Current Medicinal Chemistry - Anti-Cancer Agents - Volume 4, Issue 3, 2004

In addition to all-trans-retinoic acid and its 9 and 13-cis isomers, four synthetic retinoids are currently available to treat diseases of hyperproliferation, such as acne, psoriasis, and actinic keratosis, or cancers such as acute promelocytic leukemia, cutaneous T-cell lymphoma, and squamous or basal cell carcinoma. The retinoids extert their antiproliferative effects by interacting with their retinoic acid and retinoid X receptors that act as ligand-inducible transcription factors. These homologous receptors function either directly on retinoid response elements or indirectly by modifying the responses of other transcription factors. Their major domains for binding DNA and their ligands have been characterized by either nuclear magnetic resonance spectroscopy or X-ray crystallography. The identification and design of synthetic retinoids are overviewed, as are their selective interactions with specific retinoid receptor subtypes and their clinical effects against cancer. Emphasis is placed on the retinoid X receptors and their ligands.

Surgery is the only method of cure in lung cancer. Seldom its application with radical intent is possible. Despite the efforts aimed at integrating all the therapeutic strategies, the overall outcome of the management of this disease remains disappointing. For this reason, in the last three decades, thousands of preclinical and clinical attempts have been realised in order to investigate any possible way to cure this disease and significant steps forward have been made on the basis of the increasing “molecular knowledge” in the so called “post-genomic era”. Particularly the impressive step forward in the biological characterization of cancer as a result of genetic / epigenetic multistep process has brought in a multitude of variables with staggering classification potentialities. “Benchside” and “bedside” scientists have assembled in functional teams to move the common efforts “translationally” to bridge basic and clinical research for a mutual synergistic enhancement. This paper represents the effort of a lung cancer focused translational research team made up of molecular biologists, medical oncologists and thoracic surgeons to achieve a comprehensive, but simple, review of the current status of the shift from cytotoxic to molecularly targeted therapy in lung cancer treatment potentially useful in the planning of translational research trials.

The conventional chemotherapy is mostly based on the evidence that proliferating cells are more sensitive to anticancer agents than non-dividing cells. This is the main reason why these compounds are not tumour specific and their selectivity is generally in favour of rapidly growing cells (haematopoietic or intestine. i.e.) rather than discriminating against any fundamental biological difference between normal and tumour cells. The critical issue is at present to identify how tumour cells differ from normal cells and how those differences can be exploited therapeutically for designing and synthesising new drugs with a selective mechanism of action and thus with an improved therapeutic index. This topic and the strategies to identify these new targets will be discussed in details in the review. The expanding knowledge on molecular biology of cancer cells has allowed in the last years the identification of different molecular pathways altered in cancer that could be exploited as potential therapeutic targets. For most of the pathways previously disclosed it has been a problem to develop selective molecules with a relevant clinic impact. To target those specific genetics defects, different kind of molecules (antibodies, “antisense oligonucleotides”, short peptides and small molecules) have been made and some of them are currently under investigation. This review will be focused mainly on three different classes of compounds: I. Compounds designed to hit or inhibit crucial molecular targets. II. Novel DNA minor groove binders. III. Products of marine origin that exhibit novel mode of action.

While the cancer protective effect of soy-based diets has been the subject of numerous studies, the constituents of soy that may give rise to this effect remain elusive. Recent publications describing anticancer activity of crude and purified soybean saponins have sparked a renewed interest in these compounds. In this review, I summarize the epidemiological studies concerning the cancer protective effects of soy and the efforts to elucidate the constituents responsible for this effect. The recent reports of the anticancer activity of soy saponins is placed in context with reports of promising anticancer activity of structurally related non-dietary saponins from other legumes. While recent studies have demonstrated a direct effect of soy saponins on cancer cells, alternative mechanisms of cancer prevention by these agents are also discussed. It is concluded that the soy saponins may represent promising leads both in terms of elucidating the soy constituents involved in the cancer protective effect of soy as well as in the discovery of anticancer agents with novel mechanisms of action.

Histone deacetylases (HDACs) play a critical role in gene transcription and have become a novel target for the discovery of drugs against cancer and other diseases. During the past several years there have been extensive efforts in the identification and optimization of histone deacetylase inhibitors (HDACIs) as novel anticancer drugs. Here we report a comprehensive quantitative structure-activity relationship (QSAR) study of HDACIs in the hope of identifying the structural determinants for anticancer activity. We have identified, collected, and verified the structural and biological activity data for 124 compounds from various literature sources and performed an extensive QSAR study on this comprehensive data set by using various QSAR and classification methods. A highly predictive QSAR model with R2 of 0.76 and leave-one-out cross-validated R2 of 0.73 was obtained. The overall rate of cross-validated correct prediction of the classification model is around 92%. The QSAR and classification models provided direct guidance to our internal programs of identifying and optimizing HDAC inhibitors. Limitations of the models were also discussed.

Due to its capability to induce accumulation of protoporphyrin IX (PpIX) selectively in a multitude of different pathologies, 5-aminolevulinic acid (ALA) and its derivatives have attracted enormous attention in the field of photodynamic therapy (PDT) in the past two decades. The photochemical and photophysical properties of PpIX have been used for the fluorescence photodetection and photodynamic treatment of neoplasms in several medical indications in which conversion of ALA into PpIX seems to take place preferentially. Recently, this has led to the approval of this therapy for the treatment of actinic keratosis and basal cell carcinoma. When applied topically or systemically, ALA bypasses the negative feedback control that haem exerts on the enzyme ALA synthase (ALAS), which catalyses the natural production of this δ-amino acid, thereby temporarily boosting the generation of PpIX, the direct precursor of haem. Despite considerable interest in this treatment methodology, only little is known concerning the reasons for the selective accumulation of PpIX in neoplastic tissue upon ALA administration. Following an introduction into the biochemical as well as the chemical principles of haem synthesis, the present review tries to summarise experimental evidences of the mechanisms underlying preferential production of PpIX in neoplastic tissues. Thereby, morphological, environmental, enzymatic, as well as cell-specific factors will be discussed.