Current Medicinal Chemistry - Anti-Cancer Agents - Volume 2, Issue 6, 2002

The last three decades have seen the development of new concepts in the biomedical and medical field based on the principle of drug carrying and in vivo pharmaco-targeting using synthetic carriers such as nanoparticles, liposomes or polymers. This review deals with the synthesis and biomedical applications of a new kind of macromolecular compounds: end-capped oligomers called telomers. The telomers, derived from Tris(hydroxymethyl)aminomethane bearing either a hydro- or a fluorocarbon tail, are described. Their functionality and biocompatibility enhance their potential in the biomedical and medical fields. Such compounds exhibit no cytotoxicity and are able to cross cell membranes by endocytosis. After i.v or per os administration in the animal, they exhibit a very good bio-avaibility and a homogeneous distribution in all tissues without any accumulation. Their ability to carry in vivo antimitotic drugs has been shown. Moreover, the grafting of different glycoside moieties onto the hydroxyl groups of telomers allows the selective targeting of specific receptors called integrins. Finally, we have shown the potential use of telomers bearing specific peptide ligands, such as RGD sequences, in the selective carrying of antimitotic drugs to the angiogenic zone surrounding tumors.

The quiescent vascular system in the adult body represents the balanced net outcome of overproduction of endogenous angiogenesis inhibitors and reduced levels of angiogenic factors. While these inhibitors are expressed under physiological conditions, they are also generated in association with tumor growth. Angiostatin is such a specific angiogenesis inhibitor produced by tumors. It inhibits primary and metastatic tumor growth by blocking tumor angiogenesis. Encouraged by its potent anti-tumor activity, angiostatin is in clinical trials for cancer therapy. Angiostatin contains the first four triple loop structures, known as kringle domains, of plasminogen. The disulfide bond-linked kringle architectures are essential for the antiangiogenic activity of angiostatin. Based on this initial finding, recent work shows that kringle fragments of several other proteins also inhibit angiogenesis. Thus, kringle domains may provide a structural basis for identification of novel angiogenesis inhibitors. Surprisingly, most kringles only inhibit angiogenesis when cleaved as fragments from their parental proteins that lack antiangiogenic activity. These findings suggest that they are cryptic fragments hidden in large protein molecules. Thus, proteolytic processing plays a critical role in down regulation of angiogenesis. The kringle structure may provide the first example of a conserved architecture that specifically inhibits blood vessel growth. This review will focus on the structural and functional relationships of kringle domains in regulation of angiogenesis and tumor growth.

The development of drugs that are highly selective and yet produce minimal toxicity to host tissue remains one of the most difficult challenges in cancer therapeutics. Since the majority of malignancies are treated with drugs in combination rather than single agents, one practical approach to circumvent this problem is to develop new therapeutic agents that will potentiate the effectiveness of current clinical protocols. This strategy would accelerate the acceptance of new drugs as adjunct therapies since these agents could be used at concentrations well below their maximal tolerated doses.Tumor cells derived from a variety of different sources have been shown to express the Vitamin D3 receptor and to be susceptible to growth arrest and / or cell death in response to Vitamin D3 and its analogues. The hypercalcemia that generally accompanies the utilization of pharmacological concentrations of Vitamin D3 has been ameliorated in part through the development of Vitamin D3 analogues. Studies in cell culture and in animal model systems as well as clinical trials have established the potential utility of Vitamin D3 and Vitamin D3 analogues as agents which can enhance the antiproliferative and / or cytotoxic effects of conventional chemotherapeutic drugs as well as ionizing radiation. Consequently, Vitamin D3 and Vitamin D3 analogues, utilized at concentrations which produce limited hypercalcemia, are likely to prove effective as adjuncts to conventional chemotherapy and radiotherapy.

The protection against some forms of cancer provided by many common foods has been observed in multiple epidemiological studies. Non-nutritive dietary compounds, such as flavonoids, have been considered as the responsible agents for such observations and since then, much research activity has been done about their potential anticancer effect. As a result, these compounds have been shown to regulate proliferation and cell death pathways leading to cancer. Thus, flavonoids such as the synthetic flavone, flavopiridol, the soy isoflavonoid, genistein, the tea catechin epigallocatechin gallate, or the common dietary flavonol, quercetin, are emerging as prospective anticancer drug candidates and some of them have already entered in clinical trials. In view of the therapeutic potential of flavonoids, many researchers have tried to elucidate possible structure-activity relationships that might lead to new drug discovery. However, and possibly due to the information being very scattered, there is very little understanding about a possible relationship between the flavonoid structure and their anticancer activity. Besides their therapeutic potential, since lots of flavonoids are present in our diet, a greater understanding of their anticancer properties might also modify our dietary habits in order to attack cancer with an effective weapon, prevention.This paper seeks to show, in a brief but comprehensive way, the anticancer properties of flavonoids. Through an understanding of the cancer process and its treatment, flavonoids are studied as possible useful compounds in cancer prevention and cancer therapy. Furthermore, this review attempts to compile and discuss the literature studying structureactivity relationships, in order to show structural requirements implicated in the anticancer activity of flavonoids, which might help to rationalize their development as antitumor agents.

A variety of treatments have recently been introduced to improve the prognosis of hepatocellular carcinoma (HCC). These anticancer therapies include the oily carcinostatic agent styrene maleic acid neocarzinostatin (SMANCS). SMANCS is a chemical conjugate of a synthetic copolymer of styrene maleic acid (SMA) and the proteinaceous anti-cancer agent neocarzinostatin (NCS), which dissolves in organic solvents such as pyridine and acetone, and particularly in Lipiodol. NCS is a simple protein capable of inhibiting DNA synthesis and inducing DNA degradation. Lipiodol is an ethyl ester of iodinated poppy seed oil in which most of the unsaturated double bonds in oleic, linoleic and linolenic acid are almost completely iodinated. When a homogeneous suspension of SMANCS with Lipiodol (SMANCS / Lipiodol) is administered intra-arterially, Lipiodol acts as a carrier of SMANCS. Many studies have demonstrated the clinical efficacy of SMANCS / Lipiodol in the treatment of HCC. We have shown that transcatheter arterial infusion (TAI) with SMANCS / Lipiodol has a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of HCC. However, recent clinical studies have indicated that SMANCS causes severe adverse reactions and complications. We have also reported a case of HCC in which multifocal hepatic infarction developed after TAI with SMANCS / Lipiodol. Arterial administration of SMANCS / Lipiodol, therefore, should be given as peripherally as possible via the tumor feeding arteries, to enhance the efficacy of the agent and to reduce the adverse effects.

DNA double strand breaks are the pivotal cellular damage induced by ionizing radiation. A plethora of molecular and cellular processes are activated as part of the cellular stress response that result in cell cycle arrest and induction of the DNA-repair machinery to restore the damage of DNA or to activate a cell death program. However ionizing radiation also initiates signal transduction cascades that are generated at cellular sites distant from and independent of DNA-damage. These signaling processes are similar to hormone activated growth factor receptor controlled signal transduction cascades and represent interesting targets for anticancer treatment modalities combining ionizing radiation with molecular defined pharmacological compounds. Activation of these signal transduction cascades upon irradiation or upregulation of growth factor mediated pathways due to oncogene-transformation often contribute to an acquired or inherent treatment resistance in malignant cells. Therefore pharmacological compounds inhibiting specific key-entities of these signal transduction cascades potentially sensitize for radiation induced cell death. Here we describe current preclinical concepts of combined treatment strategies with locoregional-applied ionizing radiation and molecular defined signal transduction inhibitors to overcome a high treatment threshold in tumor cells.