Full Journal - Journal of Cell and Molecular Biology - Haliç Üniversitesi

60 Mustafa Yatin
regulation of cell growth depending on need. The
polyamine requirement of a given cell may be
covered by de novo synthesis or by uptake from its
environment. Under physiologic conditions, the
relative importance of uptake and de novo synthesis is
a cell-typic character (Marton and Pegg, 1995; Seiler
and Dezeure, 1990; Seiler et al., 1990). The capacity
of cells for de novo synthesis and uptake is an
expression of their ability to adapt to environmental
changes.
The use of polyamine levels in body fluids as
diagnostic markers or as indices of novel therapeutic
effects has also been subject to extensive study but the
results have, with a few exceptions, been
disappointing. The extreme complexity of blood
compartment carrying free polyamines in the plasma
caused significant problems in the clinical
interpretation of circulating PA levels. By the end of
1970s the unclear potential role of PA as markers for
cancer led to an almost total disinterest in their
diagnostic use (Moulinoux et al., 1996). However,
studies of polyamine metabolism in a number of
pathogenic parasites (Seiler and Atanassov, 1994),
inflammatory, infectious conditions (Yatin and
Fischman, 2002) and under oxidative stress (Gilad
and Gilad, 1999), have led to identification a number
therapeutic targets and the development of novel
chemotherapeutic agents (Pegg and McCann, 1994;
Wallace and Morgan, 1990; Hebby, 1981; Seiler and
Atanassov, 1994). Polyamines are also modulators of
synaptic functions and play important roles in central
nervous system (CNS) (Gilad and Gilad, 1999; Yatin
et al., 2001; Williams, 1997). Some of the
non-peptide venoms of spiders and wasps are natural
polyamine analogues that are selective inhibitors of
the glutamate receptors of the CNS (Nihei et al.,
2001; Palma et al., 1998; Albensi et al., 2000).
Many plant compounds contain polyamine
residues, including several families of alkaloids (Hoet
and Nemery, 2000; Thomas and Thomas, 2001).
Resveratrol, a natural polyphenolic phytoalexine,
present abundantly in red wine, has been reported to
be an anti-proliferative agent on human cancer cells,
also caused significant decreases on ODC activity,
indicating that PA might represent one of several
beneficiary effects of moderate consumption of red
wine (Nigdigar et al., 1998; Scheneider et al., 2000).
Spm, exceptionally high in skin (human skin
concentration - epidermis is 850 mg/g tissue
compared to muscle - skeletal, 30 mg/g tissue), has
been identified as a potent antioxidant and
anti-inflammatory agent against UVB irradiation and
oxidative stress and suggested to be an important
anti-inflammatory antioxidant of epidermis.
Currently, the use of Spm as a dermatologic
antioxidant is under patent protection (Lovaas, 1995).
Biosynthesis and regulation of cellular polyamines
The biosynthesis pathway of polyamine accumulation
in the cells is kinetically rate-limited by ornithine
decarboxylase (ODC; EC 4.1.1.17), a pyridoxal
phosphate dependent enzyme, which synthesize Put
by decarboxylation of L-ornithine. The remarkable
elevation in de novo polyamine biosynthesis rate that
takes place in rapidly growing cells has led to much
effort to develop therapeutically useful antineoplastic
agents that would interfere with, or regulate, these
processes in hyperproliferative diseases (Seiler and
Atanassov, 1998). Investigation of several specific
inhibitors of ODC (i.e. difluoromethylornithine,
DFMO, a suicidal irreversible specific inhibitor of
ODC) as an experimental antineoplastic strategy
causes to reduction in total amount of cellular
polyamines (except spermine) with only cytostatic
effects. The lack of cytotoxicity may be due to
polyamine interconversion from a spermine reservoir
in the cells and/or polyamine repletion by
transmembrane uptake from extracellular sources
(Pegg and McCann, 1994; Hebby, 1981; Seiler and
Atanassov, 1998).
Many microorganisms and higher plants are able
to biosynthesize Put from agmatine produced by
decarboxylation of arginine, however all mammalian
cells and many lower eukaryotes lack arginine
decarboxylase (ADC), leaving the only route to
produce Put to utilize the ODC. Ornithine is available
for this enzymatic reaction from the circulating
plasma and can also be formed by the action of
arginase. Arginase is much more widely distributed
than any other enzymes of the urea cycle in living
organisms and present in extrahepatic tissues, and
ensures the availability of ornithine in PA production
line. In a broad sense, arginase can, therefore be
assumed of as an initial step in the PA biosynthesis
pathway.
Ornithine decarboxylase was discovered in 1968
simultaneously and independently in two laboratories
in the United States and one in Finland (Janne et al.,