Showing papers in "Current Cancer Drug Targets in 2002"

Sulfonamides and sulfonylated derivatives as anticancer agents.

Abstract: The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A host of structurally novel sulfonamide derivatives have recently been reported to show substantial antitumor activity in vitro and / or in vivo. Although they have a common chemical motif of aromatic / heterocyclic sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle arrest in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained based on computer-aided drug design, are currently being evaluated in clinical trials. This review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed ultimately as effective tumor cell growth inhibitors, or for the treatment of different types of cancer.

Cancer therapy with beta-lapachone.

Abstract: s-Lapachone is an ortho naphthoquinone, originally isolated from a tree whose extract has been used medicinally for centuries. Recent investigations suggest its potential application against numerous diseases. Its lethality at micromolar (μm) concentrations against a variety of cancer cells in culture indicates its potential against tumor growth. A few experiments with positive results have been performed that apply the compound to tumors growing in animals. Particularly promising is the remarkably powerful synergistic lethality between s-lapachone and taxol against several tumor cell lines implanted into mice; the mice did not appear to be adversely affected. Enhanced lethality of X-rays and alkylating agents to tumor cells in culture was reported when s-lapachone was applied during the recovery period, because of inhibition of DNA lesion repair. Clinical trials are still to be initiated. The detailed mechanism of cell death induced by s-lapachone remains for investigation. DNA topoisomerase I was the first biochemical target of s-lapachone to be discovered, although its role in cell death is not clear. A proposed mechanism of cell death is via activation of a futile cycling of the drug by the cytoplasmic two-electron reductase NAD(P) H: quinone oxidoreductase, also known as NQO1, DTdiaphorase and Xip3. Death of NQO1 expressing cells is prevented by the NQO1 inhibitor dicoumarol, and cells with low NQO1 are resistant. At higher drug concentrations the production of reactive oxygen species (ROS) appears to be responsible. Furthermore, this process is p53- and caspase- independent. Either apoptotic or necrotic cell death can result, as reported in various studies performed under differing conditions. s-Lapachone is one of a few novel anticancer drugs currently under active investigation, and it shows promise for chemotherapy alone and especially in combinations.

Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis.

Abstract: IGF-IR (Insulin-like growth factor receptor 1) is a tetrameric glycoprotein composed of two alpha and two beta subunits. The alpha subunit localizes extra-cellularly for ligand binding, whereas the beta subunit consists of transmembrane chains and a cytoplasmic tyrosine kinase domain for enzymatic activity. IGF-IR ligands, IGF-I and IGF-II, are mitogens and survival factors for many cancer cells. Binding of ligands to the IGF-IR initiates a cascade of events leading to activation of signal transduction pathways, mainly MAPK and PI-3K pathways, to stimulate proliferation/mitogenesis, to induce neoplastic transformation, to inhibit apoptosis, and to promote angiogenesis and metastasis. It has been shown that the presence of IGF-IR was required for transformation induced by many oncogenes and over-expression or constitutive activation of IGF-IR gave rise to transformed phenotypes. Significantly, over-expression of IGF-IR was observed in multiple human cancers including carcinomas of breast, lung, colon, and prostate. Patients with IGF-IR positive cancers had a worse prognosis in some cases. Furthermore, down-regulation or functional inactivation of IGF-IR sensitized tumor cells to apoptosis and reversed tumor cell phenotype. Thus, IGF-IR appears to be a promising cancer target. Indeed, a variety of approaches aimed at targeting IGF-IR have been utilized to prove the concept, or are being developed for potential anticancer therapies. These include targeting functional IGF-IR on cell surface, targeting ligand/receptor interaction, targeting receptor expression and functions, and targeting receptor kinase activity. Cancer patients could eventually benefit from the development of these specific IGF-IR antagonists.

Natural products and derivatives as leads to cell cycle pathway targets in cancer chemotherapy.

Abstract: The influence of natural products upon drug discovery in general has been quite impressive; one only has to look at the number of clinically active drugs that are in use in cancer therapy to see how many either are natural products or have a natural pro-duct pharmacophore. What is now becoming quite apparent is that materials from natural sources are excellent probes (indicators) for cellular targets that when modulated, may well have a deleterious effect upon the cycling of a tumor cell through the conventional cell cycle. If the particular target is not expressed in normal cell cycling, then a directed "perturbation" of the tumor cell's cycle may well lead to a novel method of treatment for specific tumor types. In this review we have not attempted to be exhaustive but have given a current overview of how natural products from marine, microbial and plant sources have permitted in-depth analyses of various parts of the cell cycle under varying conditions with the ultimate aims of attempting to "control or perturb" the cycling of tumor cells in a fashion that permits their ultimate removal via cellular death, with a minimum of trauma to the host.

Cancer-Targeted Polymeric Drugs

Abstract: A major challenge in cancer chemotherapy is the selective delivery of small molecule anti cancer agents to tumor cells. Water-soluble polymer-drug conjugates exhibit good water solubility, increased half-life, and potent anti tumor effects. By localizing the drug at the desired site of action, macromolecular therapeutics have improved efficacy and enhanced safety at lower doses. Since small molecule drugs and macromolecular drugs enter cells by different pathways, multi-drug resistance (MDR) can be minimized. Anti-cancer polymer-drug conjugates can be divided into two targeting modalities: passive and active. Tumor tissues have anatomic characteristics that differ from normal tissues. Macromolecules penetrate and accumulate preferentially in tumors relative to normal tissues, leading to extended pharmacological effects. This "enhanced permeability and retention" (EPR) effect is the principal reason for current successes with macromolecular anti-cancer drugs. Both natural and synthetic polymers have been used as drug carriers, and several bioconjugates have been clinically approved or are in human clinical trials. While clinically useful anti-tumor activity has been achieved using passive macromolecular drug delivery systems, further selectivity is possible by active targeting. Attachment of targeting moieties to the polymer backbone can further exploit differences between cancer and normal cells through selective receptor-mediated endocytosis. This strategy would augment the EPR effect, thereby further improving the therapeutic index of the macromolecular drug. This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy. Specific examples are selected to illustrate the basic design principles for soluble polymeric drug delivery systems.

Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan.

Abstract: Topotecan and irinotecan (CPT-11) are both anticancer agents active in the inhibition of topoisomerase I, an enzyme involved in DNA replication and RNA transcription. During the last decades, an immense amount of research into this class of anticancer agents has been conducted, the positive results of which led to the clinical use of topotecan and CPT-11 in ovarian cancer and colorectal cancer, respectively. Here, we review the currently most important pharmacologic aspects of these drugs, including their mechanisms of action, metabolism, activity- and toxicity-profiles and mechanisms of resistance, to provide a global insight into their pharmacology. We also discuss the effects of combinations with other anticancer agents, which have been tested for synergistic antitumor effects. Pharmacokinetic and pharmacodynamic biomodulation, to enhance the bioavailability of the active anticancer agent or to reduce drug related toxicities have currently reached clinical application. As pharmacogenetics enters the clinical stage, this will lead to more "fine-tuning" in anticancer treatment (for instance by individualized dosing). The clarification of the mechanisms of action and resistance of topotecan and CPT-11 should enable us to understand their pharmacological behavior even better and might lead to the development of more potent camptothecin-derivatives in the future.

Integrins as Novel Drug Targets for Overcoming Innate Drug Resistance

Abstract: Acquired drug resistance continues to be one of the major obstacles hindering the successful treatment of many forms of cancer. Compounds utilized as antagonists of these cytoprotective mechanisms have, for the most part, proven to be ineffective at overcoming clinical resistance to cytotoxic drugs. Recently, the tumor cell microenvironment has been found to have a significant bearing on the survival of tumor cells following exposure to a wide variety of anti-neoplastic agents, prior to the acquisition of known drug resistance mechanisms. Specifically, interactions between cell surface integrins and extracellular matrix components have been shown to be responsible for this phenomenon of innate drug resistance, which we have termed Cell Adhesion Mediated Drug Resistance, or CAM-DR. Following its discovery using a multiple myeloma cell line model, evidence for CAM-DR has been found in a multitude of other human tumor cell types. In contrast to many other drug resistance mechanisms, integrin-mediated cell signaling is capable of protecting against death induced by an extremely wide variety of structurally and functionally diverse agents from traditional DNA damaging agents to the promising novel kinase inhibitor STI-571. This review examines the role of integrins in regard to their ability to protect tumor cells from drug- and radiation-induced apoptosis through numerous intracellular mechanisms. Current and future antagonists of specific integrin heterodimers may have the potential to sensitize tumor cells when used in combination with standard chemotherapy regimens. Specific signal transduction pathways initiated by integrin ligation will also be discussed as potential bridge points for inhibiting cell survival during cytotoxic drug exposure.

Mutant Epidermal Growth Factor Receptors as Targets for Cancer Therapy

Abstract: The epidermal growth factor (EGF) receptor is overexpressed in many cancers, and is under intensive investigation as a target for cancer therapy. Cancer cells have also been shown to express mutated EGF receptors; these are potentially highly specific targets for cancer therapeutics, as they have not been detected in any normal adult tissues. The most common of these mutant EGF receptors, EGFRvIII, is one in which amino acids 6 - 273 of the extracellular domain are deleted. This specific mutation is common in glioblastoma and in several other types of cancer, and has been shown to promote aggressive growth of tumors in vivo. The loss of part of the extracellular domain results in a receptor that has constitutive tyrosine kinase activity. Current evidence suggests that EGFRvIII has altered signalling properties compared to normal EGF receptor. The mutation in EGFRvIII also creates a new, cancer cell-specific epitope. This epitope is extracellular and therefore represents a very promising target for antibody-directed therapeutics. This review covers our current understanding of the properties of EGFRvIII, and recent developments in the characterization and therapeutic application of EGFRvIII-specific antibodies.

Modulating cell cycle: current applications and prospects for future drug development.

Abstract: The cell cycle is a highly conserved and ordered set of events, culminating in cell growth and division. It is tightly controlled by many regulatory mechanisms that either permit or restrain its progression. The main families of regulatory proteins that play key roles in controlling cell cycle progression are the cyclins, the cyclin dependent kinases (Cdks), their substrate proteins, the Cdk inhibitors (CKI) and the tumor suppressor gene products, p53 and pRb. Many cell cycle control genes, when deregulated, can cause cells that are not dividing to enter the cell cycle and begin to proliferate leading to cancer development. They do so by interfacing with the basic cell cycle regulatory machinery to activate cell cycle entry. There is at present much optimism about the possibility of finding anticancer drug treatment strategies that modulate cell cycle regulatory molecules. Candidate targets for such strategies include crucial cell cycle molecules involved in G(1) to S phase or G(2) to M phase transition. This review will outline the basic regulatory machinery responsible for catalyzing cell cycle entry and describe the latest advances made in the field of cell cycle regulation. The basis of targeting the cell cycle particularly the Cdks as an approach to developing novel, specific and perhaps more effective anticancer treatments will be discussed. Examples of novel cell cycle-targeting agents that are in, or are close to being in clinical trials will be provided.

WT1 as a Novel Target Antigen for Cancer Immunotherapy

Abstract: Wild-type Wilms tumor gene WT1 is expressed at high levels not only in most of acute myelocytic, acute lymphocytic, and chronic myelocytic leukemia, but also in various types of solid tumors including lung cancer. We tested the ability of the gene product (WT1) to serve as a target antigen for tumor -specific immunotherapy both in human in vitro system and mouse in vivo system. In the latter, we can evaluate the efficacy and the side effects of WT1 vaccination in vivo. In the human in vitro system, two WT1 peptides that contain HLA-A2.1 binding anchor motifs were determined to bind to HLA-A2.1 molecules. Peripheral blood mononuclear cells (PBMC) from an HLA-A2.1-psitive donor were repeatedly stimulated in vitro with TAP-deficient T2 cells pulsed with each of these two peptides, and CD8-positive cytotoxic T lymphocytes (CTLs) that specifically lyse WT1-expressing, HLA-A2.1-positive tumor cells were induced. Other groups also have succeeded in generating CTLs which specifically lyse WT1-expressing leukemia cells, and which do not inhibit colony-formation of normal hematopoietic cells that express WT1 at physiological levels. In the mouse in vivo system, immunization of C57BL / 6 mice with one WT1 peptide with relatively high binding affinity for H-2D b molecules, which contain H-2D b binding anchor motifs, induced CTLs, which specifically lysed WT1-expressing tumor cells in an H-2D b -restricted manner. Furthermore, mice immunized with the WT1 peptide (peptide vaccination) or WT1 cDNA (DNA vaccination) rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to WT1-expressing normal organs by the induced CTLs. The WT1 protein has been identified as a novel tumor antigen and recent investigations provide a rationale for developing WT1-based adoptive T cell therapy and vaccination against various kinds of malignant neoplasms.

Examining the Relationship between Cancer Invasion / Metastasis and Drug Resistance

Abstract: Studies of cancer invasion/metastasis and drug resistance have in the past generally proceeded along the separate pathways of research. Recently, however, interest has been focused on the possible relationship between drug resistance and cancer invasion and metastasis. A relationship between these two phenotypes has been demonstrated by two types of observation: firstly, some tumor cells selected for resistance to drugs are more invasive/metastatic relative to non-resistant parental cells; secondly, in some cases, secondary (more metastatic) tumors are more resistant to chemotherapeutic drugs than their primary counterparts. In other instances reported in the literature, no correlation is seen between drug exposure/resistance and cancer invasion/metastasis. The possibility that treatment with some chemotherapeutic drugs may be able to promote cancer invasion and metastasis needs further investigation because of its potential clinical relevance. A better understanding of any relationship between drug resistance and cancer invasion could lead to more effective cancer treatment.

Clinical development of angiogenesis inhibitors to vascular endothelial growth factor and its receptors as cancer therapeutics.

Abstract: Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity The potential application of these angiogenesis inhibitors is currently under intense clinical investigation Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent potential targets for therapeutic intervention This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis A number of agents designed specifically for targeting VEGF and / or its receptors are being evaluated in various clinical trials in cancer patients This review will discuss the biology of the VEGF and its receptors, the mechanisms of action as well as the current status in clinical development of antagonistic agents to VEGF and its receptors Included in this review are antagonistic antibodies, ribozymes, immunotoxins, and synthetic small molecular inhibitors

Chromatin (dis)organization and cancer: BUR-binding proteins as biomarkers for cancer.

Abstract: Malignant transformation of cells is associated with changes in gene expression. Gross alterations in chromatin organization may be involved in such gene dysregulation, as well as the involvement of specific transcription factors. Specialized genomic DNA segments that exhibit high affinity to the nuclear matrix in vitro have been designated as matrix/scaffold attachment regions (MARs/SARs). MARs are postulated to anchor chromatin onto the nuclear matrix, thereby organizing genomic DNA into topologically distinct loop domains that are important in replication and transcription. In support of this notion, MARs often colocalize or exist in close proximity to regulatory sequences including enhancers. Base unpairing regions (BURs) are typically 100-150 bp regions within MARs, possess an intrinsic propensity to unwind under negative superhelical strain, and are considered to be hallmark of MARs. To investigate a potential mechanism that could lead to significant alterations in gene expression in cancer cells, this review focuses on a group of chromatin-associated proteins that specifically recognize double stranded BURs. Several important proteins have been identified from cancer cells as BUR-binding proteins, including poly (ADP-ribose) polymerase (PARP-1), Ku autoantigen, SAF-A, HMG-I(Y), nucleolin and p53. Many of these proteins are dramatically upregulated in malignancy of the breast. Increase in the amount of these BUR-binding proteins, some of which are known to interact with each other, may not only provide an architectural core but also recruit functional multi-molecular complexes at the base of chromatin loops to affect multiple distant genes. Experimental strategies by which these proteins can be exploited as carcinoma-specific diagnostic markers and as targets for antineoplastic therapy are discussed.

Diphtheria fusion protein therapy of chemoresistant malignancies

Abstract: Patients with widespread cancer respond initially to combination chemotherapy, immunotherapy, and/or radiotherapy, but most relapse with chemoresistant disease. Novel methods of killing resistant neoplastic stem cells are needed. One such approach is therapy with targeted toxins composed of tumor cell selective ligands covalently linked to group I peptide toxins (group II and III peptide toxins act on the cell surface). The targeted toxin is delivered to the cell by a tumor selective ligand. Once bound, the ligand-receptor complex is internalized. The catalytic domain escapes to the cytosol. The toxin then enzymatically modifies a critical cell function (protein synthesis, p21 Rho activity, protein kinase signaling, cyclic AMP signaling or others). The irreversibly damaged cells fails to divide and, eventually, undergoes lysis or programmed cell death. Targeted peptide toxins used to date in the treatment of chemotherapy refractory cancers include ricin toxin, Pseudomonas exotoxin, pokeweed antiviral protein, saporin, gelonin and diphtheria toxin. In this review, we have focused on the applications of genetically engineered diphtheria toxin for cancer therapy.

Protein kinase C-theta (PKCtheta), a potential drug target for therapeutic intervention with human T cell leukemias.

Abstract: The link between apoptosis and malignant cell growth is firmly established, and various forms of therapy in cancer, e.g., the use of DNA-damaging chemotherapeutic drugs, are based on the principle of inducing apoptosis in malignant cells. However, in many known instances, tumor cells develop resistance to apoptosis through various mechanisms. Thus, interventions designed to facilitate tumor cells apoptosis are likely to have a therapeutic benefit. PKCtheta, which is expressed relatively selectively in T cells, plays an important role in mature T cell activation and proliferation upon its translocation to the plasma membrane. PKCtheta is necessary for induction of the interleukin-2 (IL-2) gene because the transcription factors AP-1 and NF-kappaB, which are essential for IL-2 gene promoter activation, are main targets of PKCtheta. Recent studies revealed that PKCtheta provides an important survival signal that protects leukemic T cells from Fas- or UV-induced apoptosis. These findings and the constitutive localization of PKCq in the membrane of some leukemic T cells suggests that it plays a role in leukemic T cell survival and/or proliferation, and that selective PKCtheta-inhibitory strategies may facilitate elimination of malignant T cells. The high-affinity IL-2 receptor (IL-2Ralpha) is a major target of receptor-directed therapy in several human diseases, and it is constitutively expressed by the malignant cells in some T cell leukemias, suggesting an autocrine IL-2/IL-2R loop that participates in the expansion of leukemic IL-2R(+) cells. Therefore, given the essential role of PKCtheta in IL-2 production, IL-2 gene regulation by PKCtheta could also be of therapeutic interest.

Identifying Molecular Targets Mediating the Anticancer Activity of Histone Deacetylase Inhibitors: A Work in Progress

Abstract: The anticancer properties of histone deacetylase inhibitors have been known for some time. However, it is only recently that the functional identities of the intracellular targets mediating the anticancer properties have started to be revealed. These targets appear to play significant roles in cell cycle control, apoptosis and differentiation. Importantly, the modulation of these activities is likely to be mediated by alterations in the acetylation status of both histone and non-histone targets. Identification of these targets, and the specific histone deacetylase enzymes that modulate them, is an important step in designing rational-based therapies for the treatment of cancer. In this review we discuss the state of progress in identifying the molecular pathways/events mediating the anticancer activity of histone deacetylase inhibitors.

Receptor selective synthetic retinoids as potential cancer chemotherapy agents.

Abstract: For many years, the vitamin A metabolite retinoic acid (RA) has been known to have profound effects on development, cellular proliferation and differentiation, and tumor growth and invasion. The wide-ranging effects of RA on cellular proliferation and migration have made it a useful chemotherapeutic agent in the treatment of many types of cancer. In the last fifteen years, with the discovery of nuclear receptors for RA, the molecular basis for the effects of this molecule has become apparent. Retinoic acid receptors (RAR) are members of a superfamily of ligand dependent transcription factors that interact with an increasingly large array of coactivators and repressors to regulate target gene expression through binding to cognate recognition sequences in the promoters of these genes. Alterations in RAR expression and function have been demonstrated in many types of cancer. The translocation of RARalpha with PML or PLZF genes in acute promyelocytic leukemia is a paradigm of the role of RARs in cancer biology. In addition, the development of receptor selective synthetic retinoids has greatly expanded our knowledge of RAR function in tumor cells and provided additional treatment options for cancer patients. This review will examine the development of receptor selective retinoids, their uses to date, and future potential.

The use of synthetic oligonucleotides as protein inhibitors and anticode drugs in cancer therapy: accomplishments and limitations.

Abstract: The function of gene products can be altered at many levels, including the mutation of gene sequence and the change in steady state levels of mRNA and/or protein by various mechanisms. The cumulative malfunction of specific gene products underlies many pathological conditions such as the multi-step and multi-cause acquisition of cancer. Here we discuss two oligonucleotide-based strategies in which these compounds target defective gene products acting either as antiprotein or anticode agents. The SELEX technique (systematic evolution of ligands by exponential enrichment) is an antiprotein approach in which nuclease-resistant DNA or RNA aptamers are selected by their ability to bind their protein targets with high affinity and specificity of the same range as antibodies. Such inhibitors were previously evolved against a great variety of targets, including receptors, growth factors and adhesion molecules implicated in the genesis of some kinds of cancer. Moreover, some results have already been obtained in animal models. The antigene technology interferes with earlier steps in the information flow leading from gene to protein. In this approach selective gene silencing is provided by the formation of stable and specific complexes between triplex forming molecules and their DNA targets. The feasibility of this strategy as well as a molecular mechanism for the action of antigene oligonucleotides has been demonstrated in cellular systems and in vivo. The use of oligonucleotide drugs (of either the antiprotein or the anticode type) as a viable approach to cancer therapy is limited by some common problems that will be discussed.

Pharmacogenomics Opportunities in Nuclear Receptor Targeted Cancer Therapy

Abstract: Nuclear Hormone Receptors (NR) represent one of the most promising protein families in terms of therapeutic applications. These transcription factors are naturally switched on and off by small molecule hormones presenting physico-chemical properties very similar to therapeutic chemical entities. NRs represent therefore intrinsically a very good family of protein targets for the prevention and treatment of diverse diseases, including cancer. Several known anti-cancer drugs, such as tamoxifen or flutamide, are targeting NRs, and many more are expected to reach market. The detailed knowledge of the structural mechanism underlying activation and inhibition of NRs by small molecule modulators begets important therapeutic opportunities. The crystal structure of at least nine NR ligand binding domains (LBDs) revealed at the atomic level how natural or synthetic agonists and antagonists can promote recruitment of co-activator and co-repressor proteins. Interestingly, it was recently shown that nucleotide polymorphisms located in NR LBDs could alter or even reverse the response of the receptors to small molecule ligands. Mapping these polymorphisms on the structure of the LBD can reveal why agonists or antagonists become inactive against the mutated receptor, allow atomic models for resistance to cancer therapy, and open the door to the rational design of improved anti-cancer drugs, customized for each patient.

Prospects for anti-neoplastic therapies based on telomere biology.

Abstract: The maintenance of specialized nucleoprotein structures at the ends of human chromosomes called telomeres is essential for chromosome stability, and plays a fundamental role in the regulation of cellular lifespan. Without new synthesis of telomeres, chromosome ends shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cell immortalization and in cancers. Recent work has demonstrated that inhibiting or targeting telomerase shows promise as a novel anti-neoplastic strategy; however, the biology of telomeres and telomerase predict that such approaches will differ in important ways from traditional cytotoxic drug therapies. Understanding telomerase biology may eventually lead to several types of clinically effective, telomerase-based therapies for neoplastic disease.