Current Cancer Drug Targets, 2006, 6, 561-571 1 1568-0096/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. Telomeres and Telomerase: Pharmacological Targets for New Anticancer Strategies? F. Pendino 1 , I. Tarkanyi 1,2 , C. Dudognon 1 , J. Hillion 1 , M. Lanotte 1 , J. Aradi 2 and E. Ségal-Bendirdjian 1,* 1 INSERM U685, Hôpital Saint-Louis, Institut d'Hématologie, 1, avenue Claude Vellefaux, 75010 Paris, France 2 Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Egyetem ter 1, Life Science Building, H-4012 Debrecen, Hungary Abstract: Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential. "They conceive a certain theory, and everything has to fit into that theory. If one little fact will not fit it, they throw it aside. But it is always the facts that will not fit in that are significant". “Death on the Nile”. Agatha Christie. Keywords: Telomerase, telomeres, senescence, immortalization. INTRODUCTION New pharmacologically active compounds with undisclosed mechanisms promoted most of the major advances in medical oncology. During the last decade, the situation has changed significantly. Due to the tremendous new information in the field of cell biology, including the sequence of the human genome, large number of feasible targets has emerged, among them the telomerase enzyme becoming one of the most attractive and exciting ones. During the last 3 years, more than 2000 papers have been published on telomerase. Many articles among them are about the detection and the measurement of telomerase in a wide variety of human normal and tumor tissues. Telomerase was first detected in cervical cancer in 1989 [1]. Extensive characterization of telomerase activity was made possible through the development of the highly sensitive telomeric repeat amplification protocol-polymerase chain reaction (TRAP-PCR) assay [2]. The development of this assay led to an expansion in the ability to detect telomerase activity in human cancer cells [3]. *Address correspondence to this author at the Evelyne Ségal-Bendirdjian, INSERM U685, Institut d’Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France; Tel: + 33 1 53 72 21 33; Fax: + 33 1 42 40 95 57; E-mail: segal@stlouis.inserm.fr Telomerase is activated in more than 85% of malignant tumors. In contrast, telomerase activity is usually not detectable in normal somatic tissues except for some self- renewing tissues with high regenerative potential. It is not yet elucidated whether hTERT expression in human cancer cells is due to reactivation following genetic alteration, or whether there is a selection of rare telomerase-positive stem cells during tumor progression [4]. These observations suggest that telomerase is a new marker of cancer and raise the possibility that anti-telomerase compounds may provide a new generation of cancer therapeutics. This article reviews the basic background information about the biology of telomeres and telomerase and presents several approaches currently under investigation to inhibit telomerase expression and activity. TELOMERES In the late 1930s, Hermann J. Muller and Barbara McClintock defined the natural chromosomal ends as specialized structures called telomeres (from the Greek, telos, meaning end and meros, meaning part) that are distinct from the chromosomal breaks and prevent unwanted end-to-end fusion or nucleolytic degradation [5, 6].