|Year : 2015 | Volume
| Issue : 2 | Page : 426-432
Effect of taurine on attenuating chemotherapy-induced adverse effects in acute lymphoblastic leukemia
Mina Islambulchilar1, Iraj Asvadi2, Zohreh Sanaat2, Ali Esfahani2, Mohammadreza Sattari3
1 Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan; Department of Pharmacology and Toxicology, Faculty of Pharmacy; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
2 Hematology and Oncology Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
3 Hematology and Oncology Research Center; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
|Date of Web Publication||7-Jul-2015|
Dr. Mohammadreza Sattari
Hematology and Oncology Research Center, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51664 - 1476
Source of Support: None, Conflict of Interest: None
Clinical trial registration IRCT 138812123482N1
Objective: The purpose of our study was to evaluate the effect of oral taurine supplementation on the incidence of chemotherapy-induced adverse drug reactions during chemotherapy in young adults with acute lymphoblastic leukemia (ALL).
Materials and Methods: Forty young adult (aged over 16 years) with ALL, at the beginning of maintenance course of their chemotherapy, were recruited to the study. The study population was randomized in a double blind manner to receive either taurine or placebo. Life quality and adverse drug reactions were assessed using questionnaire. Blood cell count, hemoglobin (Hb), hematocrit (Hct), serum bilirubin, transaminases, urea, and creatinine concentrations were evaluated. Data was analyzed using Statistical Package for Social Sciences (SPSS) software.
Results: Of total participants, 43.8% were female and 56.3% were male. The mean age was 19.16 ± 1.95 years (range: 16-23 years). The results indicated that the levels of white blood cells were significantly (P < 0.05) increased in taurine treated group, but other hematological values did not differ significantly in either group. Taurine administration improved liver and kidney functions, indicated by decline of serum bilirubin, transaminases, urea, and creatinine, respectively in comparison to the controls (P < 0.05). Moreover, taurine significantly reduced serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels (P < 0.05).
Conclusion: In conclusion our results indicated that taurine supplementation could be a protection against chemotherapy-induced toxicities probably by its antioxidant capacity. Present study showed effectiveness of taurineon the chemotherapy-related toxicities and some of the complications during the maintenance period of treatment following coadministration in young adults with ALL.
Keywords: Acute lymphoblastic leukemia, antioxidant, chemotherapy-induced adverse effects, hepatotoxicity, nephrotoxicity, oxidative stress, taurine
|How to cite this article:|
Islambulchilar M, Asvadi I, Sanaat Z, Esfahani A, Sattari M. Effect of taurine on attenuating chemotherapy-induced adverse effects in acute lymphoblastic leukemia. J Can Res Ther 2015;11:426-32
|How to cite this URL:|
Islambulchilar M, Asvadi I, Sanaat Z, Esfahani A, Sattari M. Effect of taurine on attenuating chemotherapy-induced adverse effects in acute lymphoblastic leukemia. J Can Res Ther [serial online] 2015 [cited 2019 Dec 7];11:426-32. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/426/151933
| > Introduction|| |
Acute lymphoblastic leukemia (ALL) is thought to originate from different mutations in hematopoietic stem cells during their maturation and differentiation to mature and normal blood cells which affect cells differentiation, proliferation, or survival.  ALL is characterized by uncontrolled production of immature lymphoid cells (lymphoblast), which are not able to protect body against infections as normal cells do. Presence of excessive number of lymphoblast cells in bone marrow leads to a reduction in normal blood cells formation.  ALL affects both adults and pediatrics, but it represents 2-3% of adult's hematopoietic malignancies compared with 50% in the children. 
It is known that oxidants have an impact on carcinogenesis.  Reactive oxygen species (ROS) are the coproducts of energy production through enzymatic and nonenzymatic reactions in respiring cells.  Free oxygen radicals production is recognized to have either deleterious or beneficial effects in the biological systems.  Moreover, ROS are capable of increasing or promoting cellular aging and apoptosis, depending on the strength of the stimulation.  Accumulation of free oxygen radicals can mediate damage to biomolecules (DNA, proteins, and lipids). Producing summative amounts of ROS is designated oxidative stress, causes a redox imbalance which is more often in cancer cells than normal cells. Raising amounts of oxidative DNA damages have been indicated in a variety of tumoral cells, strongly suggests involvement of ROS in the mutagenesis and carcinogenesis. 
The harmful effects of ROS are confronting by both enzymatic and nonenzymatic antioxidants.  The most important antioxidant enzymes are superoxide dismutase (SOD) and catalase (CAD). Vitamin E and thiols are the most efficient nonenzymatic antioxidants. ,,, The studies on antioxidant enzymes activity are scanty in patients with different kinds of leukemia.  Previous studies have shown that antioxidant levels are lower in ALL patients than control group. ,,, Moreover, patients undergoing chemotherapy for cancer may have lower antioxidants level due to the fact that many of chemotherapeutic agents have the ability to liberate ROS. ,,, Some former studies reported assessment of antioxidant status in children with ALL. ,,, One of these studies showed significant lower plasma thiol levels and also significant lower antioxidant capacity.  Ina different study, both leukocytes and plasma vitamin C concentrations were significantly lower in ALL patients.  Another study found that even though vitamin C intake was more than twice higher in ALL patients than control group, plasma, and urine vitamin C concentrations were significantly higher in control than ALL group.  Al-Tonbary et al., showed that vitamin E and N-acetyl cysteine, which were antioxidants, can decrease treatment related toxicity in ALL patients. 
2-aminoethane sulfonic acid, or taurine, is a β amino acid that differs from other amino acid by having a sulfonic acid group rather than a carboxylic acid group. Taurine is one of the most abundant free amino acids in mammalian tissues, but it is not included into proteins structure. It is known as a conditionally essential amino acid which is present in the brain, heart, liver, neutrophil, retina, and kidneys of mammals in high concentrations. It acts as an antioxidant, xenobiotic conjugant, osmoregulator, intracellular calcium flux regulator, bile acid conjugant, neuromodulator, cell membrane stabilitator, and also plays an important role in cell proliferation and its viability. ,, Taurine and especially its metabolites are taking part in antioxidation of ROSby scavenging free radicals, reduce formation of malondialdehyde (MDA), a lipid peroxidation end product and stabilizing membranes. , Beneficial effects of taurine in preventing different tissue damages during inflammation were demonstrated in previous studies. It has been suggested that taurine administration has some protective effects against: Chromium (VI)-induced oxidative stress in hepatic tissue,  acetaminophen-induced hepatotoxicity,  isoprenaline-induced myocardial infarction,  iron-mediated myocardial oxidative stress,  ethanol-induced hypertension,  and diabetes mellitus and its complications. , Additionally, it has been demonstrated that patients receiving chemotherapy suffered intense taurine depletion.  Moreover, it has been suggested that taurine has protective effects against methotrexate (MTX)-induced genotoxicity in somatic and germ tissues,  oxidant organ injury, and inhibits leukocyte apoptosis. 
Hence, the present investigation has been undertaken to study the effect of taurine cotherapy in ALL patients and its possible role in prevention of chemoinduced hematologic, hepatic, or renal toxicities.
| > Materials and methods|| |
The primary objective of our study was to evaluate the effectiveness of supplemental taurine, on the incidence of chemotherapy-induced hematologic, hepatic or renal toxicities during chemotherapy in young adults with ALL. Efficacy was assessed on ALL patients during 6month of their maintenance chemotherapy by using a questionnaire and laboratory tests.
Data collection for the study was performed by a medical team in an oncology clinic. As patients entered the study, baseline information was established about their perceptions of life quality and chemotherapy-associated symptoms by a questionnaire. The same questionnaire was used and answers recorded at scheduled visits alongside their chemotherapeutic treatment. Blood samples were taken at the initiation of the study and also every visit to evaluate hematologic, hepatic, or renal laboratory tests.
Study design and setting
This double-blind, placebo-controlled trial study was conducted in the clinic of oncology, following taking written and signed informed consents from all patients. The study was approved by research ethics committee of our university.
Simple randomization method with an allocation ratio of 1:1 was used for this study. Patients were randomized to either placebo or taurine groups at the beginning of their maintenance chemotherapy.
Taurine (Aviforme, UK) was provided as pure powder. Both taurine and placebo were provided as 500 mg capsules.
Patients in both groups received two 500 mg capsules each time (with a total dosage of 2 g/day) twice a day. This supplementation was given throughout the chemotherapy, for 6 months and responses were evaluated by questionnaire and direct physical examination at 2 month's intervals. Blood samples were collected into heparinized tubes and assayed for hematological analysis. Total and differentiate leukocyte count, hemoglobin (Hb), hematocrit (Hct), platelets, and red blood cells (RBCs) were measured using an automatic cell counter. Serum bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) concentrations were evaluated by a Vitalab Selectra using an enzymatic kit. The levels of urea and creatinine in the plasma were also assayed by the Vitalab Selectra with using enzymatic kit.
The serum was separated by centrifuging the clotted blood and used for the measurement of MDA and SOD. Serum SOD levels were evaluated by SOD activity assay kit, in which superoxide is provide by xanthine oxidase and SOD scavenging superoxide. Then a water soluble tetrazolium salt dye (WST) was used to form a colored product, which was measured calorimetrically at 450 nm. For measuring serum MDA levels serum proteins were precipitated by addition of trichloroacetic acid (TCA). Then, thiobarbituric acid (TAB) reacted with MDA to form TAB reactive product, which was measured calorimetrically at 534 nm. Questionnaires were then evaluated based on occurrence of chemotherapy associated adverse drug reactions.
Patients were selected from outpatient chemotherapy clinic. Forty young adults suffering from ALL were enrolled in the trial. Patients were eligible for inclusion if they aged over 16 years. The study was open to patients being treated according to Cancer and Leukemia Group B (CALGB) 8,811 chemotherapy regimen for ALL in adults. The applied regimen described by Larson et al., consisted of five courses: "The induction phase (course I) consisted of a single dose of cyclophosphamide on 1 st day, 3 consecutive days of daunorubicin, weekly vincristine, biweekly subcutaneous (SC) L-asparaginase, and 3 weeks of prednisone. Early intensification (course II) included 2 months of treatment using cyclophosphamide, SC cytarabine, oral 6-mercaptopurine (6-MP), vincristine, SC L-asparaginase, and also intrathecal (IT) MTX. In course III, the CNS prophylaxis was completed with cranial irradiation (2,400 cGy) and 5 weekly doses of IT MTX with daily 6-MP, followed by a maintenance period of daily oral 6-MP and weekly oral MTX. Course IV was a late intensification course lasting 8 weeks, followed by prolonged maintenance treatment (course V) with daily 6-MP and weekly MTX plus monthly pulses of vincristine and prednisone". 
Patients were recruited from oncology clinic at the initiation of maintenance course of their chemotherapy treatment. During the study four samples were dismissed from each group. One patient was lost to be followed-up, one patient died during the observation period; six patients initially consented and then refused to continue as a participant in our study because of the following reasons: (1) Their symptoms were get worsening, (2) chose not to continue chemotherapy, and (3) they could not tolerate the daily dosage of taurine.
Statistical analysis was carried out using Statistical Package for the Social Science for Windows (SPSS, version 13.0). Patient's demographic data, differences in the proportion of ALL patients, and adverse drug reactions in taurine and control groups were analyzed using Pearson's Chi-square test (Fisher's exact test).
Data was expressed as the mean ± standard deviation (SD). Independent sample t-test or Mann-Whitney U test were used for comparison of differences between the groups. P value <0.05 was accepted to indicate statistical significance.
| > Results|| |
The study population consisted of 40 ALL patients during their maintenance chemotherapy period, which were divided equally into cases and control groups. During the study, four samples were dismissed from each group according to our exclusion criteria. Hence, overall 32 patients reckoned for final analysis, 43.8% were female and 56.3% were male. The mean age was 19.16 ± 1.95 years (range: 16-23 years). The mean age of the study group was 19.19 ± 2.14 years and that of the control group was 19.12 ± 1.82 years. The majority (50%) were high school students.
Throughout the study, patients in the taurine group had better appetite in comparison to the control patients [Figure 1]. Statistically significant differences were observed in 2 nd , 4 th , and 6 th months of study between taurine and control patients (P = 0.001, 0.02, 0.001, respectively), excluding baseline time (P = 0.23).
|Figure 1: Depictive incidence of appetite changes in taurine (TAU) and control groups during the study.*P < 0.05 compared with control group|
Click here to view
The incidence of taste changes and smell impairment [Figure 2]a and b were similar in both study groups at baseline (P = 0.24 and 0.50, respectively). Both taste changes and smell impairment were significantly improved in the taurine group in comparison to the placebo group during 2 nd , 4 th , and 6 th months of study period P values for taste changes were 0.017, 0.014, and 0.016 and those for smell impairments were 0.003, 0.43, and 0.001, respectively.
|Figure 2: Depictive incidence of taste changes (a) and smell impairment (b) in taurine (TAU) and control groups during the study. *P < 0.05 compared with control group|
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Compared to the placebo group, taurine supplemented patients reported a significant reduction in chemotherapy-induced nausea and/or vomiting [Figure 3] after baseline at 2 nd , 4 th , and 6 th months of study (P = 0.041, 0.041, and 0.019, respectively).
|Figure 3: Depictive incidence of nausea and/or vomiting in taurine (TAU) and control groups during the study. *P < 0.05 compared with control group|
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There were no significant differences observed at experiencing fatigue in both taurine and control groups at the baseline point (P = 0.87). Patients receiving taurine showed a reduced risk of suffering from fatigue rather than the chemotherapy only group [Figure 4]. So, there was a significant improvement in fatigue occurrence in the case group during 2 nd , 4 th , and 6 th months of study as compared to controls (P = 0.05, 0.006, and 0.005, respectively).
|Figure 4: Depictive incidence of weariness in taurine (TAU) and control groups during the study. *P < 0.05 compared with control group|
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Other chemotherapy-induced complications including defecation patterns, upper gastrointestinal (GI) and respiratory tract symptoms, skin lesions, musculoskeletal, and neurosensory problems were similar between the case and control patients.
The levels of Hb, Hct, RBCs, and platelets were slightly increased in the case patients during study compared to control patients, but the data were not statistically significant between the case patients compared to the control group. Compared to the control group, the white blood cells (WBCs) counts were significantly increased in taurine treated group (P = 0.000 in all visits). There was no elevation in blasts count [Table 1].
The levels of ALT and AST were significantly lower in the case group compared to the control group at 2 nd , 4 th , and 6 th months of study (P = 0.004,0.000, and 0.000, respectively for ALT, those were 0.000 for AST during whole study). Plasma levels of bilirubin were significantly lower in taurine-treated group compared to placebo group at 4 th and 6 th months of study (P = 0.000 in both time). Plasma creatinine and urea levels were not significantly different in the taurine-treated group rather than the chemotherapy only group at the 2ed month but the data were statistically significant at 4th and 6th month of study (P = 0.005 and 0.000 at 4 th and 6 th month of the study for creatinine, those were 0.03 for urea at 4 th and 6 th month of study) [Table 2].
Serum SOD and MDA levels were showed in [Table 3]. Taurine treatment significantly decreased serum SOD (P = 0.044, 0.008, and 0.004 at 2 nd , 4 th , and last months of study, respectively) and also significantly decreased serum MDA levels at 4 th and last months of study in comparison to the control group (P = 0.045 and 0.026, respectively).
|Table 3: Malondialdehyde and superoxide dismutase levels in the taurine and control groups|
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| > Discussion|| |
In the present study, we tried to estimate the importance of taurine as a chemoprotective agent in adult patients with ALL. The results indicated that taurine could improve patient's quality of life, increase leukocyte count, and decrease hepatotoxicity and nephrotoxicity; thus attenuating adverse drug reactions of chemotherapy such as nausea, decreased appetite, smell impairment, and weariness.
We found that oral taurine administration significantly improved taste changes and appetite in comparison to controls during the study. Pion et al., and Pushpakiran et al., demonstrated that taurine increases appetite. , It was also shown that taurine can inhibit drug-induced weight loss.  Some studies indicated that taurine deficiency can cause degrees of smell impairment. , The present study showed a significant diminution in smell impairment in the taurine group compared to the control group. According to the previous studies, taurine is present in olfactory receptors , and it has an inhibitory effect on the olfactory cells by decreasing their excitability. , Both taste and smell closely take part in flavor perception, so amendment of smell impairment and taste changes can affect the appeal of food in taurine group.  It was also reported that taurine supplementation could reduce fatigue.  Similarly, our study showed a significant antifatigue effect in the taurine-treated patients.
In our study there was an increasing level of Hb, Hct, RBC, and platelet counts in the taurine group, but no significant difference was found between two study groups. Patients receiving taurine showed a significant amelioration in WBC counts without any differences at blast cells number. Previous studies showed that taurine decrease cyclophosphamide-induced myelosupression.  Moreover, taurine inhibits MTX-induced leukocyte apoptosis by its antioxidant, immunoregulating, or membrane stabilizing activities.  The article by Bachmann indicated that taurine deficiency increased T cell apoptosis.  In another study, taurine increased lymphocyte proliferation dose dependently.  It also reported that taurine not only increased leukocyte count but also enhanced their function after cyclophosphamide chemotherapy. 
Taurine supplementation in this study significantly decreased levels of bilirubin, ALT, and AST and mitigated MTX-induced hepatotoxicity. It has already been demonstrated that taurine administration protects against several hepatotoxic agents like acetaminophen, , lipopolysaccharide, ,, cyclosporine A,  tamoxifen,  iron and ethanol,  cadmium, , aluminum,  copper,  and arsenic.  Additionally, it has been shown that antioxidants like melatonin,  β-glucan,  and taurine  reduce MTX-induced toxicity. The protective effect of taurine against hepatotoxicity was caused by its antioxidant ability which was demonstrated in previous studies. ,, Our study demonstrated a significant diminution in SOD and MDA levels in taurine-administered patients, implicated its antioxidant activity.
In the present study, our results indicated that taurine could significantly decrease serum urea and creatinine levels during chemotherapy of ALL patients. Previous studies showed that antioxidants such as pentoxyfylline,  melatonin,  and N-acetylcysteine  can protect MTX-induced nephrotoxicity. Furthermore, it was reported that taurine can prevent drug-induced nephrotoxicity including tamoxifen,  cisplatin,  aluminum chloride,  and MTX.  It has been found that MTX administration can cause renal failure and increase serum creatinine and urea.  In addition, an antioxidant such astaurine, melatonin, and N-acetyl cysteine attenuates MTX-induced elevation in SOD and MDA , by their antioxidant activities. In the present study, chemotherapy resulted in elevated levels of MDA and SOD, were significantly reduced by taurine supplementation.
| > Conclusion|| |
In conclusion, present study points out that taurine decreases the risk of chemotherapy-induced hepatotoxicity and nephrotoxicity and also increases WBC count and attenuate chemotherapy complications (e.g. taste and smell impairment) in ALL patients during their maintenance chemotherapy. It can lead to a more tolerable chemotherapy with lower incidence of adverse drug reactions for the patients.
| > Acknowledgments|| |
The authors would like to thank the authorities of Hematology and Oncology Research Center of Tabriz University of Medical Science, for their financial support. We also thank the patients and their families, who were participated in this trial. The nurses, laboratory, and other staffs of Shahid Ghazi Hospital of Tabriz are also acknowledged for their cooperation. This article is based on a thesis submitted for PhD degree (No. 49) in the faculty of pharmacy of Tabriz University of Medical Sciences in Tabriz, Iran.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]