Antisense oligonucleotides and the rational design of new antitumor drugs.

suming and resource-costly. For colon cancer, as for many other tumors, this goal is far from accomplished nowadays despite considerable effort. High costs should include, as a relevant issue, the high number of agents to be assessed and then discarded along the various stages of selection. To render this search more efficient, both official agencies and private ventures tend to rationalize this sort of projects from the start (1). Aside from the major contribution of large-scale empirical analysis using substance banks, there is now the option of searching for drugs specifically directed to increasingly well-defined therapeutic targets. In this respect, currently ongoing advances in the fields of genomics and proteomics allow to recognize an increasingly well-detailed profile of genes as preferentially expressed by tumor tissues (2). A most direct approach is the inhibition of the expression of genes involved in the pathogenesis of a specific tumor type. In this sense, oncogenes such as K-Ras or the telomerase catalytic subunit (TERT) gene are preferential candidates, as both have been involved in malignant phenotype development for a high percentage of colon cancers (3,4). In the article by Lledó et al. (5) being published in this issue, the strategy selected for such inhibition is the use of antisense oligonucleotides (ASO). These are artificial DNA sequences complementary to those of the messenger RNA corresponding to the gene whose inhibition is attempted (6). Several mechanisms account for the blocking of gene expression, with the most widely spread and studied being the degradation of RNA-DNA hybrids by cell nucleases such as RNAse H. The therapeutic potential of such scientifically smart approach is dependent on a number of determining factors. In the first place one must be certain that inhibiting the target gene will result in the death of tumor cells or at least a reversal of their malignant phenotype. For colon cancer, a need to accumulate successive mutations so that tissue may progressively acquire cancer characteristics has been established (7). An activation of selected oncogenes is needed to increase cell proliferation rates or alter control systems thus allowing the development of new mutations, but this activation may possibly become dispensable for tumor growth later on. Fortunately though, evidence suggests that both TERT and Ras oncogene inhibition may bring about the death of cancer cells on its own. Telomerase is a ribonucleoprotein complex whose better established function is the synthesis of repeat sequences at the ends of chromosomes (telomers) (8). Since these ends become progressively shorter as a consequence of each cell division, the number of divisions most somatic cells may endure is restricted by telomer length. In this way, tumor cells require a mechanism (telomerase) to keep telomer length despite restless cell division. Along this line, it would seem only logical that telomerase expression blockade in tumor cells would ultimately afAntisense oligonucleotides and the rational design of new antitumor drugs 1130-0108/2005/97/7/467-471 REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS Copyright © 2005 ARÁN EDICIONES, S. L. REV ESP ENFERM DIG (Madrid) Vol. 97, N. ° 7, pp. 467-471, 2005