Current Drug Targets, Volume 4, No. 7, 2003
Contents
The Adenine Nucleotide Translocator: A New
Potential Chemotherapeutic Target Pp.517-524
A-S.
Belzacq and C. Brenner
Tumor Escape from Immune Response: Mechanisms
and Targets of Activity
Pp.525-536
D.
Gabrilovich and V. Pisarev
Thirty Years of Polyamine-Related Approaches
to Cancer Therapy. Retrospect and Prospect. Part 1. Selective Enzyme Inhibitors Pp.537-564
Thirty Years of Polyamine-Related Approaches
to Cancer Therapy. Retrospect and Prospect. Part 2. Structural Analogues and
Derivatives Pp.565-100%
N.
Seiler
Melanocortins and their Receptors and
Antagonists Pp.586-597
J.
Voisey, L. Carroll and A. van Daal
Abstracts
[Back to top] The Adenine Nucleotide Translocator: A New
Potential Chemotherapeutic Target
A-S.
Belzacq and C. Brenner
Identification of new
targets is of utmost importance for the development of efficient
apoptosis-modulating drugs. This has become possible from the unraveling of the
basic apoptosis mechanisms and notably, from the demonstration of the
mitochondrial membrane permeabilization as a central rate-limiting step of
numerous models of cell death. Indeed, molecular and pharmacological studies
revealed that the adenine nucleotide translocator (ANT) could be a therapeutic
target. First, ANT is a bi-functional protein. It mediates the exchange of
cytosolic ADP and mitochondrial ATP, and contributes to apoptosis via its
capacity to become a lethal pore. Second, both ANT functions are under the
control of the (anti)-oncogenes from the Bax/Bcl-2 family, and third, agents as
diverse as proteins, lipids, ions, pro-oxidants or chemotherapeutic agents
directly modulate the pore-forming activity of ANT. Here, we will review the
mode of apoptosis induction by various classes of chemotherapeutic agents,
which all influence directly ANT pro-apoptotic function. Hopefully, this will
yield several clues to the modulation of apoptosis from a therapeutic
perspective.
[Back to top] Tumor Escape from Immune Response: Mechanisms
and Targets of Activity
D.
Gabrilovich and V. Pisarev
Immune system
plays an important role in control of tumor progression. Effective antitumor
immune response depends on close interaction of several elements of immune
system. They include antigen-presenting cells, different subsets of T cells, B
cells and NK cells. However, tumor cells developed a number of mechanisms to
escape recognition and elimination by immune system. In this review we will
discuss these mechanisms and address possible approaches to correct them.
[Back to top] Thirty Years of Polyamine-Related Approaches
to Cancer Therapy. Retrospect and Prospect. Part 1. Selective Enzyme Inhibitors
N.
Seiler
As soon as the
natural polyamines (PAs), putrescine (Put), spermidine (Spd) and spermine
(Spm), were recognized as ubiquitous constituents of eukaryotic cells, their
involvement in growth-related processes attracted particular interest. The high
activities of ornithine decarboxylase (ODC) and S-adenosylmethionine
decarboxylase (AdoMetDC) in rapidly growing tissues and cells, particularly in
tumour cells, suggested PA biosynthesis as a target for antineoplastic therapy.
In the course of the years selective inhibitors have been developed for
literally all enzymes of PA metabolism. Some became important as tools in the
elucidation of the PA metabolic system, but only few of them were efficient as
inhibitors of tumour growth. A major reason for the inefficacy of selective
enzyme inhibitors as anticancer drugs is the sophistication of the system,
which regulates intracellular PA pools. Selective blockade of a single enzyme
induces changes of metabolism and transport, which compensate for the deficit.
The selective impairment of tumour growth is in addition hampered by the
ubiquitous occurrence of the PAs, their importance in normal functions of
nearly all mammalian cells, and the ability of the mammalian organism to
utilize exogenous (gastrointestinal) PAs. Among the inhibitors of PA-related
enzymes, the ODC inactivator (R, S)-2-(difluoromethyl)ornithine (DFMO) became
most famous. Although it was disappointing in most therapeutic attempts to use
it as single drug, it has – based on its low toxicity - considerable potential
in cancer chemoprevention, and it turned out to be a highly efficient
anti-trypanosome agent. Very likely DFMO is suitable to improve the efficacy of
some of the current cytotoxic drugs, and it may allow one to create new
therapies in combination with other PA-directed drugs. Some of the less
selective enzyme inhibitors, particularly those, which inhibit two or more
enzymes of PA metabolism, appear to have had a chance to become practically
useful, but they have not been developed energetically. Disregarding DFMO, the
AdoMetDC inhibitor SAM486A is the only compound for which clinical trials were
published. The future of this drug is unclear at present; presumably phase III
clinical trials have been discontinued. One of the lessons that had to be
learned from the work on selective enzyme inhibitors was that PA metabolism is
a much more difficult target, than has been expected on the basis of the
simplicity of the PA structures, and the simple reactions involved in their
biosynthesis. In order to inhibit tumour growth several reactions or regulatory
functions of PA metabolism have to be impaired at the same time. Recent efforts
devoted to the development new types of anticancer drugs, which are based on
the perturbation of PA metabolism by structural analogues of the natural PAs,
take this message into account. These approaches are the topic of the 2nd
part of this overview.
[Back to top] Thirty Years of Polyamine-Related Approaches
to Cancer Therapy. Retrospect and Prospect. Part 2. Structural Analogues and
Derivatives
N. Seiler
Owing to their role
in growth-related processes the natural polyamines (PAs), putrescine (Put),
spermidine (Spd) and spermine (Spm) were identified about 30 years ago as
potential targets for the development of anticancer drugs. It was presumed that
inhibition of a key enzyme of PA biosynthesis, followed by the depletion of the
intracellular PA pools results in the prevention of cell growth. Initial
efforts were nearly exclusively focused on the design and synthesis of
selective inhibitors of the PA biosynthetic enzymes. This period is reviewed in
the 1st part. Selective inhibition of ODC caused in various cell
lines growth inhibition, but was usually not sufficient to inhibit tumour
growth , because the PA regulatory system outbalances selective enzyme blockade
by enhancing compensatory reactions, and because exogenous PAs are used if de
novo synthesis is impaired. When these facts were recognized, new targets were
envisaged. Among these the PA uptake system and the deregulation of PA
homeostasis became most attractive. They are the major topic of the present 2nd
part.
Inhibition of PA
uptake from the cellular environment is expected to improve the efficacy of
drugs, which rely on the depletion of intracellular PA pools. During the past
few years several potent inhibitors of the PA uptake system became known.
However, more work will be needed to allow their assessment as anticancer drugs
in combination with DFMO and other compounds capable of depleting PA pools. The
PA transport system also offers the possibility to improve the accumulation by
tumors of compounds, which are tethered to PA structures. This can be achieved
for the following reasons: (a) Structural requirements of the PA uptake systems
are not stringent. (b) Tumour cells accumulate PAs more avidly than most non-transformed
cells. (c) The transport rate for PAs is higher in cells with depleted PA
pools, than in cells with a normal PA content. (d) In cells, which proliferate
rapidly, PA depletion by biosynthesis inhibitors is more effective, than in
slowly growing cells.
The most actively
pursued approach is currently based on the inhibition of tumour growth by
cytotoxic structural analogues of the natural PAs. Some of these compounds
mimic regulatory properties of the natural PAs. If a PA mimetic accumulates in
cells, it induces catabolic processes, suppresses biosynthetic reactions, and
depletes the pools of Put, Spd and Spm. N1,N11-bis(ethyl)norspermine
is a prototype of the PA mimetics. During the last decade a very large number
of PA derivatives and structural analogues have been prepared, which are
capable of inhibiting cell growth at low µM concentrations. Among the new
PA-like structures several compounds were identified, which prevent cells from
growing, without depleting PA pools to an extent that would be necessary to
prevent cell growth. They may be considered as PA antagonists, although their
mode of action is not well understood. A therapeutically useful drug has not
yet been identified among the PA analogues. In many instances investigations
were stopped at a preliminary stage. Recently synthesized compounds have not
yet been pursued far enough to justify the initiation of clinical trials. Only
very few toxicological results of the new structures have been reported,
although the knowledge of the toxicology of Spm analogues is of eminent
importance. PAs are ubiquitous cell constituents and are indispensable for
normal cell function. However, extracellular PAs, and particularly
extracellular Spm is cytotoxic and neurotoxic. These properties are shared by close
structural analogues. A major difficulty in the development of PA analogues to
therapeutically useful drugs is, therefore, the identification of structures,
which do not share neurotoxic properties with Spm. Several tetramines are
presently in early phases of clinical trials. It will be a matter of a few more
years to allow one to decide, whether PA-related approaches of cancer therapy
are a success or a failure.
[Back to top] Melanocortins and their Receptors and Antagonists
J.
Voisey, L. Carroll and A. van Daal
The melanocortins
are a group of small protein hormones derived by post-translational cleavage of
the proopiomelanocortin (POMC) gene product. The known melanocortin hormones
include a-melanocyte stimulating hormone (MSH), b-MSH, g-MSH
and adrenocorticotropic hormone (ACTH). Five melanocortin receptors (MC1R
through to MC5R) have been identified and most of these show tissue-specific
expression patterns, as well as different binding affinities for each of the melanocortin
hormones. The central melanocortin system consists of a-MSH, agouti-related
protein (AGRP), MC3R and MC4R. AGRP and a-MSH
are believed to be the natural antagonist and agonist respectively of MC3R and
MC4R. This central melanocortin system is thought to play a fundamental role in
the control of feeding and body weight.
Knock-out mice
models and genetic studies have pointed to the importance of the melanocortins
in complex human pathways such as pigmentation, lipolysis, food intake,
thermogenesis, sexual behaviour, memory and inflammatory response. Recently the
melanocortins and their receptors have been the target for drug-based treatment
of human physiological processes. MC3R and MC4R are likely targets for
controlling body weight; MC1R may be used in the treatment of inflammation and
MC2R for the treatment of glucocortical deficiency. A role for MC5R still
remains unclear, but the evidence suggests an exocrine gland function.