Catching colon cancer

A new method of identifying DNA mutations in faecal samples allows colorectal cancer to be non-invasively detected at very early stages. In the 31 January issue of the New England Journal of Medicine, Giovanni Traverso et al. report the development of a new assay to screen faecal samples for mutations in the adenomatous polyposis coli (APC) gene. Mutations in APC are the earliest detectable molecular abnormalities in both familial and sporadic colorectal cancer. As that colon cancer cells are shed into the faeces, the authors devised a technique to detect cancer-associated mutations in stool samples. Most cancer-associated APC mutations are clustered in a small region and interrupt transcription of the gene, leading to production of a truncated protein. The authors used an in vitro transcription –translation reaction to identify truncated APC protein within sloughed cells in stool samples. Using this assay, they were able to identify 57% of the patients with colorectal cancer or colonic polyps, and the test did not yield any false-positive results. The assay is also technically impressive, as mutant APC genes are hard to detect, comprising only 0.4–14.1% of all APC genes in the sample. Further studies are required to determine whether or not these results can be repeated on a large-scale basis, but this is an important step towards a reliable, non-invasive molecular test for colorectal cancer. ORIGINAL RESEARCH PAPERTraverso, G. et al. Detection of APC mutations in fecal DNA from patients with colorectal tumors. N. Engl. J. Med. 346, 311–320 (2002)

A promising drug for mesothelioma

Results of a Phase II multicentre trial indicate that the ribonuclease-based drug ranpirnase (Onconase) shows promise as a treatment for patients with inoperable malignant mesothelioma. This asbestos-related cancer of the inner lining of the chest and abdomen will kill over 250,000 people in Europe alone in the next 35 years. As reported in the Journal of Clinical Oncology, the tumours either shrank or stopped growing in 41 of the 81 patients that were assessable for tumour response. The median survival time for these patients was 18.5 months — a dramatic improvement over the 6–8-month life expectancy for the average mesothelioma patient. The results were especially encouraging in light of the fact that over one-third of these patients did not respond successfully to prior systemaic therapy. Ranpirnase — a ribonuclease that was developed from the eggs of the frog, Rana pipiens — interrupts protein synthesis, resulting in the inhibition of cell growth and the induction of apoptosis in cancer cells. The drug has been shown to be well tolerated in most patients, and has not been associated with the toxicity that is typically associated with chemotherapy. A randomized, controlled Phase III trial of the combination of ranpirnase with doxorubicin in patients with inoperable malignant mesothelioma, compared with doxorubicin therapy alone, is also underway in the United States and Europe. ORIGINAL RESEARCH PAPERMikulski, S. M. et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J. Clin. Oncol. 20, 274–281 (2002).

A select bunch

The largest ever chemoprevention trial for prostate cancer began recruiting participants on 25 July. The SELECT study (Selenium and Vitamin E Cancer Prevention Trial) needs 32,000 participants. Men over 55 and with no previous history of prostate cancer will be randomized into four groups, taking both supplements, either supplement plus placebo, or two placebos.

Previous studies to determine the chemopreventive power of selenium or vitamin E in other cancers showed encouraging declines in prostate cancer rates in men taking either of these antioxidant supplements, but this is the first purpose-built trial to study the effects of both compounds on prostate cancer incidence. Secondary objectives of the trial include assessing the effect of the two supplements on lung cancer and colorectal cancer incidence. FURTHER READINGClark, L. C. et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276, 1957–1963 (1996) | Heinonen, O. P. et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J. Natl Cancer Inst. 90, 440–446 (1998)

The SELECT home page http://www.crab.org/select/ SWOG http://swog.org/

Proteasome blocker for myeloma

Multiple myeloma is a difficult cancer to cure, as most patients become resistant to the available drugs. PS-341 — a proteasome inhibitor developed by Millennium Pharmaceuticals — could now be set to change this.

PS-341 prevents degradation of key cell-cycle regulatory proteins, such as the tumour suppressor p53, and the cyclin-dependent kinase inhibitors p21 and p27. The proteasome pathway also regulates the activation of the transcription factor NF-κB, so PS-341 might inhibit transcription of important target genes — such as E-selectin, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) — that are involved in metastasis and angiogenesis.

One patient had a complete response — a normal bone marrow test and disappearance of the myeloma protein — and several patients had a partial response. The drug is now moving into phase II trials, so watch this space for new developments. FURTHER READINGhttp://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7412

COX-2 inhibitors: a breath of fresh air?

Celebrex (celecoxib), a non-steroidal anti-inflammatory that has been shown to prevent colon cancer, will soon be tested for its ability to prevent lung cancer. Researchers at UCLA's Jonsson Cancer Center are seeking individuals who are at high risk of developing lung cancer for enrollment in two different trials. with Celebrex. The second trial will study the ability of Celebrex to prevent lung cancer in 20 smokers over the age of 45 who have smoked a minimum of a pack of cigarettes a day for 20 years and have mild chronic obstructive pulmonary disease. New approaches are desperately needed to prevent lung cancer, which kills over 150,000 people in the US each year. FURTHER READINGSteinbach, G. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342,1946–1952 (2000)