Current Medicinal Chemistry – Anti -Cancer Agents, Vol. 2, No. 6, 2002
Contents
Amphiphilic Oligomers: A New Kind of Macromolecular Carrier of Antimitotic Drugs Pp. 645-665
Christiane Contino-Pépin, Jean Claude Maurizis and Bernard Pucci
Kringle Structures and Antiangiogenesis Pp. 667-681
Yihai
Cao, Renhai Cao and Niina Veitonmäki
Vitamin D3 and Vitamin D3 Analogues as an Adjunct to Cancer Chemotherapy and Radiotherapy Pp. 683-690
David
A. Gewirtz, Mona S. Gupta and Sujatha Sundaram
Flavonoids as Anticancer Agents: Structure-Activity Relationship Study Pp. 691-714
M.
López-Lázaro
Styrene Maleic Acid Neocarzinostatin Treatment for Hepatocellular Carcinoma Pp. 715-726
Shintaro
Abe and Makoto Otsuki
Signal Transduction Inhibitors as Radiosensitizers Pp. 727-742
A.Tenzer,
D. Zingg, O. Riesterer, V. Vuong, S. Bodis and M. Pruschy
Abstracts
[Back to top] Amphiphilic Oligomers: A New Kind of Macromolecular Carrier of Antimitotic Drugs
Christiane
Contino-Pépin, Jean Claude Maurizis and Bernard Pucci
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.
[Back to top] Kringle Structures and Antiangiogenesis
Yihai Cao, Renhai Cao
and Niina Veitonmäki
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.
[Back to top] Vitamin D3 and Vitamin D3 Analogues as an Adjunct to Cancer Chemotherapy and Radiotherapy
David A. Gewirtz, Mona
S. Gupta and Sujatha Sundaram
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.
[Back to top] Flavonoids as Anticancer Agents: Structure-Activity Relationship Study
M. López-Lázaro
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.
[Back to top] Styrene Maleic Acid Neocarzinostatin Treatment for Hepatocellular Carcinoma
Shintaro Abe and
Makoto Otsuki
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.
[Back to top] Signal Transduction Inhibitors as Radiosensitizers
A.Tenzer,
D. Zingg, O. Riesterer, V. Vuong, S. Bodis and M. Pruschy
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.