Current Medicinal Chemistry - Anti-Cancer Agents - Volume 4, Issue 5, 2004

The pages of Current Medicinal Chemistry - Anti-Cancer Agents - Anti-Cancer Agents (CMC-ACA) are usually devoted to review articles on specific, well defined subjects. I thought that this strict, conventional format could be temporarily modulated to led more space to opinions and critical ideas. Expressing general views and comments is also a legitimate function of a journal like CMC-ACA devoted to covering the anti-cancer enterprise in its entirety. It is interesting to comment on current strategic issues that involve the anti-cancer field. To do so, the member of the Editorial Board have been solicited to contribute to short (but sharp) letters, mainly to express their point of view on our field of research. The development of anticancer agents has taken new directions over the past few years with the increased design of target-oriented compounds. “Where is antitumor pharmacology going ?”. This is the question addressed in this issue of CMC-ACA. Of course there is no simple answer to that question but problems and strengths have been identified to propose solutions and raise novel approaches for the development of efficient anticancer drugs. Many members of the editorial board have contributed to this special issue and their contributions are greatly appreciated. A few articles are concerned with accurate, timely and balanced coverage of various elements of the anticancer drug discovery aspects. Other articles are devoted to commentaries on issues that affect our field at the chemical and biological levels. These opinions are intended to stimulate informed discussions among the readers of the journal.

In recent years, efforts have been made to improve the selectivity of anti-cancer agents via the targeting of cancer-specific proteins or signalisation pathways. Novel anticancer drugs inhibiting defined kinases, the proteasome, and selected growth factor receptors for examples have been developed with success for a few cancer types. But in parallel to these novel “soft” drugs, conventional “hard” cytotoxic molecules targeting DNA, topoisomerases or tubuline remain extensively used to treat solid tumors. This letter evokes the utility and limitations of the two drug categories and comments on new directions of the antitumor pharmacology taken to improve the efficacy of cancer chemotherapy and the development of new molecules.

The cancer mortality remains high, although progress has been attained by chemotherapy and other therapeutic strategies. Effective cancer prevention interventions would markedly reduce the cancer mortality burden, thus chemoprevention and chemotherapy must be seen as complementary approaches to fight human cancers. Nevertheless, our understanding of drug mechanisms of action is rather limited as we do not know the behaviour of highly-complex regulatory networks of the cell and how they respond to a particular small molecule. Similarly, that limits a truly rational approach to drug discovery and identification of good molecular targets. Until we get deeper insights into fundamental mechanisms of cellular functions, the approach to drug design and discovery will remain empirical.

The occurrence of hypoxic cells in solid tumors, and their resistance to radiotherapy and many chemotherapeutic drugs, has engendered an interest in non-toxic prodrugs that can be activated selectively under hypoxic conditions. Despite this, no such compounds are yet registered for clinical use, due to the difficulty of their design and of measuring the extent of hypoxia clinically, and the failure of early examples. A new appreciation of the critical importance of the extravascular diffusion of the parent prodrug from the blood vessels to the remote hypoxic cells, and the back-diffusion of the activated cytotoxin from the hypoxic cells to surrounding tumor cells, is now guiding drug design in this area. New principles for the selective activation of prodrugs have also been reported, including using the re ducing spec ies gene ra ted in c ells by ra diother apy itse lf , a nd using non-pathogenic anerobic bacteria as a hypoxia-dependent vector for the delivery of prodrug-activating enzymes in a suicide gene therapy context.

The availability of high-quality molecular graphics tools in the public domain is changing the way macromolecular structure is perceived by researchers, educators and students alike. Computational methods have become increasingly important in a number of areas such as comparative or homology modelling, functional site location, characterization of ligand-binding sites in proteins, docking of small molecules into protein binding sites, protein-protein docking, and molecular dynamics simulations. The results obtained yield information that sometimes is beyond current experimental possibilities and can be used to guide and improve a vast array of experiments. On the basis of our improved level of understanding of molecular recognition and the widespread availability of target structures, it is reasonable to assume that computational methods will continue aiding not only in the design and interpretation of hypothesis-driven experiments in the field of cancer research but also in the rapid generation of new hypotheses.

This short perspective briefly covers selected aspects of the past, present and future of antifolates in chemotherapy. Both classical and nonclassical analogs currently in the preclinical stage and clinically used agents are covered.

The recent approval of cetuximab and bevacizumab by FDA for the treatment of metastatic colorectal cancer witnesses the investments of biotech companies in the development of monoclonal antibodies (Mabs) as cancer therapeutics. Several analyses point to the growth of the market for these drugs, and forecast an even higher expansion of sales following completion of several clinical trials, both of approved Mabs tested for other cancers, and of new Mabs aimed at different tumor antigens. Not unsurprisingly, the latest additions to the number of therapeutic Mabs belong to the classes of chimeric and humanized antibodies. A great effort has been made in the last years to overcome the intrinsic limitations of the technology used to produce monoclonal antibodies. The knowledge accumulated in the search of newer ways of production of recombinant therapeutic proteins is reflected by the number of fully human Mabs in the pipeline. Moreover, a thorough understanding of the cellular and molecular events underlying the activity of cancer-aimed antibodies allows the optimisation of these drugs for the treatment of high incidence solid tumors.

A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Most anticancer drugs are known to cause severe side effects. Nontoxic amplification of DNA-cleaving activity of anticancer drugs would enable to reduce drug dose and side effects, leading to development of effective chemotherapy. As a method to approach new cancer chemotherapy, we have investigated the enhancing effects of DNA-binding ligands (“amplifiers”), especially minor groove binders and intercalators, on anticancer drug-induced apoptosis and DNA cleavage, using human cultured cells and 32P-labeled DNA fragments obtained from the human genes. We have demonstrated as follows: a) DNA-binding molecules (unfused aromatic cations, distamycin A and synthtic triamides) induced amplification of bleomycin-induced DNA cleavage and apoptosis; b) a minor-groove binder distamycin A enhanced duocarmycin A-induced DNA cleavage; c) actinomycin D altered the site specificity of neocarzinostatininduced DNA cleavage and distamycin A enhanced C1027-induced apoptosis. The mechanism of amplification of DNA cleavage can be explained by assuming that binding of amplifier changes the DNA conformation to allow anticancer drug to interact more appropriately with the specific sequences, resulting in enhancement of anticancer effect. The study on amplifiers of anticancer agents shows a novel approach to the potentially effective anticancer therapy.

Despite a number of advances in the past decades the medicinal cancer therapy is hampered by problems of severe unwanted side effects and the development of resistances. Many established anti-cancer drugs are directed toward targets that are not specific for cancer but are essential biochemical molecules in living cells. Because cancer cells do not only carry one but multiple genetic alterations which are more characteristic for the individual patient than for the tumor entity, an individualized medicinal approach could improve the success of a tumor therapy. A prerequisite for personalized tumor therapies is an upgrade of the array of anticancer drugs directed to different molecular targets. Therefore, a systematic search for anticancer drug targets should constitute a research priority. The database of fingerprints of new chemical entities generated in the National Cancer Institute's Anticancer Drug Screening is a rich source of novel targets which might be uncovered by the interdisciplinary application of methods from bioinformatics, biochemistry, chemistry, tumor biology and related sciences.

A major need in cancer chemotherapy is the availability of cancer cell-specific drugs. This paper discusses recent advances and perspectives in the field of selective drug recognition considering the key targets tyrosine kinases, DNA-topoisomerases and telomerase.

Camptothecins selectively target topoisomerase I (Top1) by trapping the catalytic intermediate of the Top1- DNA reaction, the cleavage complex. Hence, camptothecins represent a paradigm for targeting macromolecular interactions. Instead of preventing the binding of the two macromolecules they target (Top1 and DNA), camptothecins slow down the dissociation of these macromolecules. The activity of camptothecins underlines the usefulness of screening for drugs that inhibit the dissociation of macromolecules. Camptothecins and non-CPT Top1 inhibitors are being developed to improve the pharmacodynamics, pharmacokinetics and clinical pharmacology of camptothecins, and it is likely that drugs with improved anticancer activity will be discovered. Although Top1 is the only primary target of camptothecins, the mechanisms of camptothecins' anticancer activity rest beyond the formation of cleavage complexes. Indeed, Top1 cleavage complexes lead to replication- (and transcription-) mediated DNA damage. It is likely that DNA damage can be repaired more efficiently in normal than in cancer cells that are intrinsically deficient for DNA repair and cell cycle checkpoints. Evaluating such deficiencies in clinical samples is becoming possible. If specific deficiencies are associated with clinical responses, their detection should guide therapeutic decisions. Furthermore, targeting DNA repair (Tdp1) and checkpoints (ATM, Chk1 and Chk2) might increase the selectivity of Top1 inhibitors for tumors, thereby increasing the antitumor activity while reducing the side effects of Top1 inhibitors.

During the cell cycle that leads to mitosis, checkpoints are activated in response to DNA damage. The checkpoints control the ability of cells to arrest the cell cycle allowing time to repair the DNA. In more than 50% of cancer cells, the G1 checkpoint is inactive due to mutations of p53. Therefore, the combination of a DNA damaging agent with a G2 checkpoint inhibitor should force selectively cancer cells into a premature and lethal mitosis. This approach which has recently drawn considerable interest is discussed in this paper.

The extremities of chromosomes end at telomeres in a G-rich single stranded overhang that may adopt peculiar structures such as T-loop and G-quadruplex. G-quadruplex is a poor substrate for telomerase activity and different classes of small molecule ligands that selectively stabilize this structure and inhibit telomerase activity have been selected by screening or synthesized by oriented chemistry. These ligands differ from catalytic inhibitors of telomerase by several points that were discussed in the present review, with a special emphasis on their biological activity as potential antitumor agents.

Successful cancer treatments of the future are being developed with a focus on the molecular targets underlying the pathophysiology of neoplasia. Prominent targets which have emerged are those which are mutated in the course of a cancer's development, and mediate activation or release from suppression of pathways mediating proliferation or apoptosis. These arguably are “pathogenic” targets. However, equally important are targets which can be defined on the basis of “large scale” analysis techniques of gene or protein expression in tumors which define targets expressed as a result of a tumor's differentiation state or tissue of origin (“ontogenic” targets); targets mediating drug uptake or metabolism (“pharmacologic” targets), and “microenvironmental” targets mediating the alteration of tumor stromal elements. Irrespective of the nature of the molecular target which is the focus of new therapeutic efforts, target definition in susceptible tumors or patients ideally would be part of the development plan. In addition, an understanding of the therapeutic index which might be achieved in host vs tumor tissues using a surrogate or actual marker of drug effect ideally would be available from animal models and inform the development strategy in humans.

Small-molecule drug discovery for cancer therapy is making extraordinary progress within the realm of advancing novel oncogenic protein kinase inhibitor lead compounds of significant impact to both basic research and clinical testing. In this perspective, structure- and mechanism-based drug design are highlighted relative to such progress. Also, evolving concepts in novel oncogenic protein kinase inhibitor drug discovery is highlighted relative to therapeutic target selectivity, including the recent identification of oncogenic kinase mutants effecting drug-resistance or enhanced drug susceptibility to small-molecule inhibitors.

Resistance remains a major problem in the clinical utility of cancer chemotherapy. However, it also represents a tumour cell phenotype that is in many ways different, and thus distinguishable, from the majority of normal cells. Two approaches to the targeting of resistant cells are described involving intratumoral P450 expression, mechanisms of drugefflux and defective DNA repair. It is suggested that the view of the solid tumour as a complex organ rather than a collection of individual cells will inform future drug development and both overcome and target multiple resistance mechanisms.

The abstract for this article is not available.