Current
Pharmaceutical Biotechnology
ISSN: 1389-2010
Current Pharmaceutical Biotechnology
Volume 8, Number 2, April 2007
Contents
New Research Tolls for Antique Pediatric Tumors: The
Dilemma of Transposing Drug-Resistance
Guest Editor: E.T. Valera
Editorial Pp. 57
Drug Resistance in Childhood Acute Myeloid Leukemia
Pp. 59-75
J. Styczynski
[Abstract]
Drug Resistance and Methylation in Myelodysplastic
Syndrome Pp. 77-81
D.O. Vidal, L.F. Lopes and E.T. Valera
[Abstract]
Classification of Sarcomas Using Bioinformatics and
Molecular Profiling Pp. 83-91
T.A. Dang and T.K. Man
[Abstract]
Drug Resistance in Hepatoblastoma Pp. 93-97
S.W. Warmann and J. Fuchs
[Abstract]
Drug Resistance in Renal Tumors of Childhood
Pp. 99-104
C. Ramachandran
[Abstract]
Drug-Resistance in Central Nervous System Tumors:
From the Traditional Cell-Resistance Model to the Genetically
Driven Approaches on Therapy Pp. 105-113
E.T. Valera, H.R. Machado, C.A. Scrideli, A.K. Lucio-Eterovic
and L.G. Tone
[Abstract]
Abstracts
[Back to top]
Editorial
Despite many advances in the management of cancer,
a substantial portion of cancer patients will still suffer
a relapse. Drug-resistance remains a major problem in dealing
with malignant tumors, both in children and adults. The molecular
events related to this resistant phenotype are far from being
fully understood. For many pediatric tumors, molecular assays
are starting to give insights about the complex relationship
between tumor and individual.
In an era of genomic-based hypotheses, the understanding of
the molecular events is of critical importance to better treat
oncological diseases. New techniques such as cDNA microarrays,
real-time PCR, spectral karyotyping (SKY) and comparative
genomic hybridization (CGH) represent new tools that may be
useful in identifying genetic pathways or events beneath drug
resistance. Researchers, physicians and pharmaceutical scientists
are designing new pharmacological approaches and drugs for
treating those resistant tumors based upon their molecular
pattern of resistance. This may represent the ‘era of
the disease in the search for its specific drug’ and
not the opposite anymore.
This special issue covers some very exciting aspects related
to drug resistant phenotype in cancer. Dr. Styczynski presents
a thorough review about drug resistance in childhood acute
myeloid leukemia. Dr. Vidal et al. focus on drug
resistance in myelodysplastic syndromes and describe an approach
on the epigenetic process of methylation in that disease.
Drs. Tu Anh Dang and Tsz-Kwong Man introduce the bioinformatic
classification of sarcomas using genomic and proteomic profilings.
Drs. S.W. Warmann and J. Fuchs gave us an excellent analysis
on drug resistance in children with hepatoblastoma. Dr. Ramachandran
reviews ways to inhibit the multidrug resistance mechanisms
in renal tumors.Finally, Dr. Valera et al. examine
drug-resistance in central nervous system tumors over the
past decade, evolving from the traditional cell-resistance
model to the genetically driven approaches on therapy.
Specialists in the field discuss a number of molecular events
in some difficult-to-treat neoplastic diseases, both in children
and adults. I sincerely hope that this special issue will
be of interest to researchers in their quest to find more
rationale therapeutic approaches.
E.T. Valera
Pediatrics Department
Faculdade de Medicina de Ribeirão Preto
Universidade de São Paulo
Brazil
[Back to top]
Drug Resistance in Childhood Acute Myeloid
Leukemia
J. Styczynski
Therapy results in childhood AML differ from those of ALL.
The development of drug resistance is the limiting factor
in the therapy of AML. Different problems of drug resistance
in childhood AML, with emphasis to age and in comparison to
adult AML are presented. In vitro and in vivo
aspects are discussed, together with mechanisms of resistance
to cytostatic drugs, focused on clinical relevance of cellular
drug resistance profile and its prognostic value. Possibilities
of modulation and circumvention of drug resistance are reviewed,
with stress on new drugs being tested. Taking into account
both children and adults, it seems that age is adversely related
to therapy outcome in AML, and the percentage of patients
with favorable cytogenetics decreases with age; however, age
is positively correlated with multi-drug resistance and the
proportion of patients with unfavorable cytogenetics. AML
is considered a stem cell disease. BCRP, PGP and MRP’s
are preferentially expressed in leukemic stem cells, making
this disease drug resistant. Cellular drug resistance in AML
cells seems to be similar throughout all other age groups,
however the higher the age, the worse the outcome. In childhood
AML, no drug is more effective in comparison to ALL, and cellular
drug resistance is partially related to chromosomal abnormalities.
Pediatric AML is equally resistant as adult AML. Pediatric
and adult AML, respectively, are possibly equally drug resistant
on initial diagnosis and at relapse. In contrast to ALL, the
prognostic value of in vitro drug resistance in childhood
AML has not been well documented yet.
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Drug Resistance and Methylation in Myelodysplastic
Syndrome
D.O. Vidal, L.F. Lopes and E.T. Valera
Myelodysplastic syndrome is a clonal hematopoietic stem cell
disorder that presents a poor survival for patients treated
with standard therapies other than stem-cell transplantation.
Multi-drug resistance (MDR) to simultaneous drugs used in
chemotherapy is a major concern in the treatment of cancer
and also in MDS. ATP-binding cassette (ABC) transporters are
involved in the main mechanism that confers drug resistance
to cells. Increased expression of drug resistance genes, such
as MDR1, MRP1 and LRP, is involved with multi-drug resistance
in MDS. The expression of these drug efflux transporters acts
in synergy with other alterations, such as epigenetic events,
increases in multidrug resistance in MDS. Methylation, the
main epigenetic mechanism is widely explored in other hematological
malignancies; however, in MDS, this mechanism is poorly investigated.
Clinical trials evaluated or are under ongoing evaluation
of drugs that abrogated ABC transporters action or reversed
the abnormal methylation of some genes in MDS. In this report,
we explore the data available in the field of drug resistance
and methylation both in pediatric and adult MDS.
[Back to top]
Classification of Sarcomas Using Bioinformatics and
Molecular Profiling
T.A. Dang and T.K. Man
Recent advances in genomic and proteomic technologies have
revolutionized our way of classifying cancers. These high-throughput
technologies allow the use of powerful and multivariate bioinformatic
approaches to develop molecular classifiers. These classifiers
can then be used to distinguish different types of tumors
based on their molecular profiles. This is particularly important
for heterogeneous groups of tumors such as sarcomas. Although
sarcomas have a variety of histological appearances, the distinction
among some of the diagnostic groups is vague. Therefore, molecular
classification provides a new way to distinguish histologically
similar but molecularly different types of sarcomas, and hence
improves tumor diagnosis and stratification. In addition,
identification of discriminatory genes that carry information
to differentiate clinical subtypes of sarcomas will further
elucidate the underlying molecular pathways and pathological
mechanisms of these tumors. In this article, we review some
current methods used in genomic and proteomic profiling, outline
the approach of using bioinformatic techniques to develop
a molecular classifier, and discuss some recent examples to
illustrate the use of molecular classification to distinguish
different types of sarcomas and understand the biology of
these tumors.
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Drug Resistance in Hepatoblastoma
S.W. Warmann and J. Fuchs
Treatment results of human hepatoblastoma (HB) have been improved
remarkably during recent years, mainly through the establishment
of integrated regimens controlled and coordinated by multicentric
treatment studies. Today, neoadjuvant and adjuvant chemotherapy
is combined with surgical resection of the tumors. The main
therapeutic goal is a complete surgical removal of tumor masses,
which is also essential for the survival of the patients.
Despite improved overall survival rates, treatment results
of advanced tumors are still far from being satisfying. Multidrug
resistance has been identified as a major factor responsible
for the bad prognosis of children suffering from advanced
staged hepatoblastoma. During recent years investigations
focused on factors contributing to drug resistance in hepatoblastoma
and on possible approaches towards overcoming this therapeutical
challenge. Alternative approaches that are currently evaluated
in experimental and clinical settings comprise new cytotoxic
agents, chemosensitizers, gene directed applications but also
surgical techniques and an expansion of indication for liver
transplantation.
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Drug Resistance in Renal Tumors of Childhood
C. Ramachandran
Renal cancers are as one of the most common drug resistant
neoplasms affecting children and multidrug resistance (MDR)
happened to be an important reason for the failure of chemotherapy
in refractory cancers of childhood. MDR can be intrinsic or
acquired, depending on the time of its occurrence, either
at diagnosis or during chemotherapy. Renal cancers often have
intrinsic form of MDR because of de novo expression
of P-glycoprotein (P-gp) in renal cells. Molecular investigations
on MDR during the past two decades have led to the isolation
and characterization of genes coding for P-gp, multidrug resistance-associated
protein (MRP), lung resistance-related protein (LRP), breast
cancer resistance protein (BCRP/MXR), drug resistance-associated
protein (DRP), and ATP-binding cassette protein (ABCP). Several
molecular probes, primer pairs, and monoclonal antibodies
have been developed over the years to quantify the regulation
and expression of these drug resistance markers in tumor cells.
Methodologies have also been standardized to estimate the
gene amplification, mRNA and protein expression, and functionality
of drug resistance proteins in clinical specimens from cancer
patients. Because of the recent developments in microarray
technology, DNA and protein arrays against drug resistant
genes are available commercially now. This review includes
techniques for detection and quantification of the expression
and function of these drug resistance genes in childhood renal
tumors. Since these markers have clinical sig-nificance, currently
available technology warrants the application of these markers
in clinical oncology. Moreover, the first, second and third
generation drug resistance modifiers have been developed over
the past several years for overcoming drug resistance problem
in tumor cells. Unfortunately, these reversing agents are
yet to be proved successful clinically. Since treatment protocols
are usually adopted from adult tumor patients into childhood
population, clinical trials with modifying agents are yet
to be undertaken and/or concluded in pediatric renal cancer
patients. More clinical studies may be required to analyze
the genes involved in the MDR of childhood renal cancer patients
and trials have to be undertaken to evaluate the efficacy
of MDR modifying agents in them, at least in parallel with
adult patients.
[Back to top]
Drug-Resistance in Central Nervous System Tumors:
From the Traditional Cell-Resistance Model to the Genetically
Driven Approaches on Therapy
E.T. Valera, H.R. Machado, C.A. Scrideli, A.K. Lucio-Eterovic
and L.G. Tone
The advances in the cure rates observed in the oncology field
in the past decades were not fully assembled by primary brain
tumors. In this heterogeneous group of diseases, resistance
to either chemotherapy or radiotherapy still is a major problem
to be addressed. Several genetic and epigenetic events may
directly influence the response to treatment in these tumors.
Throughout recent discoveries, drug resistance in brain tumors
was better understood as a final product of different and
complexes pathways that interact and modulate cell performance
to treatment. The last years experienced a new paradigm in
the way brain tumor drug-resistance genes are elected out
of the vast human genomic universe. In the former era, models
of cell resistance that were documented on solid tumors other
than brain were investigated at the central nervous system’s
counterpart. Nowadays, genomic-based hypothesis generation,
supported by modern genetic technique tolls, seem effective
in revealing new candidate-genes that might confer the resistance
phenotype. Nevertheless, new treatment approaches and novel
drugs based on the pharmacogenomic resistance profile, particularly
for brain tumors, are just starting to become a reality for
clinical purposes.
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