Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 5, 2009

Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.

It is well known that cancer is defined as a group of diseases that differ both regarding the tissues they affect as well as their origin. For this reason, much effort is being made in the development of new drugs with the aim of increasing survival and patients' quality of life. There is already a wide spectrum of anti-cancer agents that follow different mechanisms of action, such as the inhibitors of topoisomerases I and II and anti-mitotic chemicals, among others. Usually, these drugs are able to increase the patient's survival, although their toxicity worsens the patient's quality of life. Therefore, we should seriously consider alternative mechanisms, as well as the co-administration of these drugs with non-toxic compounds, such as melatonin or retinoic acid. This would increase the toxic effects of these drugs at low doses. Obviously, a better understanding of modified physiological systems during the development of these diseases would improve the diagnostic tools. This would be translated, in turn, into a higher survival index. The alteration of the proteolytic enzymes involved in the renin-angiotensin system and in the regulation of the gonadotrophins and TRH synthesis in breast cancer are examples of the above. These two proteins are regulated by the same enzyme, pyrrolidon carboxipeptidase, and both are directly involved in the initiation and development of breast cancer. Therefore, the aim of the present review is to revise the different options available at present to improve patients' survival and to show alternative mechanisms that may be beneficial to patients' well being.

Although cancer is considered to be a disease caused by DNA alterations, the high genetic variability of tumor cells makes it difficult to exploit these alterations for the treatment of cancer. The influence of non-genetic factors on cancer is increasingly being acknowledged and a growing line of research suggests that hypoxia (a decrease in normal oxygen levels) may play a fundamental role in the development of this disease. This line of research is supported by the fact that tumors often have hypoxic areas, that hypoxia activates the hypoxia-inducible factor 1 (HIF-1) and that HIF-1 activation plays a key role in cancer development. Evidence suggests, however, that the idea of hypoxia playing a central role in cancer development has some drawbacks. For instance, hypoxia has not been found in many tumors, HIF-1 activation has been observed in non-hypoxic tumor areas, and hypoxic tumor cells commonly have a reduced nutrient supply that restricts cell proliferation and tumor growth. This article reviews the literature that does not support the idea of hypoxia playing a central role in cancer development and discusses a broader view in which the role of oxygen in cancer is not limited to a reduction in its normal levels. According to this novel view, a deviation of the oxygen metabolism from the pathway that generates energy to the pathway that produces reactive oxygen species is crucial for cancer development. Interestingly, this switch in oxygen metabolism occurs under both hypoxic and normoxic conditions and may be exploited therapeutically.

Inhibitors of isoprenoid biosynthesis are widely used to treat human disease including statins and nitrogenous bisphosphonates. Due to the importance of core human isoprenoid biosynthesis for diverse cellular processes related to cancer cell growth and metastasis, inhibition of this pathway may produce beneficial anticancer consequences. For example, ras oncogenes are well known; ras proteins are overexpressed in many human cancers, and these proteins must be isoprenylated to function. The rho proteins are important for regulating cell motility, and also must be isoprenylated. This has drawn significant attention to inhibitors of protein prenyl transferases. In addition to the reactions that are targeted in current clinical applications, there are other enzymes that have not been studied as extensively. Inhibition of these enzymes, from mevalonate kinase to geranylgeranyl diphosphate synthase, could be attractive as a single agent therapy or in combination with current agents for treatment of cancers in which isoprenylated proteins have been implicated. While detailed in vivo data for many of these putative targets is lacking, there have been several breakthroughs in recent years that could facilitate further studies. In particular, compounds that specifically inhibit some of the downstream isoprenoid biosynthesis enzymes have been developed and their effects in cancer models are emerging. This review will discuss current knowledge of these lesser known isoprenoid pathway enzymes, identify trends in the development of their small molecule inhibitors, and describe the applications and effects of these compounds in cancer models.

Taxanes (paclitaxel and docetaxel) are currently used to treat ovarian, breast, lung, and head and neck cancers. Despite its clinical success taxane-based treatment could be significantly improved by identifying those patients whose tumors are more likely to present a clinical response. In this mini-review we discuss the accumulating evidence indicating that the breast and ovarian cancer susceptibility gene product BRCA1 mediates cellular response to taxanes. We review data from in vitro, animal, and clinical studies, and discuss them in context of response to therapy. We argue that levels of BRCA1 in tumors may provide a predictive marker for the response to treatment with taxanes. In addition, the study of the role of BRCA1 in the mechanism of action of taxanes might reveal alternative approaches to avoid resistance.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a central role in growth, proliferation, and anti-apoptotic mechanisms to promote cell cycle and survival not only in normal cells but also in a variety of tumor cells. Thus, the PI3K/Akt pathway, including the downstream effectors, may be a critical target for cancer therapy. Although this pathway has been investigated rigorously and dissected in detail in many physiological systems, its role in molecular target therapy for cancer remains to be established. Hematological malignancies such as leukemia, lymphoma, and myeloma can be ideal models for molecular targeting therapy because of the ease in obtaining samples for examining the effect of inhibitors of target molecules with critical roles in tumor growth and progression. In fact, several inhibitors, such as imatinib in Philadelphia chromosome-positive leukemia and bortezomib in multiple myeloma, have proved quite useful in clinics. Because the PI3K/Akt pathway is active in various hematological malignancies, inhibitors related to this pathway have been confirmed to induce apoptosis in these tumor cells. Efforts to exploit selective inhibitors of the PI3K/Akt pathway that show effectiveness and safety in the clinical setting are underway. We review the recent progress in molecular targeting therapy for the PI3K/Akt pathway in hematologic malignancies.

Environmental pollution resulting from fast-paced industrialization, various chemicals used in agriculture, additives in food, smoking and use of alcohol, radiation, some viruses and poor dietary habits all have currently increased the incidence and types of cancer. Polycyclic hydrocarbons are an example of this type of carcinogens. Living things are exposed to this free radical-increasing substance due to various reasons. Oxidative stress caused by reactive oxygen species has an important place in the etiology of cancer, which develops in relation to many factors. Injury caused by cancer in the organism may affect other organs, as well as the tumors organs and tissues. In addition, it is known that some changes take place in the content of macro and trace elements due to cancer in the organism. Our study is intended to explore the protective role of alpha-lipoic acid, which has antioxidant characteristics in living tissues exposed to oxidative stress, in the macro and trace element levels.

Protein tyrosine kinases are enzymes which catalyze the phosphorylation of tyrosine residues and activate a downstream cascade of cellular signalling pathways which regulate cell proliferation, differentiation and apoptosis and a wide variety of cellular functions. Clinical developments over the past decade have identified several novel therapeutic agents which inhibit tyrosine kinase activity, either by direct receptor inhibition or indirect inhibition of tyrosine kinase controlled pathways. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib have been studied extensively in patients with refractory non-small cell lung cancer (NSCLC). Early studies with gefitinib showed undoubted clinical activity but failed to show a survival benefit, whereas studies with erlotinib showed a small but statistically significant benefit in overall survival. Subsequent studies explored the possibility of synergistic activity between targeted agents (gefitinib or erlotinib) and conventional chemotherapy drugs reporting disappointing results. Clinical trial results with gefitinib and erlotinib, either as monotherapy or in combination with chemotherapy, have failed to match the encouraging results noted in the pre-clinical setting. It is now increasingly recognised that clinical exploration of molecular targeted agents may not conform well to traditional phase I/II/III drug trial designs. Therapeutic responses may be limited to a small subpopulation of patients, therefore diluting the overall therapeutic effect. Hypothesising a genetic basis for the heterogeneity in trial results, biomarkers (such as EGFR gene mutation analysis, EGFR protein expression, and increased EGFR gene copy number) have been studied with a view to identifying a target population most likely to benefit from these drugs. Future clinical trials with targeted agents need to be carefully designed to incorporate correlative translational research elements that will allow selection of appropriate treatment strategies for individual patients. For assessment of phase III trial results in advanced disease, progression free survival may serve as a more appropriate end-point than response rate in an adequately designed trial in the appropriately selected population, although there should be no substitute for the overall survival and quality of life end points. The role of EFGR TKI in NSCLC will be discussed in detail and data from these studies will be used to illustrate the challenges in designing clinical trials and interpreting outcomes.

Collagen, the major constituent of human dermis, represents the main barrier against progression of melanoma cells. Several matrix metalloproteinases (MMPs), i.e. collagenase-1 (MMP-1), gelatinase A (MMP-2) and membrane-type 1-MMP (MMP-14), favor melanoma cell invasion through their capacity of degrading collagen and thus, are considered as main targets. Potent inhibitors, as hydroxamate- derived pseudopeptides were first proposed as pharmacological agents to control melanoma invasiveness. These molecules have major drawbacks linked to i) toxicity and ii) absence of specificity, in keeping with the high Zn chelating property of hydroxamates, that might hinder the contribution of the occupancy of other subsites in enzyme inhibition. To date, research focuses on the design of compounds which display a lower affinity for Zn in enzyme active site. For instance, hydroxamate can be replaced by phosphinic acid or hydrazide which further allows synthesis of both right- and left- hand side inhibitors and therefore occupancy of non-primed enzyme subsites. Novel types of selective MMP inhibitors also include non-competitive and mechanism- based inhibitors. Finally, collagenolysis may be controlled by modulating enzyme-substrate interaction through the identification of substances that bind to MMP exosites. Such compounds could be of value by impeding collagenases to associate to plasma-membrane of invading cancer cells.