Current Medicinal Chemistry - Anti-Cancer Agents - Volume 2, Issue 4, 2002

The concept of cancer prevention by use of naturally occuring substances that could be included in the diet is under investigation as a practical approach towards reducing cancer incidence, and therefore the mortality and morbidity associated with this disease. Tea, which is the most popularly consumed beverage aside from water, has been particularly associated with decreased risk of various proliferative diseases such as cancer and atherosclerosis in humans. Various studies have provided evidence that polyphenols are the strongest biologically active agents in green tea. Green tea polyphenols (GTPs) mainly consist of catechins (3-flavanols), of which (-)-epigallocatechin gallate is the most abundant and the most extensively studied. Recent observations have raised the possibility that green tea catechins, in addition to their antioxidative properties, also affect the molecular mechanisms involved in angiogenesis, extracellular matrix degradation, regulation of cell death and multidrug resistance. This article will review the effects and the biological activities of green tea catechins in relation to these mechanisms, each of which plays a crucial role in the development of cancer in humans. The extraction of polyphenols from green tea, as well as their bioavailability, are also discussed since these two important parameters affect blood and tissue levels of the GTPs and consequently their biological activities. In addition, general perspectives on the application of dietary GTPs as novel antiangiogenic and antitumor compounds are also presented.

5-aminolevulinic acid (ALA) is the first intermediate in heme biosynthesis and is therefore a precursor of protoporphyrin IX (PpIX). PpIX is used as an endogenous photosensitizer in photodynamic therapy (PDT). Several chemical modifications have been made, both on the amino and carboxyl groups of ALA to induce higher PpIX production and photosensitisation. Esterification of ALA with aliphatic lineal and cyclic alcohols was found to reduce the amount of ALA required for photosensitization. Esterification by aliphatic alcohols with carbohydrate chains equal or lower than C4 leads to porphyrin accumulation lower than ALA, whereas equal or longer than C6 chains leads to greater synthesis of porphyrin. A branch point in the alcohol located next to the site of ester cleavage limits access of the esters to the esterase active site, resulting in lower PpIX production. ALA esters of the polyethylenglycol family can induce high levels of PpIX, with some selectivity for endothelial cells toward tumor cells. On the basis of the differential expression of some aminopeptidases in tumor vasculature when compared to normal vasculature, some ALA-pseudopeptides were synthesized. In a rational design of ALA derivatives, the transport mechanism of these aminoacids into the cell is central. Due to the similar characteristics between ALA and GABA transport, a novel approach for designing new ALA derivatives which could penetrate more easily into tumoral cells, would be to take into account the structures of the inhibitors of GABA transport.

Recent reports have shown that pharmacological manipulation of chromatin remodeling by histone deacetylase (HDAC) inhibitors, might develop into a potent and specific strategy for the treatment of cancer. Alterations in histone acetylation may lead to changes in chromatin structure and transcriptional dysregulation of genes that are implicated in controlling either cell cycle progression or pathways regulating cell differentiation and / or apoptosis. Dimethyl sulphoxide was one of the first chemicals to be identified as an inducer of transformed cell differentiation. In the class of HDAC inhibitors, now included a short-chain fatty acids, such as 4-phenylbutyrate and valporic acid, hydroxamic acids, such as suberoylanilide hydroxamic acid (SAHA), pyroxamide, trichostatin A, oxamflatin and CHAPSs, cyclic tetrapeptides, such as trapoxin, apicidin and depsipeptide-also known as FK-228 or FR 901228, and benzamides, such as MS-275. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. Thus, HDAC inhibitors remains one of the most promising class of new anticancer agents. Further studies are needed in order to delineate the optimal dosage, the duration of therapy and possibly the efficacy of other agents able to synergize with HDAC inhibitors in the fight against cancer.

Natural products have been regarded as important sources that could produce potential chemotherapeutic agents. Over 50% of anticancer drugs approved by United States Food and Drug Administration since 1960 were originated from the natural resources, especially from terrestrial plants. Based on cytotoxicity bioassay, over 400 compounds have been isolated from plants, marine organisms and microorganisms from the period of 1996 to 2000. Recently, interest of natural product research has slowly moved to marine organisms. As a result, almost 50% of reported cytotoxic compounds were isolated from marine organisms such as sponges and corals. Also, traditional cytotoxic compounds of acetogenins, alkaloids and terpene skeletons have been reported continuously. In this review, we will present the cytotoxic compounds obtained from natural sources from 1996 to 2000, and the structures and cytotoxic activity of natural compounds isolated from territorial, marine and microorganism resources.

The limitations of cisplatin as an anticancer drug have stimulated the search for other antitumor-active platinum complexes with improved pharmacological properties. The two main goals in the search for new platinum anti-cancer agents are the reduction of the dose-limiting toxicities of cisplatin and the circumvention of cisplatin resistance. However, it should be pointed out that this has proven to be a difficult task. In fact, less than 1% of the thousand of platinum complexes tested for preclinical antitumor activity have entered clinical trials in the past 30 years. Nonetheless, right now, several new platinum complexes are in clinical trials, a proof of the continued belief that platinum complexes may still fulfil the needs for novel antitumor drugs. This review will focus on the three main innovative approaches found in the platinum anticancer-field, namely, (1) compounds with decreased reactivity against nucleophiles, (2) compounds with carrier ligands, and (3) compounds which bind differently to DNA as compared to cisplatin. In the latter class, special attention is paid to dinuclear and polinuclear platinum complexes.

Environmental conditions such as temperature, radiation, hypoxia, nutrients and drugs stimulate the adaptive sensory and signaling machinery of the cell. This stress response may influence cell cycle regulation, cellular differentiation, oncogenic transformation, cell survival and apoptosis. The impact of the cytoprotective reprogramming in cancer pharmacology is presented by the recent extensive literature regarding the interplay between stress tolerance and anticancer drug effectiveness and resistance, relying on the dominating intrinsic pathways, which are simultaneously activated and regulate the death process either positively or negatively. This review presents the data that argue for the emergence of either common or specific mechanisms depending on the type, duration and severity of stress in all eukaryotic organisms from yeast to mammals. The understanding of the complexity and the balance between noxious and protective signal transduction pathways would contribute to a more explicit evaluation of the current therapeutic regiments and to the development of new leads targeting malignancy.