The arotinoids: early clinical experience and discussion of future development

There has been great interest in the use of drugs attempting to modify the properties of malignant cells without necessarily destroying them. The family of compounds known as the retinoids have shown particular promise in this area. Current interest is directed towards established retinoids such as ATRA and 13-CRA. Newer synthetic retinoids such as fenretinide, the arotinoid Ro 40-8757, and 9-cis retinoic acid have been entering clinical trials. Ro 40-8757 is a particularly interesting new arotinoid with properties quite distinct from the other retinoids. It has different binding proteins and appears to regulate different genes than the classical retinoids such as ATRA or 13-CRA. Furthermore, it appears active against a different spectrum of malignancies. It also appears to have a relatively favourable side-effect profile. In addition to its anti-proliferative effects, this arotinoid may play a role in protection of bone marrow function after use of cytotoxic drugs. Development of Ro 40-8757 was halted before the compound had entered phase II testing due to lack of resources. Future developmental programmes for retinoids should move rapidly to explore the potential of interesting combinations identified in preclinical models. Retinoids should be considered primarily as drugs which modulate and enhance the effects of other active anticancer agents. Their development should not be prevented because they are unlikely to be active as single agents against common solid tumours.