting N. Engl. J. Med. 347 790?796 (2002)