Current Pharmaceutical Biotechnology - Volume 8, Issue 2, 2007

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.

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.

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.

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.

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.

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 significance, 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.

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.