Ras biochemistry and farnesyl transferase inhibitors: a literature survey

Over the last decades, knowledge on the genetic defects involved in tumor f ormation and growth has increased rapidly. This has launched the developmen t of novel anticancer agents, interfering with the proteins encoded by the identified mutated genes. One gene of particular interest is ras, which is found mutated at high frequency in a number of malignancies. The Ras protei n is involved in signal transduction: it passes on stimuli from extracellul ar factors to the cell nucleus, thereby changing the expression of a number of growth regulating genes. Mutated Ras proteins remain longer in their ac tive form than normal Ras proteins, resulting in an overstimulation of the proliferative pathway. In order to function, Ras proteins must undergo a se ries of post-translational modifications, the most important of which is fa rnesylation. Inhibition of Ras can be accomplished through inhibition of fa rnesyl transferase, the enzyme responsible for this modification. With this aim, a number of agents, designated farnesyl transferase inhibitors (FTIs) , have been developed that possess antineoplastic activity. Several of them have recently entered clinical trials. Even though clinical testing is sti ll at an early stage, antitumor activity has been observed. At the same tim e, knowledge on the biochemical mechanisms through which these drugs exert their activity is expanding. Apart from Ras, they also target other cellula r proteins that require farnesylation to become activated, e.g. RhoB. Inhib ition of the farnesylation of RhoB results in growth blockade of the expose d tumor cells as well as an increase in the rate of apoptosis. In conclusio n, FTIs present a promising class of anticancer agents, ac:ting through bio chemical modulation of the tumor cells. [(C) 2001 Lippincott Williams & Wil kins].