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Fulltext Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues

Ali Hassan NZ, Mokhtar NM, Kok Sin T, Mohamed Rose I, Sagap I, Harun R, et al.

PLoS One, 2014;9(4):e92553.
PMID: 24694993 DOI: 10.1371/journal.pone.0092553

Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV) and gene expression in colorectal cancer (CRC) samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.
Spatial analysis of colorectal cancer cases in Kuala Lumpur

Shah SA, Neoh HM, Rahim SS, Azhar ZI, Hassan MR, Safian N, et al.

Asian Pac J Cancer Prev, 2014;15(3):1149-54.
PMID: 24606433

BACKGROUND: In Malaysia, data from the Malaysian Health Ministry showed colorectal cancer (CRC) to be the second most common type of cancer in 2007-2009, after breast cancer. The same was apparent after looking at males and females cases separately. In the present study, the Geographic Information System (GIS) was employed to describe the distribution of CRC cases in Kuala Lumpur (KL), Malaysia, according to socio-demographic factors (age, gender, ethnicity and district).
MATERIALS AND METHODS: This retrospective review concerned data for patients diagnosed with colorectal cancer in the years 1995 to 2011 collected from the Wilayah Persekutuan Health Office, taken from the cancer notification form (NCR-2), and patient medical records from the Surgical Department, Universiti Kebangsaan Malaysia Medical Centre (UKMMC). A total of 146 cases were analyzed. All the data collected were analysed using ArcGIS version 10.0 and SPSS version 19.0.
RESULTS: Patients aged 60 to 69 years accounted for the highest proportion of cases (34.2%) and males slightly predominated 76 (52.1%), Chinese had the highest number of registered cases at 108 (74.0%) and staging revealed most cases in the 3rd and 4th stages. Kernel density analysis showed more cases are concentrated up in the northern area of Petaling and Kuala Lumpur subdistricts. Spatial global pattern analysis by average nearest neighbour resulted in nearest neighbour ratio of 0.75, with Z-score of -5.59, p value of <0.01 and the z-score of -5.59. Spatial autocorrelation (Moran's I) showed clustering significant with p<0.01, Z score 3.14 and Moran's Index of 0.007. When mapping clusters with hotspot analysis (Getis-Ord Gi), hot and cold spots were identified. Hot spot areas fell on the northeast side of KL.
CONCLUSIONS: This study demonstrated significant spatial patterns of cancer incidence in KL. Knowledge about these spatial patterns can provide useful information to policymakers in the planning of screening of CRC in the targeted population and improvement of healthcare facilities to provide better treatment for CRC patients.
Gelsolin and ceruloplasmin as potential predictive biomarkers for cervical cancer by 2D-DIGE proteomics analysis

Lokamani I, Looi ML, Md Ali SA, Mohd Dali AZ, Ahmad Annuar MA, Jamal R

Pathol Oncol Res, 2014 Jan;20(1):119-29.
PMID: 23925487 DOI: 10.1007/s12253-013-9670-9

This study aimed to identify candidate proteins which may serve as potential biological markers for cervical cancer using 2D-DIGE. Serum samples of controls, patients with cervical intraepithelial neoplasia grade 3 (CIN 3), squamous cell carcinoma of early (SCC I and II) and late (SCC III and IV) stage were subjected to 2D-DIGE. Differentially expressed spots were identified by tandem mass spectrometry. Validation of candidate proteins in serum and tissue samples were then performed by ELISA and immunohistochemistry (IHC) analysis respectively. A total of 20 differentially expressed proteins were identified. These proteins were found to play key roles in the apoptosis pathway, complement system, various types of transportation such as hormones, fatty acids, lipid, vitamin E and drug transportation, coagulation cascade, regulation of iron and immunologic response. Based on their functional relevancy to the progression of various cancers, 4 proteins namely the complement factor H, CD5-like antigen, gelsolin and ceruloplasmin were chosen for further validation using ELISA. Biological network analysis showed that ceruloplasmin and gelsolin are closely interacted with the oncogene NF-κb. These two proteins were further validated using the IHC. Gelsolin and ceruloplasmin may serve as potential predictive biomarkers for the progression of high grade lesions.
Microarray profiling of secretory-phase endometrium from patients with recurrent miscarriage

Othman R, Omar MH, Shan LP, Shafiee MN, Jamal R, Mokhtar NM

Reprod Biol, 2012 Jul;12(2):183-99.
PMID: 22850470

The aim of the present study was to identify differentially expressed genes and their related biological pathways in the secretory phase endometrium from patients with recurrent miscarriage (RM) and fertile subjects. Endometrial samples from RM and fertile patients were analyzed using the Affymetrix GeneChip® ST Array. The bioinformatic analysis using the Partek Genomic Suite revealed 346 genes (175 up-regulated and 171 down-regulated) that were differentially expressed in the endometrium of RM patients compared to the fertile subjects (fold change ≥1.5, p<0.005). Validation step using quantitative real-time polymerase chain reaction (qPCR) confirmed a similar expression pattern of four exemplary genes: one up-regulated gene (fibroblast growth factor 9, FGF9) and three down-regulated genes: integrin β3 (ITGB3), colony stimulating factor 1 (CSF1) and matrix-metalloproteinases 19 (MMP19). The Gene Set Enrichment Analysis (GSEA) and the Pathway Studio software have found 101 signaling pathways (p<0.05) associated with the affected genes including the FGFR3 /signal transducer and activator of transcription (STAT) pathway and the CSF1R/STAT pathway. Cell adhesion, cell differentiation and angiogenesis were among biological processes indicated by this system. In conclusion, microarray technique is a useful tool to study gene expression in the secretory phase-endometrium of RM patients. The differences in endometrial gene expressions between healthy and RM subjects contribute to an increase in our knowledge on molecular mechanisms of RM development and may improve the outcome of pregnancies in high-risk women with RM.
Fulltext Molecular markers associated with nonepithelial ovarian cancer in formalin-fixed, paraffin-embedded specimens by genome wide expression profiling

Vui-Kee K, Mohd Dali AZ, Mohamed Rose I, Ghazali R, Jamal R, Mokhtar NM

Kaohsiung J. Med. Sci., 2012 May;28(5):243-50.
PMID: 22531302 DOI: 10.1016/j.kjms.2011.11.007

Nonepithelial ovarian cancer (NEOC) is a rare cancer that is often misdiagnosed as other malignant tumors. Research on this cancer using fresh tissues is nearly impossible because of its limited number of samples within a limited time provided. The study is to identify potential genes and their molecular pathways related to NEOC using formalin-fixed paraffin embedded samples. Total RNA was extracted from eight archived NEOCs and seven normal ovaries. The RNA samples with RNA integrity number >2.0, purity >1.7 and cycle count value <28 cycles were hybridized to the Illumina Whole-Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation). We analyzed the results using the GeneSpring GX11.0 and FlexArray software to determine the differentially expressed genes. Microarray results were validated using an immunohistochemistry method. Statistical analysis identified 804 differentially expressed genes with 443 and 361 genes as overexpressed and underexpressed in cancer, respectively. Consistent findings were documented for the overexpression of eukaryotic translation elongation factor 1 alpha 1, E2F transcription factor 2, and fibroblast growth factor receptor 3, except for the down-regulated gene, early growth response 1 (EGR1). The immunopositivity staining for EGR1 was found in the majority of cancer tissues. This finding suggested that the mRNA level of a transcript did not always match with the protein expression in tissues. The current gene profile can be the platform for further exploration of the molecular mechanism of NEOC.
Fulltext Peripheral blood gene expression profile of atherosclerotic coronary artery disease in patients of different ethnicity in Malaysia

Abdullah MH, Othman Z, Noor HM, Arshad SS, Yusof AK, Jamal R, et al.

J Cardiol, 2012 Sep;60(3):192-203.
PMID: 22738689 DOI: 10.1016/j.jjcc.2012.05.009

The molecular basis of coronary artery disease (CAD) has been widely studied in the western world but there is no published work on the Malaysian population. This study looked at the global gene expression profiling of the peripheral blood of patients with CAD from the 3 main ethnic groups in Malaysia. Male subjects selected were based on angiographically confirmed CAD (≥50% stenosis) and normal control subjects (0% stenosis) with age range of 55.6±5.3 and 51.0±5.5 years, respectively. The global gene expression of 12 angiographically documented CAD patients and 11 matched control subjects were performed. The combined group samples identified 6 up regulated differential expression (DE) genes (GHRL, LTA, CBS, HP, ITGA2B, and OLR1) and 12 down regulated DE genes (IL18R1, ITGA2B, IL18RAP, HP, OLR1, SOD2 ITGB3, IL1B, MMP9, PLA2G7, UTS2, and CBS) to be involved in CAD at the fold change of 1.3 with fault discovery rate (FDR) of 1%. Three genes, MMP9, IL1B, and SOD2 were down regulated in all the 3 ethnic groups making them potential biomarker candidates for CAD across all three ethnicities. Further verification in a cohort study is needed.
Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia

Sivalingam M, Looi ML, Zakaria SZ, Hamidah NH, Alias H, Latiff ZA, et al.

Int J Lab Hematol, 2012 Aug;34(4):377-82.
PMID: 22335963 DOI: 10.1111/j.1751-553X.2012.01405.x

INTRODUCTION: To study the ß-gene mutations spectrum, the genotype/phenotype correlation, the modulatory effect of co-inherited factors such as α-gene mutations and of Xmn1 polymorphism in a large cohort of Malaysian patients.
METHODS: A total of 264 cases clinically diagnosed as Thalassemia major (TM) (111), Thalassemia intermedia (21), HbE-β Thalassemia (131), and 1 HbE homozygous were studied. The detection of α and ß gene mutations and characterization of Xmn1 polymorphism were performed by multiplex PCR, amplification refractory mutation system (ARMS), DNA sequencing, and restriction fragment length polymorphism (RFLP)-PCR.
RESULTS: A total of 19 ß Thalassemia mutations were characterized. CD26 and CD41/42 were the most common found in the Malay and Chinese population, respectively. The sensitivity of the clinical diagnosis for β TM, thalassemia intermedia, and HbE/β thalassemia was 94.0%, 15.2%, and 89.2%, respectively. Patients with Xmn1 heterozygosity [+/-] required less frequent transfusion compared with those without the polymorphism. Co-inheritance of α-thalassemia alleviates the severity of HbE-β thalassemia in our cohort.
CONCLUSION: Molecular analysis should be used for a better diagnosis and management of β thalassemia.
Fulltext Dengue epidemic in Malaysia: Not a predominantly urban disease anymore

Muhammad Azami NA, Salleh SA, Neoh HM, Syed Zakaria SZ, Jamal R

BMC Res Notes, 2011;4:216.
PMID: 21714858 DOI: 10.1186/1756-0500-4-216

BACKGROUND:
Dengue infection has been an important and serious public health concern in Malaysia ever since its first reported case here in 1902. Nevertheless, to our knowledge, no nationwide investigation has been carried out to determine the actual magnitude of dengue endemicity in the Malaysian population. In this study, we describe a cross sectional seroepidemiology study of dengue IgG seroprevalence in the Malaysian adult population.

FINDINGS:
From 1000 subjects (35-74 years old), 91.6% subjects were found to be dengue seropositive. Age is found to be a significant risk factor associated with dengue seroposivity, where the seroprevalence increased with every 10 year increase in age. Nevertheless, gender and ethnicity did not have an effect. Interestingly, there were similar seroprevalence rates between urban and rural samples, showing that dengue is presently not confined to urban areas in Malaysia.

CONCLUSIONS:
High dengue IgG seropositivity found in the population is an indication that dengue might be endemic in Malaysia for a long time into the future. Public awareness, proper vector control and vigilant surveillance are critical to keep the infection rates low and to prevent outbreaks.
Clusterin as a potential marker in distinguishing cervical neoplasia

Lokamani I, Looi ML, Ali SA, Dali AZ, Jamal R

Anal. Quant. Cytol. Histol., 2011 Aug;33(4):223-8.
PMID: 21980627

To assess the immunoexpression of clusterin (CLU) in the progression of cervical neoplasia.
Fulltext Spectrum of infections in splenectomised thalassaemia patients

Zarina AL, Norazlin KN, Hamidah A, Aziz DA, Zulkifli SZ, Jamal R

Med J Malaysia, 2010 Dec;65(4):283-5.
PMID: 21901946

Splenectomised thalassaemia patients are at risk of developing sepsis. As the infection may be life-threatening, treatment should be sought and given promptly. A retrospective study was performed amongst our thalassaemia major patients who were splenectomised. The vaccination status of each patient and the types of infections seen were reviewed to obtain a local perspective. In our cohort of 49 splenectomised patients, 25 patients required hospitalization for the treatment of infection. There were a total of 40 febrile episodes within this hospitalised group of which 27.5% were microbiologically documented infection with bacteraemia. The predominant causative organisms were gram negative rods and three patients succumbed to overwhelming septicaemic shock as a result of delayed presentation. Sixty percent of the febrile episodes were clinically documented infection and comprised mainly upper respiratory tract infections. Based on the spectrum of infections seen, there is a need to improve the patients' awareness level so that early treatment is sought. There is also a need to re-address the approach towards vaccination in this immunocompromised group of patients by administering a booster pneumococcal and influenza vaccination in an attempt to reduce morbidity.
Laser capture microdissection with genome-wide expression profiling displayed gene expression signatures in endometrioid endometrial cancer

Mokhtar NM, Ramzi NH, Yin-Ling W, Rose IM, Hatta Mohd Dali AZ, Jamal R

Cancer Invest, 2012 Feb;30(2):156-64.
PMID: 22122087 DOI: 10.3109/07357907.2011.633290

This research determined genes contributing to the pathogenesis of endometrioid endometrial cancer (EEC). Eight pairs of microdissected EEC samples matched with normal glandular epithelium were analyzed using microarray. Unsupervised analysis identified 162 transcripts (58 up- and 104 down-regulated) that were differentially expressed (p < .01, fold change ≥ 1.5) between both groups. Quantitative real-time polymerase chain reaction (qPCR) validated the genes of interest: SLC7A5, SATB1, H19, and ZAK (p < .05). Pathway analysis revealed genes involved in acid amino transport, translation, and chromatin remodeling (p < .05). Laser capture microdissection (LCM) followed by microarray enabled precise assessment of homogeneous cell population and identified putative genes for endometrial carcinogenesis.
Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients

Then SM, Rani ZZ, Raymond AA, Ratnaningrum S, Jamal R

Asian Pac J Allergy Immunol, 2011 Sep;29(3):290-3.
PMID: 22053601

We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.
Health-related quality of life (HRQOL) among pediatric leukemia patients in Malaysia

Hamidah A, Wong CY, Tamil AM, Zarina LA, Zulkifli ZS, Jamal R

Pediatr Blood Cancer, 2011 Jul 15;57(1):105-9.
PMID: 21465639 DOI: 10.1002/pbc.23125

Health-Related Quality of Life (HRQOL) in pediatric leukemia patients in Malaysia has not been studied before. This was mainly due to a lack of databases on patients in the past. Many patients abandoned treatment or were lost to follow up. With more children now fully compliant and completing treatment nowadays, with higher cure rate, HRQOL has become important for our patients. The purpose of the current study was to determine the HRQOL scores in children with acute leukemia and to compare the scores for those on maintenance chemotherapy with those off-treatment as well as to determine factors which might affect HRQOL.
Vincristine-induced vocal cord palsy: case report and review of the literature

Latiff ZA, Kamal NA, Jahendran J, Alias H, Goh BS, Syed Zakaria SZ, et al.

J Pediatr Hematol Oncol, 2010 Jul;32(5):407-10.
PMID: 20505534 DOI: 10.1097/MPH.0b013e3181e01584

Vincristine-induced vocal cord paralysis is a rare but serious complication. We report 2 patients with acute lymphoblastic leukemia who developed progressive stridor during induction chemotherapy. There were no clinical features of peripheral or autonomic neuropathy. Flexible laryngoscopy confirmed the diagnosis of bilateral vocal cord palsy; interestingly, the nerve conduction test revealed axonal motor neuropathy involving the median and common peroneal nerves in both patients. The first patient required prolonged ventilatory support necessitating unilateral cordectomy before extubation, whereas the second only required supplemental oxygen therapy. There was resolution of stridor in the first patient after cordectomy and gradual clinical improvement in the second. These cases illustrate that a high index of suspicion of vincristine-induced vocal cord palsy with prompt otolaryngology consultation for laryngoscopy is required in the diagnostic evaluation of a patient who has received vincristine.
Fulltext Juvenile myelomonocytic leukaemia: a case series

Azma RZ, Zarina AL, Hamidah A, Jamal R, Sharifah NA, Ainoon O, et al.

Malays J Pathol, 2009 Dec;31(2):121-8.
PMID: 20514855 MyJurnal

Juvenile myelomonocytic leukaemia (JMML), previously known as juvenile chronic myeloid leukaemia (JCML) is a rare, myelodysplastic - myeloproliferative disease typically presenting in early childhood. This disorder is difficult to distinguish from other myeloproliferative syndrome such as chronic myeloid leukaemia (CML) because of the similarities in their clinical and bone marrow findings. However, because of its unique biological characteristics such as absolute monocytosis with dysplasia, absence of Philadelphia chromosome or BCR-ABL fusion protein, hypergammaglobulinaemia and raised fetal haemoglobin level, this disorder does not satisfy the criteria for inclusion in the CML or chronic myelomonocytic leukaemia (CMML) group, as seen in adult patients. We describe a series of three patients with JMML, who had almost similar clinical and laboratory findings, and discuss the difficulty in the classification and treatment of the disease.
Assessment of P-gp and MRP1 activities using MultiDrugQuant Assay Kit: a preliminary study of correlation between protein expressions and its functional activities in newly diagnosed acute leukaemia patients

Fazlina N, Maha A, Zarina AL, Hamidah A, Zulkifli SZ, Cheong SK, et al.

Malays J Pathol, 2008 Dec;30(2):87-93.
PMID: 19291917

Multidrug resistance (MDR) is believed to be responsible for poor response of patients towards chemotherapy particularly patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The best-characterized resistance mechanism is the one mediated by permeability-glycoprotein (P-gp) encoded by MDR1 gene, which is responsible for drug efflux. We studied P-gp and multidrug resistance-associated protein 1 (MRP1) expression and functional activities in 43 newly diagnosed acute leukemia cases (19 paediatric ALL cases and 24 adult AML cases). The expression and functional activities were examined using flow cytometry and MultiDrugQuant assay kit (involving calcein AM uptake and efflux). P-gp and MRP1 expression and its functional activities were observed in 68.4% of paediatric ALL. In adult AML cases, all cases expressed MRP1 and its functional activities but only 58.3% were positive for P-gp and its functional activities. We were able to show a significant correlation between the expression of the multidrug resistant protein (P-gp and MRP1) and their functional activity in adult AML and paediatric ALL samples.
Fulltext Prevalence of human papillomavirus in abnormal cervical smears in Malaysian patients

Sharifah NA, Seeni A, Nurismah MI, Clarence-Ko CH, Hatta AZ, Ho NP, et al.

Asian Pac J Cancer Prev, 2009 Apr-Jun;10(2):303-6.
PMID: 19537900

Cervical cancer is the second most common female malignancy in Malaysia. Despite advances in treatment, the overall survival for this disease has not changed in the last decade. Infection by certain types of HPV is recognized as a causal and necessary factor for its development. This study was carried out to determine the prevalence of HPV infection in abnormal cervical smears in Malaysian patients using archival cervical smears retrieved from the Cytopathology Unit, Universiti Kebangsaan Malaysia Medical Centre (UKMMC) between the years 1992-1995. DNA was extracted from 38 abnormal smears comprising 25 intraepithelial lesions and 13 cervical carcinomas and 10 normal smears. Amplification of HPV genes was carried out using the polymerase chain reaction (PCR) technique. HPV genotypes were determined using direct sequencing and the results were compared to the database from Genebank. DNA was successfully extracted from all 48 cervical smears. High-risk HPV (HR-HPV) genotypes were detected in 95% of the abnormal smears. Eight high-risk oncogenic types were identified: 16, 18, 31, 51, 52, 56, 58 and 66. All (100%) cervical cancer smears showed presence of HR-HPV compared to 92% of the cervical intraepithelial lesions. Among the eight HR-HPV genotypes identified, HPV 16 and 52 were the commonest (23.7% each) HPV genotypes encountered and among the CIN lesions, HPV 16 (28%) was the most frequent. We conclude that HPV 16 is the most prevalent HPV genotype present in abnormal cervical smears in Malaysian patients, and that the use of archival material to assess the presence of HPV is potentially worthwhile, and can be utilized for longitudinal studies of HPV presence and persistence.
Fulltext Transient abnormal myelopoeisis in newborns with Down syndrome

Zarina AL, Hamidah A, Yong SC, Rohana J, Hamidah NH, Azma RZ, et al.

Malays J Pathol, 2007 Dec;29(2):107-11.
PMID: 19108403 MyJurnal

Transient abnormal myelopoeisis (TAM) is a haematological phenomenon commonly seen in newborns with Down syndrome. Although the majority show spontaneous resolution, this condition should not be dismissed too readily as there have been associated fatalities. Furthermore, even for those who do show spontaneous resolution, a significant percentage will develop acute megakaryoblastic leukaemia within the next few years of life. We report a series of four patients with TAM who presented with hepatosplenomegaly and leucocytosis detected on preliminary investigations.
Prevalence and parental perceptions of complementary and alternative medicine use by children with cancer in a multi-ethnic Southeast Asian population

Hamidah A, Rustam ZA, Tamil AM, Zarina LA, Zulkifli ZS, Jamal R

Pediatr Blood Cancer, 2009 Jan;52(1):70-4.
PMID: 18937312 DOI: 10.1002/pbc.21798

The purpose of the current study was to determine the prevalence of use of complementary and alternative medicine (CAM) by children with cancer and to compare the characteristics of CAM users and CAM nonusers.
Expression of multidrug resistance (MDR) proteins and in vitro drug resistance in acute leukemias

Fazlina N, Maha A, Jamal R, Zarina AL, Cheong SK, Hamidah H, et al.

Hematology, 2007 Feb;12(1):33-7.
PMID: 17364990

The expression of the multidrug resistance (MDR) proteins may influence the outcome of treatment in patients with acute leukemia. The aim of this study was to determine the IC50 of cytotoxic drugs (cytosine arabinoside, ara-C and daunorubicin, dnr) using the in vitro 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)2H-tetrazolium, inner salt (MTS) assay method. A total of 82 newly diagnosed acute leukemia cases (43 adult myeloid leukaemia, AML cases and 39 acute lymphoblastic leukaemia, ALL cases) and 16 relapsed cases (8 AML cases and 8 ALL cases) were studied. The MTS assay was performed using two cytotoxic drugs, dnr and ara-C. Cells were incubated with different concentrations of drugs for 4 days and the IC50 was extrapolated from the viability curve. In newly diagnosed cases, we found that childhood ALL samples showed higher IC50 values of dnr (0.040 +/- 2.320) compared to adult AML samples (0.021 +/- 0.158). In contrast, newly diagnosed adult AML samples showed higher IC50 values of ara-C (0.157 +/- 0.529) compared to childhood ALL samples (0.100 +/- 2.350). In relapsed cases, two samples of childhood ALL showed IC50 values of dnr (0.910 +/- 1.760) and ara-C (1.310 +/- 2.390), which was higher compared to childhood AML samples (0.129 +/- 0.214 and 0.210 +/- 0.003, respectively). However, there was no correlation between IC50 values of these drugs tested with clinical outcome. In conclusion, we found that MTS assay is an easy, rapid and non laborious method to study in vitro drug resistance in acute leukaemia cases.

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