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Profil pengekspresan gen mengekod delta 6 dan delta 12-asid lemak Desaturase Cunninghamella Bainieri semasa Biosintesis asid Gamma-Linolenik

Noor Adila Abdul Karim, Zamri Zainal, Aidil Abdul Hamid, Farah Diba Abu Bakar, Abdul Munir Abdul Murad

Sains Malaysiana, 2016;45:1443-1451.

Delta 6-asid lemak desaturase dan delta 12-asid lemak desaturase merupakan enzim yang diperlukan bagi langkah desaturasi semasa proses biosintesis asid gamma-linolenik (GLA) oleh kulat oleaginus. Objektif kajian ini ialah untuk menganalisis profil pengekspresan gen mengekod enzim delta 6-asid lemak desaturase (des6) dan delta 12-asid lemak desaturase (des12) kulat oleaginus Cunninghamella bainieri semasa penghasilan GLA. Jujukan gen separa bersaiz 1372 pb bagi des6 dan 1008 pb bagi des12 telah dipencil daripada C. bainieri. Analisis pengekspresan gen menggunakan kaedah tindak balas berantai polimerase kuantitatif masa sebenar (RT-qPCR) menunjukkan perubahan kadar pengekspresan des6 adalah lebih tinggi berbanding kadar pengekspresan des12 semasa penghasilan GLA. Pengekspresan des6 adalah tertinggi selepas 24 jam dikultur dalam medium penghasilan GLA. Namun, kadar pengekspresannya menurun hingga jam ke-96 pertumbuhan tetapi meningkat semula pada jam ke-120. Bagi des12, kadar pengekspresannya adalah lebih sekata dengan pengekspresan tertinggi dikesan pada jam ke-120. Analisis penghasilan GLA menunjukkan jumlah GLA dalam sel berkolerasi dengan kadar pengekspresan des6. Hasil kajian mencadangkan bahawa aras pengekspresan des6 adalah penting dalam menentukan aras GLA dalam C. bainieri.

Matched MeSH terms: Cytarabine
HPLC method development and validation for simultaneous detection of Arabinoside-C and doxorubicin

Mistiran AF, Dzarr AA, Gan SH

Toxicol. Mech. Methods, 2010 Oct;20(8):472-81.
PMID: 20626302 DOI: 10.3109/15376516.2010.503246

This paper describes a new validated high performance liquid chromatography (HPLC) method for the simultaneous determination of two anti-cancer drugs, Arabinoside-C (Ara-C) and doxorubicin hydrochloride (DOX). A simultaneous determination method saves cost and time as both drugs can be injected into a single HPLC system without the need to change or re-equilibrate with a new mobile phase. The objective of the study is to develop a simultaneous determination method of two anti-cancer drugs, Ara-C and DOX. The mobile phase consisted of a mixture (45:55) of acetonitrile:ammonium hydrogen phosphate aqueous solution (0.01 M) at pH 6.2 at a flow rate of 0.3 ml/min, with UV detection at 252 nm. Separation was achieved on a C-18 column (5 µm: 250 mm × 4.6 mm) maintained at 30°C in a column oven. The method was linear between 325 ng/ml and 10 µg/ml for Ara-C and 625 ng/ml and 20 µg/ml for DOX. The limit of detection (LOD) was 20 ng/ml for Ara-C and 60 ng/ml for DOX. The developed HPLC method achieved good precision and accuracy as well as limit of quantitations. The developed and validated method is suitable to be used for routine analysis of Ara-C and DOX.

Matched MeSH terms: Cytarabine/analysis*
Two successful deliveries of healthy children by a young woman diagnosed and treated during induction and relapsed therapy for acute promyelocytic leukemia

Dang CC, Guan YK, Lau NS, Chan SY

J Oncol Pharm Pract, 2020 Dec;26(8):2034-2037.
PMID: 32279594 DOI: 10.1177/1078155220915764

INTRODUCTION: Acute promyelocytic leukemia is an oncologic emergency. The limited cases reported in the literature have led to poor understanding of the safety of management of acute promyelocytic leukemia during pregnancy.
CASE REPORT: Herein is an acute promyelocytic leukemia case of a 22-year-old young pregnant woman who had various social problems. The patient was diagnosed with acute promyelocytic leukemia in her the second trimester of her first pregnancy.Management and outcome: She was treated with all-trans-retinoic acid with idarubicin and successfully delivered a healthy baby. She completed induction with idarubicin but defaulted her all-trans-retinoic acid, 6-mercaptopurine and methotrexate maintenance. She relapsed after one year and was salvaged with all-trans-retinoic acid high dose cytarabine and arsenic trioxide. She went into remission and had autologous stem cells collected and was planned for an autologous stem cell transplant but she defaulted. She relapsed when she was pregnant with her second baby during her third trimester (29+weeks) 10 months later. Salvage chemotherapy with arsenic trioxide, all-trans-retinoic acid and idarubicin was given. Patient underwent an emergency lower segment caesarian section at 31 weeks of pregnancy due to abnormal fetal cardiotocography. A healthy baby was delivered.
DISCUSSION: This drug regimen is controversial during pregnancy owing to the teratogenic effects and fatal retinoic acid syndrome especially in early gestation. In this case, patient was started the induction therapy of all-trans-retinoic acid treatment at her second trimester during her first pregnancy.
CONCLUSION: Our lady demonstrated the possibility of using all-trans-retinoic acid and arsenic trioxide and chemotherapy during second and third trimester with successful pregnancy outcomes.

Matched MeSH terms: Cytarabine/administration & dosage
Complex karyotypic abnormalities in a case of acute myeloid leukaemia--M4Eo

Leong CF, Azma RZ, Cheong SK, Salwati S, Sharifah NA

Malays J Pathol, 2005 Jun;27(1):45-50.
PMID: 16676693

A 25-year-old man was referred to Hospital UKM with a 2-week history of fever, productive cough and loss of appetite. Physical examination revealed an ill-looking, tachypnoeic young man. No obvious lymphadenopathy or organomegaly was noted. Examination of the respiratory system revealed right pleural effusion. Full blood picture demonstrated leukocytosis with 90% blasts, and bone marrow examination confirmed the diagnosis of acute myeloid leukemia (AML) French-American-British (FAB) classification of M4 with eosinophilia. His chromosome karyotyping showed complex karyotypic abnormalities. Cytological examination of the pleural fluid demonstrated numerous blast cells indicating leukemic infiltration of the lungs, which is a rare presentation in AML. He was then started on induction chemotherapy with intravenous daunorubicin and cytarabine. In the midst of treatment, he developed an episode of seizure and cerebro-spinal fluid cytology confirmed central nervous system (CNS) leukaemic infiltration. Additional intrathecal methotraxate was given. Repeat bone marrow examination done on day 15 of chemotherapy showed persistence of excess blasts indicating refractory AML. He was then reinduced with high dose cytarabine but to no avail. The disease progressed and he succumbed about 8 weeks after the initial diagnosis was made. We highlight here a case of AML-M4Eo with complex karyoyptic abnormalities presenting with leukaemic infiltration of the lungs and CNS which had imparted a bad prognosis for this subtype of AML, AML-M4Eo.

Matched MeSH terms: Cytarabine/therapeutic use
Treating childhood acute myeloid leukaemia with the AML-BFM-83 protocol: experience in a developing country

Chan LL, Abdel-Latif ME, Ariffin WA, Ariffin H, Lin HP

Br J Haematol, 2004 Sep;126(6):799-805.
PMID: 15352983

Treatment for childhood acute myeloid leukaemia (AML) consists of remission induction chemotherapy followed by postremission chemotherapy with or without bone marrow transplantation. The AML Berlin-Frankfurt-Munster (BFM)-83 protocol with induction-consolidation-maintenance chemotherapy for 2 years has been reported to result in a 6-year event-free survival (EFS) and event-free interval (EFI) of 49% and 61% respectively. A total of 174 Malaysian children were treated with this protocol between 1985 and 1999. The 5-year EFS and EFI was 30.7% and 48.0% respectively. The overall mortality from sepsis was 24%, which needs urgent address. The 5-year EFS for patients treated before 1993 and after 1993 was 18.6% and 41.3%, respectively (P = 0.04), while the EFI was 32% and 60.6% respectively (P = 0.034). The improvement seen after 1993 was related to a reduction in induction deaths for that period and probably reflected increased capability and familiarity to cope with the demands of the AML-BFM-83 protocol and accompanying complications in the treatment of AML.

Matched MeSH terms: Cytarabine/administration & dosage
Fulltext Extensive myelofibrosis responsive to treatment for acute erythroblastic leukaemia

Fadilah SA, Raja-Zahratul-Azma RS, Leong CF

Malays J Pathol, 2006 Jun;28(1):55-8.
PMID: 17694960 MyJurnal

Intense myelofibrosis is rarely associated with de novo acute myeloid leukaemia (AML) except in acute megakaryoblastic leukaemia (AML-M7) where there is diffuse marrow fibrosis as a consequence of proliferation of neoplastic myeloid cells. AML associated with significant myelofibrosis developing both de novo or secondary to primary (idiopathic) myelofibrosis is characterised by a fulminant course and extremely poor prognosis, primarily due to treatment-resistant disease. The prognostic value of degree of marrow fibrosis in de novo AML has been poorly investigated. We describe a case of extensive myelofibrosis associated with acute erythroblastic leukaemia (AML-M6) that responded to induction therapy of the leukaemia.

Matched MeSH terms: Cytarabine/therapeutic use
Fulltext Transverse myelopathy following intrathecal administration of chemotherapy

Teh HS, Fadilah SA, Leong CF

Singapore Med J, 2007 Feb;48(2):e46-9.
PMID: 17304378

Transverse myelopathy is one of the rare complications following administration of intrathecal chemotherapy. We report two cases of transverse myelopathy following administration of intrathecal methotrexate and cytarabine arabinoside. One patient was a 17-year-old Malay man who had lymphoblastic lymphoma in the leukaemic phase, while the other patient was a 40-year-old Malay man with relapsed Hodgkin's lymphoma. Both cases demonstrated variability in onset of symptoms, clinical progression and final outcome from the complication.

Matched MeSH terms: Cytarabine/adverse effects*
Fulltext Effective Dose Estimation of Patients Administered with 18F-FDG and Ga-68 DOTATATE in PET/CT Examination Associated with Gender and Weight

Kamal, I., Said, M. A., Bathumalai, J., Abdul Razak, H. R., Abdul Karim, M. K.

Physics and Technology in Medicine, 2020;1(1):15-21.
MyJurnal

The whole-body fluorodeoxyglucose F18 (18F-FDG) and gallium-68 (Ga-68 DOTATATE) are the most common radiopharmaceutical use in PET/CT imaging for cancer staging. Although radiopharmaceutical for PET/CT examination has been acknowledged for its safety and efficacy, the internal dosimetry and effective dose (ED) from the examinations are rarely discussed. Hence, this study aimed to evaluate radiation ED for whole-body radiopharmaceuticals PET/CT concerning patients’ gender and their weight. A total of 82 oncology patients (44 males and 38 females) were collected retrospectively from Institut Kanser Negara, Putrajaya. Data, such as 18F-FDG and Ga-68 DOTATATE activity and patient demography (weight, height, age), were recorded and analyzed. Effective doses from both internal and external exposure were calculated using the coefficient
provided by the International Commission on Radiological Protection (ICRP) report. The total ED of 18F-FDG for male patients was 20.2 ± 8.6 mSv and for female patients were 19.0 ± 8.2 mSv while total whole-body ED for Ga-68 DOTATATE for male patients was 18.5 ± 7.0 mSv and 17.0 ± 5.6 mSv for female patients. The ratio for ED between male and female were 1:1 for both examinations ranged from 12.0 – 23 mSv. From this study, it indicated that the ED of Ga-68 DOTATATE was far lower when compared to the ED of 18F-FDG by a factor of 0.7. Therefore, it is crucial to optimize the PET/CT protocol dose in order to uphold the dose as low as reasonably achievable (ALARA).

Matched MeSH terms: Cytarabine
Fulltext Challenging lymphoid malignancy of primary central nervous system lymphoma: A case report

Kasinathan G, Kori AN, Hassan N

Ann Med Surg (Lond), 2020 Sep;57:307-310.
PMID: 32874561 DOI: 10.1016/j.amsu.2020.08.011

Introduction: Primary central nervous lymphoma is an aggressive disease without evidence of systemic spread with an annual incidence of 7 cases per 1,000,000 people in the United States.
Case presentation: A 68-year-old gentleman of Malay ethnicity presented with left sided weakness associated with reduced sensation for one month. The patient was healthy and denied any constitutional symptoms, joint pains, rash or seizures. There was no recent trauma. Physical examination revealed left upper and lower limb motor grade power of 3/5 with upper motor neurone weakness of the left facial nerve. He had brisk reflexes and an upgoing extensor plantar response. Brain imaging (Magnetic Resonance Imaging) showed two lesions: one occupying the right head of the caudate nucleus and the other seen at the right side of the body of the corpus callosum. Histomorphology and immunohistochemistry confirmed Diffuse Large B-Cell Lymphoma (DLBCL) of non-germinal center type. He was treated with De Angelis protocol which involves chemoradiotherapy consisting of high dose methotrexate and whole brain radiotherapy (WBRT), followed by high dose cytarabine. Brain imaging post chemoradiation showed complete remission.
Conclusion: Prompt detection with appropriate therapeutic protocol could significantly minimise the permanent neurological deficits in patients with this rare and challenging lymphoid malignancy.

Matched MeSH terms: Cytarabine
Fulltext Biphenotypic acute leukemia: a report of two cases

Azma, R.Z., Hamidah, N.H., C-F, Leong, Ainoon, O., Fadilah, S.A.W., S-K, Cheong, et al.

Medicine & Health, 2006;1(1):53-60.
MyJurnal

We report two cases of biphenotypic acute leukaemia diagnosed in Hospital Universiti Kebangsaan Malaysia (HUKM), their clinical, haematological characteristics and response to chemotherapy. Both patients are middle-aged ladies who presented with hepatosplenomegaly and high white cell count, mainly composed of blast cells. Their bone marrow aspirations were hypercellular comprising of more than 90% heterogenous blast cells. Cytochemical analyses show more than 3% positivity towards peroxidase, with smaller blasts showing block positivity towards PAS. Immunophenotypically, the blasts showed dual expression of CD 33 and CD 19, CD 19 and CD34, intra CD22, intra TdT and intraMPO. One of the patients showed presence of the Philadelphia chromosome on cytogenetic analysis which was confirmed by Fluorecsence In Situ Hybridisation (FISH). Molecular analysis also showed presence of the BCR-ABL fusion protein. Both patients were given combination chemotherapy consisting of daunorubicin and cytosine arabinoside.However, the patient with positive Philadelphia chromosome BCR-ABL did not achieve morphological remission after induction chemotherapy. In view of the poor prognosis of this disease, both the patients were planned for upfront peripheral blood stem cell transplantation.

Matched MeSH terms: Cytarabine
Fludarabine, High Dose Cytarabine and Granulocyte Colony-Stimulating Factor (FLAG) as Consolidation Chemotherapy in Older Patients with Acute Myeloid Leukemia: A Retrospective Cohort Study

Law KB, Chang KM, Hamzah NA, Ng KH, Ong TC

Indian J Hematol Blood Transfus, 2017 Dec;33(4):483-491.
PMID: 29075058 DOI: 10.1007/s12288-017-0790-3

The study aimed to investigate the effect of consolidation treatment with fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor or FLAG in older AML patients. The study included 41 eligible patients above 54 years old, who received both induction and consolidation chemotherapy for AML from 2008 to 2013. The study cohort had a minimum 24 months follow-up period. Survival analysis was carried out to assess patients' overall survival and disease free survival based on types of consolidation regimens. The consolidation treatment with FLAG exerted a protective effect to both overall survival and disease free survival in older patients. Patients who were consolidated with FLAG regimen had a significant longer overall survival (log-rank, p = 0.0025) and disease free survival (log-rank, p = 0.0026). The median overall survival was longer (18.70 months) with the use of FLAG when compared to non-FLAG group (8.09 months). The median disease free survival was also longer (13.84 months) with use of FLAG when compared to the non-FLAG group (4.44 months). Regression analysis with Cox model yielded hazard ratio of 0.245 (p = 0.0094) in overall survival and 0.217 (p = 0.0068) in disease free survival. The use of FLAG as consolidation treatment was associated with approximately 60-80% reduction in hazard rates. The result was adjusted for age, race and gender in regression analysis. Older AML patients had longer remission and survival when consolidated with FLAG regimen after the induction chemotherapy.

Matched MeSH terms: Cytarabine
Outcome of treatment in adult acute lymphoblastic leukaemia in an Asian population: comparison with previous multicentre German study

Bosco I, Teh A

Leukemia, 1995 Jun;9(6):951-4.
PMID: 7596183

Reports on the outcome of treatment in ALL in Asian (non-Caucasian) adults have been few, and published results compare very unfavourably with results of treatment from 'Western' centres. Seventy-four newly diagnosed Malaysian patients with ALL between the ages of 15 and 69 were treated from 1986 to 1990. The clinical features and prognostic factors were similar to those reported in 'Western' series. The chemotherapy protocol utilized was adapted from the one used by Hoelzer et al in the multicentre German study. The complete remission rate was 73%. The probability of continuous complete remission at 5 years was 29% with a median duration of remission of 15 months. This compares with Hoelzer's initial results of 77% CR rate and 35% CCR at 5 years. Patients with an initial white cell count of less than 30 x 10(9)/l at presentation were found to have a significantly better disease-free survival than those with a count of more than 30 x 10(9)/l (35 vs 22%, P = 0.026, univariate analysis). There was no difference in leukaemia-free survival according to age, sex, ethnic group, or immunophenotype. These results show that the use of moderately intensive chemotherapy protocols in Asian (non-Caucasian) patients achieves similar results to those used in Caucasians. We also showed that the difficulties in 'curing' approximately 70% of adult patient with ALL are universal.

Matched MeSH terms: Cytarabine/administration & dosage
Fulltext Molecular responses during chemotherapy in acute myeloid leukemias in predicting poor-response to standard chemotherapy

Maha A, Cheong SK, Leong CF, Seow HF

Malays J Pathol, 2009 Dec;31(2):81-91.
PMID: 20514850 MyJurnal

Signal transduction pathways are constitutively expressed in leukaemic cells resulting in aberrant survival of the cells. It is postulated that in cells of chemo-sensitive patients, chemotherapy induces apoptotic signals leading to cell death while survival signals are maintained in cells of chemo-resistant patients. There is very little information currently, on the expression of these mediators in patients immediately after chemotherapy initiation. We examined the expression pattern of proinflammatory cytokines, signaling molecules of the PI3K and MAPK pathways molecules and death receptor, DR5 on paired samples at diagnosis and during chemotherapy in acute myeloid leukaemia patients treated with cytosine arabinoside and daunorubicin. The results were correlated with remission status one month after chemotherapy. We found that in chemo-sensitive patients, chemotherapy significantly increased the percentage of cases expressing TNF-alpha (p = 0.025, n = 9) and IL-6 (p = 0.002, n = 11) compared to chemo-resistant cases. We also observed an increased percentage of chemo-sensitive cases expressing DR5 and phosphorylated p38, and Jnk. Thus, expression of TNF-alpha, IL-6, DR5, phospho-p38 and phospho-Jnk may regulate cell death in chemo-sensitive cases. In contrast, a significantly higher percentage of chemo-resistant cases expressed phospho-Bad (p = 0.027, n = 9). IL-beta and IL-18 were also found to be higher in chemo-resistant cases at diagnosis and during chemotherapy. Thus, expression of various cellular molecules in leukaemic blasts during chemotherapy may be useful in predicting treatment outcome. These cellular molecules may also be potential targets for alternative therapy.

Matched MeSH terms: Cytarabine/administration & dosage
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.

Matched MeSH terms: Cytarabine/pharmacology

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