CD271, a retinoid with potential for the treatment of colon cancer

The retinoids play a key role in differentiation, proliferation and apoptosis. Since each of these processes play a part in tumor progression almost 20 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market as anti-cancer treatments. Although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers has been limited. In our recent dossier “Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development” (click here for access) we set out to offer a full and up to date insight into the complexities of the retinoids and strategies for improving their therapeutic efficacy.

Cancers of the colon and rectum remain responsible for 40,000 deaths every year in the US, second only to lung cancer. Early detection of the disease is particularly important and in the US alone, around 140,000 new cases of colorectal cancer were estimated to have been detected in 2002. This makes colorectal cancer the third most common cancer in the US. Surgery remains the main form of treatment and is often the only treatment used in early-stage disease. Current surgical practices can however cure only 40%-50% of early-stage cases. The global colorectal cancer market was estimated to be worth approximately US$1 billion in 2001, of which 60% of the revenues were derived from the US. The market has been predicted to rise further to US$2.5-3 billion within a five-year period. Camptosar™ (Pharmacia Corp.) currently dominates the US colorectal cancer market, but severe diarrhea as a side effect is a clear drawback for this drug (for a full analysis of therapeutic and market opportunities for colon cancer click here).

Colon cancer is one type of cancer that has been addressed in the context of retinoid therapeutics and indeed adapalene (CD271) is one of the retinoids profiled in our recent retinoid dossier. This molecule is a naphtoic acid derivative with retinoid-like biologic properties and which is commonly used in the topical therapy of acne vulgaris. Researchers at the University of Erlangen-Nuernberg have now evaluated the ability of CD271 to induce apoptosis in a variety of colon cancer cells.

This therapeutic agent was able to reduce proliferation in each of the cells lines investigated and the potency of this effect and possibly the maximum level of anti-proliferative activity was much greater than with 9-cis retinoic acid. This effect of CD271 was mirrored by an impressive increase in apoptotic index in each of the cell lines, contrasting with 9-cis retinoic acid that produced only a small increase in apoptosis.

In addition to improved activity against colon cancer cells, CD271 also has a better safety profile than that of 9-cis retinoid acid. Its toxicity profile is more favorable than that of other retinoids and the oral LD50 is >5g/kg in rats and mice. Furthermore, even high doses of orally administered CD271 fail to produce neurologic, hematologic, cardiovascular or respiratory side effects. Further studies are therefore eagerly awaited to determine the therapeutic activity of CD271 in in vivo models and eventually in clinical trials.

Entry date Monday, November 10, 2003

Adapted from Ocker et al, Int J Cancer. 2003 Nov 10;107(3):453-9.