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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 4, April 2006
Contents
SMALL MOLECULES OF NATURAL ORIGIN FOR CANCER
THERAPY AND CHEMOPREVENTION
Part II: Pharmacogenomics and Biotechnological Applications
of Small Molecules of Natural Origin for Cancer Therapy and
Chemoprevention
Guest Editor: Thomas Efferth
Editorial Pp. 385
Investigating the Molecular Basis of Drug Action and
Response: Chemocentric Genomics and Proteomics Pp.
387-395
G. Zybarth and N. Kley
[Abstract]
Discovery of New Small Molecules and Targets Towards
Angiogenesis Via Chemical Genomics Approach Pp.
397-405
H.J. Kwon
[Abstract]
Molecular Pharmacology and Pharmacogenomics of Artemisinin
and its Derivatives in Cancer Cells Pp. 407-421
T. Efferth
[Abstract]
Resveratrol as a Chemopreventive Agent: A Promising
Molecule for Fighting Cancer Pp. 423-442
D. Delmas, A. Lançon, D. Colin, B. Jannin
and N. Latruffe
[Abstract]
Histone Deacetylases as Targets for Dietary Cancer
Preventive Agents: Lessons Learned with Butyrate, Diallyl
Disulfide, and Sulforaphane Pp. 443-452
M.C. Myzak and R.H. Dashwood
[Abstract]
Production of Paclitaxel and the Related Taxanes by
Cell Suspension Cultures of Taxus Species Pp.
453-461
H. Tabata
[Abstract]
Biology & Pathology of Human Fungal Pathogens
Guest Editor: Karl Kuchler
Editorial Pp. 463
Biofilms and their Role in the Resistance of Pathogenic
Candida to Antifungal Agents Pp. 465-470
C. d’Enfert
[Abstract]
Fungal ATP-Binding Cassette (ABC) Transporters in
Drug Resistance & Detoxification Pp. 471-481
G. Sipos and K. Kuchler
[Abstract]
Host-Pathogen Interactions and the Pathological Consequences
of Acute Systemic Candida albicans Infections in
Mice Pp. 483-494
B. Rozell, P.O. Ljungdahl and P. Martínez
[Abstract]
Epidemiology of Candida albicans Infections and Role
of Non-Candida-albicans Yeasts Pp. 495-504
M. Ruhnke
[Abstract]
Getting in Touch with Candida albicans: The
Cell Wall of a Fungal Pathogen Pp. 505-512
K. Sohn, J. Schwenk, C. Urban, J. Lechner, M. Schweikert
and S. Rupp
[Abstract]
Laboratory Diagnosis and Therapy of Invasive Fungal
Infections Pp. 513-522
B. Willinger
[Abstract]
Abstracts
[Back
to top]
EDITORIAL
Part II: Pharmacogenomics and Biotechnological Applications
of Small Molecules of Natural Origin for Cancer Therapy and
Chemoprevention
In continuatin of the previous issue, part II of the issue
“Small molecules of natural origin for cancer therapy
and chemoprevention” comprises of the following chapters.
3. From Pharmacogenomics and –proteomics to
systems biology
The recently developed genomic and proteomic technologies
are thriving and fertilize many disciplines of life sciences,
including pharmaceutical biology and pharmacognosy. The prospect
is fascinating to gain mechanistic insights, how small molecules
from natural origin act against cancer cells. The next wave
– the construction of signalling and metabolic pathways
with the help of data obtained from “-omics” technologies
– is the task of systems biology, which will add another
dimension to current pharmacology.
Gabriele Zybarth and Nikolai Kley (Waltham,
MA, USA) report the recent achievements in the field of genomics
and proteomics, e.g., genome-wide transcription-profiling,
genotyping of polymorphisms to predict drug efficacy, knock-out
technology, chemical proteomics, target engineering, drug
resistance and others.
The chemical genomics-based target identification using anti-angiogenic
agents as example is described by Ho Jeong Kwon
(Seoul, Korea). Small molecules chemically synthesized or
taken from natural sources are used to elucidate biological
mechanisms and as lead compounds for the directed optimization
of chemical compounds with drug-like properties. Sophisticated
bioinformatics tools are applied to make this approach rapid
and efficient. In analogy to classical genetics, one can distinguish
forward from reverse chemical genomics. The forward approach
aims to identify small molecule-induced cellular phenotypes
and molecular target proteins affected. By reverse genomics,
validated target proteins are used to searches for small molecules,
which modulate the function of the target molecules.
The article on artemisinin and its derivatives by Thomas
Efferth (Heidelberg, Germany) gives a comprehensive
overview of molecular pharmacology and pharmacogenomics of
this drug class for anti-cancer treatment. Artemisinin is
the active principle of the Chinese herb, Artemisia annua
L., which shows profound cytotoxicity to cancer cells in addition
to its anti-malarial properties.
4. Chemoprevention
Chemopreventive agents inhibit the development of cancer,
whereas chemotherapeutics are used to treat already established
cancers. Since mechanisms of carcinogenesis frequently affect
effectiveness of chemotherapy too, compounds which prevent
carcinogenesis might also improve responsiveness of tumor
cells to anti-tumor drugs.
Dominique Delmas, Allan Lançon, Didier Colin,
Brigitte Jannin and Norbert Latruffe (Dijon, France)
report on resveratrol as promising chemopreventive agent.
The beneficial effects of wine are associated with the physiological
protection conferred by phenolic compounds such as resveratrol.
It is a chemopreventive compound with multi-facetted features.
It acts anti-carcinogenic, anti-angiogenic, anti-invasive,
anti-metastatic, activates programmed cell death, arrests
the cell cycle, and inhibits signal transduction pathways.
Whereas it is not cytotoxic itself, it enhances the anti-tumor
effect of anticancer drugs.
Melinda C. Myzak and Roderick H. Dashwood
(Corvallis, OR, USA) give an introduction in the field of
histone deacetylases as targets for dietary cancer preventive
agents and explain the relevance of aberrant histone acetylation
for tumorigenesis. The authors also introduce the reader to
histone deacetylase inhibitors of natural origin with chemopreventive
activity and point to molecular mechanisms of action. Three
examples are discussed in more detail, butyrate, diallyl disulfide,
and sulphoraphane, all of which are constituents of relevant
nutrients.
5. Biotechnology: plant cell culture for sustainable
production of plant-derived drugs
The knowledge on natural compounds and their molecular modes
of action in cancer cells represents one side of the coin.
The other side is the production of drugs for treatment of
patients. There is an increasing demand in medicinal plants
worldwide, most of which are collected from the wild. Although
cultivation of medicinal plants is getting more and more important,
sustainable supply remains uncertain. This limits clinical
use and is a considerable issue for the preservation of nature.
Homare Tabata (Chiba, Japan) turns the
attention to current biotechnological efforts to produce large-scale
of paclitaxel and related taxanes by cell suspension cultures
of Taxus species. Paclitaxel represents one of the
most prominent natural products in cancer therapy during the
past years and is, hence, suited as model drug to address
this question. Techniques like this may be suited to fuel
the still increasing demand for the general production of
plant-derived drugs for cancer therapy.
With completion of part II of the hot topic issue “Small
molecules of natural origin for cancer therapy and chemoprevention”,
I hope that the work summarized in both parts attempt to bridge
the gaps between different disciplines and to span a bow from
ethnobotany, phytochemistry, pharmacology, molecular biology
and pharmacogenomics to bioinformatics. There is reason to
hope that inter- and cross-disciplinary platforms like this
will foster the scientific collaboration and the development
of new strategies for chemotherapy and chemoprevention of
malignant tumors.
Thomas Efferth
German Cancer Research Center
M070, Im Neuenheimer Feld 280
69120 Heidelberg
Germany
E-mail: t.efferth@dkfz.de
[Back to top]
Investigating the Molecular Basis of Drug Action and
Response: Chemocentric Genomics and Proteomics
G. Zybarth and N. Kley
The genomics and proteomics sciences have fundamentally changed
the ways in which drug targets are being identified, characterized
and validated. Here we review how genomics and proteomics
research is improving our understanding of genetic determinants
of drug susceptibility and response and, conversely, how organic
small molecules mediate their pharmacological effects by modulating
genome and proteome activities. We also examine the effect
this improved understanding has on the drug discovery and
development process.
[Back to top]
Discovery of New Small Molecules and Targets
Towards Angiogenesis Via Chemical Genomics Approach
H.J. Kwon
Chemical genetics/genomics is an inter- and multi-disciplinary
research engine, which utilizes small molecules to explore
the function of genes and accelerate the drug discovery. Bioactive
small molecules that are permeable to cellular membrane and
bind to its cognate target protein can exert the phenotype
changes of the cells or organisms. Functional target proteins
of these small molecules have been successfully identified
by affinity, genetics and genomics based target identification.
The specific molecular recognition of small molecule with
target protein has facilitated to decipher the mode of actions
of small molecules and developed better drug based on their
structure activity relationship. Based on this idea, we have
applied chemical genomics to angiogenesis, a new blood vessel
formation, resulting in the identification of new small molecules
as well as targets. In this review, our application of chemical
genomics towards a cellular phenotype, angiogenesis, will
be demonstrated.
[Back to top]
Molecular Pharmacology and Pharmacogenomics of Artemisinin
and its Derivatives in Cancer Cells
T. Efferth
Secondary metabolites from plants can serve as defense against
herbivores, microbes, viruses or competing plants. Many compounds
from medicinal plants have pharmacological activities and
thus may be a source for novel anti-tumor agents. We have
analyzed natural products from traditional Chinese medicine
during the past decade and focused our interest on the compound
artemisinin from Artemisia annua L. (qinghao, sweet
wormwood) and its derivatives. In addition to their anti-malarial
properties, artemisinins are cytotoxic for cancer cells. The
present review focuses on the mechanisms of action of artemisinins
in cancer cells relating to: 1. anti-proliferative and anti-angiogenic
effects, 2. induction of apoptosis, 3. oxidative stress, 4.
oncogenes and tumor suppressor genes, and 5. multidrug resistance.
Data on putative target molecules of artemisinins are presented
and discussed, e.g. the translationally controlled tumor protein
(TCTP). Emphasis is given to pharmacogenomic approaches to
analyze the pleiotropic nature of mechanisms of artemisinins
in cancer cells.
[Back to top]
Resveratrol as a Chemopreventive Agent: A Promising
Molecule for Fighting Cancer
D. Delmas, A. Lançon, D. Colin, B. Jannin
and N. Latruffe
Resveratrol (3,4’,5 tri-hydroxystilbene) is a phytoalexin
produced in hudge amount in grapevine skin in response to
infection by Bothrytis cinerea. This production of
resveratrol blocks the proliferation of the pathogen, thereby
acting as a natural antibiotic.
Numerous studies have reported interesting properties of
trans-resveratrol as a preventive agent against important
pathologies i.e. vascular diseases, cancers, viral infection
or neurodegenerative processes. Moreover, several epidemiological
studies have revealed that resveratrol is probably one of
the main microcomponents of wine responsible for its health
benefits such as prevention of vasocoronary diseases and cancer.
Resveratrol acts on the process of carcinogenesis by affecting
the three phases: tumor initiation, promotion and progression
phases and suppresses the final steps of carcinogenesis, i.e.
angiogenesis and metastasis. It is also able to activate apoptosis,
to arrest the cell cycle or to inhibit kinase pathways. Interestingly,
resveratrol does not present any cytotoxicity in animal models.
Moreover, concentrations of resveratrol in blood seem to be
sufficient for anti-invasive activity. The enterohepatic recirculation
may contribute to a delayed elimination of the drug from the
body and bring about a pro-longed effect. By its binding to
plasmatic proteins, resveratrol also exhibits a prolonged
effect. Interestingly, low doses of resveratrol can sensitize
to low doses of cytotoxic drugs and so provide an innovative
strategy to enhance the efficacy of anticancer therapy in
various human cancers. By these properties, resveratrol appears
to be a good candidate in chemopreventive or chemotherapeutic
strategies and is believed to be a novel weapon for new therapeutic
strategies.
[Back to top]
Histone Deacetylases as Targets for Dietary Cancer
Preventive Agents: Lessons Learned with Butyrate, Diallyl
Disulfide, and Sulforaphane
M.C. Myzak and R.H. Dashwood
Cancer is a multi-factorial process involving genetic and
epigenetic events which result in neoplastic transformation.
Reversal of aberrant epigenetic events, including those that
modulate the transcriptional activity of genes associated
with various signaling pathways, holds the prospect of influencing
multiple stages of tumorigenesis. Perturbation of normal histone
acetylation status can result in undesirable phenotypic changes,
including developmental disorders and cancer. Indeed, aberrant
histone acetylation may be an etiological factor in several,
if not all, types of cancer. In general, histone acetylation
leads to chromatin remodeling and a derepression of transcription.
Histone deacetylase (HDAC) inhibitors may be useful for cancer
prevention and therapy by virtue of their ability to ‘reactivate’
the expression of epigenetically silenced genes, including
those involved in differentiation, cell cycle regulation,
apoptosis, angiogenesis, invasion, and metastasis. Several
natural and synthetic HDAC inhibitors have been shown to affect
the growth and survival of tumor cells in vitro and
in vivo. Interestingly, three dietary chemopreventive
agents, butyrate, diallyl disulfide, and sulforaphane, also
have HDAC inhibitory activity. This review discusses the role
of aberrant histone acetylation in tumorigenesis and describes
the potential for cancer chemoprevention and therapy with
a particular emphasis on dietary HDAC inhibitors.
[Back to top]
Production of Paclitaxel and the Related Taxanes by
Cell Suspension Cultures of Taxus Species
H. Tabata
Medicinal plants are the most promising source for the development
of drugs, and many types of active ingredients from the plant
resources have been studied in order to clarify the relationship
between the chemical structure and the activity. However,
it is not easy to develop drugs from those active compounds,
and in many cases, the supply of active compounds can have
some problems: 1) limited quantity of active compounds in
plant; 2) low plant growth rate; 3) the limited localization
of active ingredients in the specific organs; and 4) from
the perspective of the conservation of natural resources.
Therefore, the stable supply of the compounds commercially
is very difficult and contains risk hedge. Plant cell culture
is an attractive technology to solve these problems by securing
the stable supply of the active compounds without damage to
the natural plant resources.
Recently, an efficient production process of anticancer drug
paclitaxel by Taxus cell suspension cultures was
constructed. The established Taxus cell lines produced
paclitaxel and related taxanes by specific external stimuli,
such as methyl jasmonate. The time-course analysis revealed
that there are two regulatory steps existing in the paclitaxel
bio-synthesis: the taxanering formation step that is up-regulated
by MeJA, and the acylation step at the C-13 position. By applying
the data from the two-stage culture and the high-density culture,
a large-scale culture process was developed with a stable
paclitaxel production in the range of 140-295 mg L-1,
reaching 295mg L -1 at maximum.
[Back to top]
Editorial: Biology & Pathology of Human Fungal
Pathogens
Fungal infections constitute an ever-growing and significant
medical problem in the world. The major fungal pathogens affecting
humans include Candida species (such as C. albicans,
C. glabrata, C. parapsilosis and C. tropicalis) and Aspergillus
spp. (mainly A. fumigatus). Fungal diseases
include simple toe nail infections, deep-seated and recurrent
vaginitis, as well as life-threatening systemic mycoses in
patients with impaired immune systems. Hence, individuals
with organ or bone marrow transplants, acquired immune deficiency
syndrome, those undergoing intensive chemotherapy regimens,
neonates and infants, as well as long-term hospitalized and
intensive care unit patients are at very high risk to contract
fungal infections. Candida species are the most frequent
causes, representing the fourth leading cause of hospital-acquired
diseases. Several hundred thousand cases are reported worldwide
every year, about 70% of which are caused by Candida spp.,
and 20% by Aspergillus spp. Aspergillosis, affecting
up to 25% of all leukemic patients, is the most frequent invasive
mould worldwide with a mortality exceeding 90%. The overall
mortality of about 35% just for candidemias, exceeds that
of all Gram-negative bacterial septicaemias. Moreover,
the incidence of systemic infections is rising, partly because
improved clinical procedures are also leading to better survival
of critically ill patients. The consequences and costs for
health-care budgets are enormous, also since fungal infections
significantly extend the average length of patient stays in
hospitals.
The stunning high mortalities of aspergilloses and candidemias
are in part due to a lack of accurate and speedy diagnostic
tests, but also because current antifungal therapies are not
always effective enough. Diagnosis is further complicated
by emergence of new and less prevalent pathogens, with Cryptococcus
neoformans, Trichophyton spp., Microsporum spp. Epidermophyton
spp. and Fusarium spp acting as the main culprits.
Taken together, systemic mycoses are serious medical conditions,
demanding permanent attention not only in a clinical setting,
but also in antifungal drug discovery, as well as in basic
research addressing the molecular pathology and mechanisms
of disease progression.
Therefore, this special issue, which includes six chapters,
provides a comprehensive overview on the biology and pathology
of major fungal pathogens, covering all aspects from epidemiology
to molecular mechanisms of antifungal resistance and pathogenicity.
One chapter shall discuss epidemiology related to the prevalence,
distribution and frequency of fungal infections and their
causative species. Another chapter will delineate state-of-the-art
methods for the clinical diagnosis and therapy of mycoses
in various clinical settings. Further, the cell wall is a
barrier not only protecting fungi, but also mediating adhesion
to host cells, thereby enabling subsequent tissue penetration.
Hence, one chapter shall discuss the role of cell wall and
its components in pathogenicity, as well as suitability as
target for drug discovery. Tissue penetration, invasion, the
bypass of a residual immune surveillance and spread are major
steps during manifestation of systemic disease, yet we have
a limited understanding of how mycoses actually progress in
vivo. Thus, one chapter describes the molecular routes of
host cell invasion, including a description of animal models
used for studies on pathogenicity. Moreover, biofilms, as
formed by certain pathogens, can constitute serious clinical
complications, since they display intrinsic resistance to
antifungal drugs. Approaches to better understand their fomation
and role in systemic disease are therefore discussed in another
chapter. Finally, a chapter on molecular mechanisms of antifungal
resistance phenomena, including those caused by membrane-bound
drug efflux pumps, will complete this special section on the
biology and pathology of fungal pathogens. Since all chapters
were written by leaders in the respective field, I am confident
that this all-in-one issue will be attractive for students,
researchers, newcomers, as well as clinicians working in the
field of infectious diseases caused by human fungal pathogens.
Karl Kuchler
Medical University Vienna
Max F. Perutz University Laboratories
Department of Medical Biochemistry
Campus Vienna Biocenter
Dr. Bohr-Gasse 9/2
A-1030 Vienna
Austria
E-mail: karl.kuchler@meduniwien.ac.at
[Back to top]
Biofilms and their Role in the Resistance of Pathogenic
Candida to Antifungal Agents
C. d’Enfert
Fungal pathogens of the genus Candida form biofilms
on catheters and prosthetic devices. These three-dimensional
structures composed of yeast and hyphal cells embedded in
an extracellular matrix constitute an important pitfall in
the management of disseminated Candida infections
because of their intrinsic resistance to almost all antifungals
in clinical use. Candida biofilms are especially
resistant to azoles and amphotericin B but remain sensitive
to the newly introduced echinocandins that target cell wall
β-glucan
biosynthesis. Antifungal resistance of biofilms results most
probably from the conjunction of several mechanisms that act
in a time-dependent manner. While drug efflux is likely to
contribute to resistance during the early phases of biofilm
formation, changes in the sterol composition of membranes
might explain the resistance of mature biofilms. The original
physiology of mature Candida biofilms is mirrored
by specific gene expression patterns that may pinpoint genes
important for the acquisition of pleiotropic antifungal resistance.
[Back to top]
Fungal ATP-Binding Cassette (ABC) Transporters in
Drug Resistance & Detoxification
G. Sipos and K. Kuchler
Pleiotropic drug resistance (PDR) is a well-described phenomenon
occurring in fungi. PDR shares several similarities with processes
in bacteria and higher eukaryotes. In mammalian cells, multidrug
resistance (MDR) develops from an initial single drug resistance,
eventually leading to a broad cross-resistance to many structurally
and functionally unrelated compounds. Notably, a number of
membrane-embedded energy-consuming ATP-binding cassette (ABC)
transporters have been implicated in the development of PDR/MDR
phenotypes. The yeast Saccharomyces cerevisiae genome
harbors some 30 genes encoding ABC proteins, several of which
mediate PDR. Therefore, yeast served as an important model
organism to study the functions of evolutionary conserved
ABC genes, including those mediating clini-cal antifungal
resistance in fungal pathogens. Moreover, yeast cells lacking
endogenous ABC pumps are hypersensitive to many antifungal
drugs, making them suitable for functional studies and cloning
of ABC transporters from fungal pathogens such as Candida
albicans. This review discusses drug resistance phenomena
mediated by ABC transporters in the model system S. cerevisiae
and certain fungal pathogens.
[Back to top]
Host-Pathogen Interactions and the Pathological Consequences
of Acute Systemic Candida albicans Infections in
Mice
B. Rozell, P.O. Ljungdahl and P. Martínez
Candida albicans is a commensal organism that lives
as benign member of the microflora of healthy individuals.
In response to changes in the host immune status or microflora,
C. albicans ceases to be a commensal organism and
infects a variety of host tissues. The capacity to shift from
a commensal to pathogenic state requires a coordinated metabolic
response that triggers discrete developmental programs and
that induce the expression of specific virulence traits. Several
virulence traits have been described in C. albicans
including adhesion, morphological and phenotypic switching,
and the production of secreted hydrolytic enzymes. These attributes
contribute to host tissue recognition, tissue invasion and
colonization, as well as evasion of the host immune response.
Recent experimental progress has illuminated some of the cellular
processes that enable Candida cells to sense and
respond to changes in the host environment. Similarly, cells
of the host innate immune system are able to recognize invading
C. albicans cells and induce a complex immune response
that ultimately determines the clinical outcome of the infection.
In this review we describe the current understanding of the
events taking place during systemic infections of C. albicans.
The interplay between defined pathogen and host specific responses
are discussed. Additionally, we provide experimental data
on the pathological consequences resulting from acute systemic
infections of C. albicans in mice.
[Back to top]
Epidemiology of Candida albicans Infections
and Role of Non-Candida-albicans Yeasts
M. Ruhnke
Infections of the skin and the mucous membranes due to Candida
species may occur either in immuncompromised or in non-immuncompromised
patients. This is in contrast to systemic candidiasis (e.g.
candidemia) which is only seen in severely immunocompromised
patients.
Bloodstream infections caused by Candida species are increasingly
recognized in critical ill adult and pediatric individuals,
with significant associated morbidity and mortality. Candida
albicans is the single most common fungal species causing
nosocomial infections. However, non-Candida albicans
spp., including fluconazole-less-susceptible Candida
glabrata, have become more common pathogens. In some
patient populations such as hematological (neutropenic) patients
Non-C. albicans species are detected much more frequently
as compared to non-neutropenic patients in the intensive care.
Non-C. albicans species are more likely to occur
in patients, who receive or have received antifungal therapy
with azoles (e.g. fluconazole). In this review the current
epidemiological trends in mucosal and invasive candidiasis
are discussed with regard to the role of non-Candida albicans
species as the causative agent in immunocompromised patients.
[Back to top]
Getting in Touch with Candida albicans: The
Cell Wall of a Fungal Pathogen
K. Sohn, J. Schwenk, C. Urban, J. Lechner, M. Schweikert
and S. Rupp
The cell wall of fungi is a highly complex structure consisting
of a network of polysaccharides in which a plethora of different
proteins are embedded. It is one of the major organelles of
the cell surrounding it like an armor which protects from
environmental stresses like osmotic pressure and defines the
shape and physical strength of the fungal cell. It is crucial
for colonization and infection since it defines the interface
between host and pathogen. No similar structure is present
in the host, therefore it defines a prime target for drug
development. In this context, it has been shown that cell
surface proteins are required for adhesion to host cells.
The fact, that both pathogenic fungi, like Candida albicans
as well as non-pathogenic fungi, like Saccharomyces cerevisiae,
in general, have a very similar polysaccharide structure but
differ significantly in their protein composition which underscores
the importance of cell wall proteins for pathogenesis. However,
cell wall proteomics of fungi is a highly challenging task
due to the complex biochemistry of these proteins. The extensive
post-translational modifications and covalent attachment to
the polysaccharide backbone of a large proportion of cell
wall proteins makes it a demanding task to isolate and identify
them. In this article, we describe the recent approaches that
have been developed to describe cell wall dynamics and to
isolate and identify cell wall proteins in the pathogenic
yeast C. albicans.
[Back to top]
Laboratory Diagnosis and Therapy of Invasive Fungal
Infections
B. Willinger
Diagnosing fungal infections remains a problem, particularly
in the immunocompromised patient. Symptoms are mostly non-specific
and colonization is difficult to distinguish from invasive
disease. Existing diagnostic tools often lack sensitivity.
Thus, the combination of various diagnostic tools is mandatory
to allow earlier diagnosis of systemic fungal infections.
Microscopy, culture based methods, antigen detection, and
PCR may help to facilitate and accelerate the diagnosis. Galactomannan
and glucan are two promising antigens that may be useful for
early detection of the infection, but also for therapeutic
monitoring. Sensitive and specific PCR assays to detect fungal
DNA are an important part of the diagnostic approach. But
extensive validation and standardization is strongly needed,
before PCR assays can be used in a routine laboratory.
The tremendous increase in invasive fungal infections has
led to an increased interest in new antifungal agents and
the field of antifungal chemotherapy evolved even more rapidly
than diagnostic assays. The development of less toxic formulations
of amphotericin B, the introduction of improved azoles and
the availability of the echinocandins are opening new opportunities
for the treatment of fungal infections. However, continuing
efforts in the laboratory and well-designed clinical trials
are still needed.
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