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5-fluorouracil

در نشریات گروه پزشکی
  • Lekhaa Mohanraj *, Somu Lakshmanan, Urvashi Singh
    Introduction
    Endoscopic nasal surgery has numerous potential adverse effects, adhesions are at the top of the list. 5-fluorouracil (5-FU), which is an analogue of pyrimidine, is utilized in a wide variety of areas for the purpose of preventing adhesions. In the present investigation, our purpose was to analyze the impact of intra-operative application of 5-flurouracil in the nasal cavity following FESS, as well as to evaluate both subjective and objective outcomes. 
    Materials and Methods
    Following the acquisition of institutional ethical approval, a testing procedure that was randomized, prospective, and double-blinded was carried out. After the FESS, a cotton swab soaked in 1 mL of 5-flurouracil at 5 mg/mL was inserted in one side of the nasal cavity and a saline-soaked one in the other. Both of these swabs were kept in place for a period of five minutes. Postoperatively, patients were assessed over 6 months duration, wherein, adhesions, discharge, crustation, edema and polypoidal changes were analyzed. Subjective symptoms such as nasal block, nasal discharge and loss of smell were also assessed.
    Results
    At the one-week follow-up, the test group had a significantly higher incidence of adhesions (32% vs. 11.76%, respectively) (p = 0.004) than the control group. Mucosal edema, crusting, polypoidal change and nasal discharge continued to significantly diminish in both groups. Furthermore, improvement in smell perception in the test group at the 20th week post-operatively was statistically significant (p= 0.014).
    Conclusions
    Adhesions are less common in the early postoperative period in individuals who underwent FESS with or without polypectomy when 5-FU is administered topically. There is also an improvement in smell perception with a reduction of mucosal edema, crusting, polypoidal change and nasal discharge enabling better healing.
    Keywords: Randomized Control Trial, Functional Endoscopic Sinus Surgery, Outcomes, 5-Fluorouracil, Adhesions, Synechia
  • Nader Pazyar*, Nasrin Kheirkhah, Reza Yaghoobi, Nima Bakhtiari
    Background

    Vitiligo, a pigmentary skin disorder, poses therapeutic challenges due to its progressive nature and varied treatment responses. We aimed to investigate the efficacy of a novel approach, combining microneedling with topical 5-Fluorouracil (5-FU), compared with microneedling with Fluocinolone and microneedling alone for treating vitiligo lesions.

    Methods

    A single-blinded clinical trial was conducted from Aug 2022 to Feb 2023 at Ahvaz University of Medical Sciences, Ahvaz, Iran. Twenty patients with persistent vitiligo lesions were randomly assigned to three treatment groups. Microneedling was performed using Dermapen cartridge 36 once a week for 12 wk. In patch A, 5% 5-FU cream was applied immediately after microneedling; in patch B, patients used fluocinolone 0.025% cream twice daily; and in patch C, microneedling was performed alone. Clinical repigmentation was evaluated using the G-score scale, and treatment side effects were recorded.

    Results

    Microneedling combined with 5-FU demonstrated significantly higher repigmentation rates, with 70% of lesions showing moderate to excellent responses (P<0.001). In contrast, microneedling with Fluocinolone and microneedling alone exhibited lower response frequencies. Side effects were minimal, with only one patient experiencing burning and itching in the microneedling and 5-FU group. No corticosteroid-related complications were observed. Six months follow-up revealed sustained repigmentation in the microneedling and 5-FU group, contrasting with no response or recurrence in microneedling alone-treated lesions.

    Conclusion

    Microneedling combined with topical 5-FU presents a promising therapeutic strategy for vitiligo lesions, yielding superior repigmentation outcomes compared to other treatments.

    Keywords: Vitiligo, Microneedling, 5-Fluorouracil, Fluocinolone
  • بهمن مرادی پوده*
    زمینه و هدف

    سرطان کولورکتال یکی از سرطان های رایج در دنیا است که سالانه باعث مرگ ومیر زیادی در جهان می شود. داروی 5-فلوئورواوراسیل به عنوان خط اول درمان در این نوع سرطان است. مقاومت به این دارو و عوارض جانبی متعددش از نقاط ضعف این دارو به حساب می آید. سیلیبینین جزء فعال زیستی اصلی سیلیمارین است و از گیاه خار مریم استخراج می شود، مخلوطی از پلی فلاونوئیدها است و به طور سنتی به عنوان یک عامل ضد کبدی استفاده می شود. در سال های اخیر اثرات ضد توموری سیلیبینین در رده های مختلف سلول های سرطانی گزارش شده است. مطالعه حاضر با هدف بررسی اثرات سیتوتوکسیک سیلیبینین در ترکیب با 5-فلوئورواوراسیل بر روی زنده ماندن سلولی و بیان P53 در رده سلولی سرطان کولورکتال HT29 انجام شد.

    مواد و روش ها

    بقای سلولی سلول های HT29 با روش MTT پس از 48 ساعت تیمار با غلظت های مختلف سیلیبینین و 5-فلوئورواوراسیل به تنهایی و به صورت ترکیبی ارزیابی شد. میزان بیان پروتئین P53 با روش وسترن بلات اندازه گیری شد.

    نتایج

    سیلیبینین و 5-فلوئورواوراسیل به صورت وابسته به دوز توانستند بقای سلولی HT29 را به طور معنی داری مهار کنند. استفاده هم زمان از تیمار سیلیبینین و 5-فلوئورواوراسیل نشان داد که سیلیبینین اثرات سیتوتوکسیک 5-فلوئورواوراسیل را تقویت می کند. همچنین سیلیبینین در غلظت100 میکرو گرم بر میلی لیتر، باعث تشدید در اثرات غلظت 100 میکرومولار 5-فلوئورواوراسیل بر روی میزان بیان پروتئین P53 شد.

    نتیجه گیری

    این مطالعه نشان داد که ترکیب سیلیبینین - 5-فلوئورواوراسیل ممکن است کاندیدای ارزشمند برای بیماران مبتلا به سرطان کولورکتال باشد؛ البته برای نتیجه گیری قطعی مطالعات بیشتری لازم است.

    کلید واژگان: سرطان کولورکتال، سیلیبینین، 5-فلوئورواوراسیل، پروتئین P53، رده سلولی HT2
    Bahman Moradi Poodeh*
    Background and Aim

    Colorectal cancer is one of the most common types of cancer in the world, causing many deaths worldwide each year. 5-Fluorouracil is the first choice for the treatment of this type of cancer. Drug resistance and its many side effects are among the weaknesses of this drug. Silibinin, the main bioactive component of silymarin, is originally extracted from Silybum marianum, which is commonly used as an anti-hepatic agent. In recent years, the anticancer effect of silibinin has been observed on different cancer cells. This study aimed to investigate the combined cytotoxic effects of silibinin and 5-fluorouracil on cell viability and p53 expression in the colon cancer HT29 cell line.

    Material and Methods

    Survival of HT29 cells was evaluated by the MTT method after 48 hours of treatment with different concentrations of silibinin and 5 fluorouracil alone and in combination. The expression level of the P53 protein was measured by Western blot method.

    Results

    Silibinin and 5-fluorouracil significantly inhibited HT29 cell survival in a dose-dependent manner. The simultaneous use of silibinin and 5-fluorouracil showed that silibinin enhances the cytotoxic effects of 5-fluorouracil. In addition, 100 μg/ml silibinin enhanced the impact of 100 μM 5-fluorouracil on P53 protein expression.

    Conclusion

    This study suggested that silibinin-5-fluorouracil combination may be a valuable candidate for colon cancer patients. Of course, further studies are needed to reach definitive conclusion.

    Keywords: Colorectal Cancer, Silibinin, 5-Fluorouracil, P53 Protein, HT29 Cell Line
  • ساناز سالک، الهام معظمیان*، افشین محمدی بردبری، سیده عذرا شمس دین
    مقدمه

    اگرچه 5-فلوراوراسیل به عنوان داروی شیمی درمانی برای سرطان کولورکتال موثر است؛ اما به علت مقاومت و عوارض جانبی مرتبط با آن، جستجو برای درمان های کمکی از اهمیت بالایی برخوردار است. متابولیت های پروبیوتیک ها ظرفیت ضدسرطانی دارند. در مطالعه حاضر، اثر ضدسرطانی سویه های پتانسیل پروبیوتیکی جداشده از شیر الاغ، شتر و سویه پروبیوتیک استاندارد لاکتوباسیلوس رامنوسوس GG (LGG) علیه رده سرطانی کولون انسان HT-29 و  نرمال کلیه جنینی انسان HEK-293 به تنهایی و به همراه 5-فلورواوراسیل ارزیابی شدند.

    مواد و روش ها

    در این مطالعه، سویه هایی که از شیر الاغ و شتر جدا شده بودند، با استفاده از روش های بیوشیمیایی و مولکولی شناسایی گردیدند. اثر ضدسرطانی سویه های لاکتوباسیلوس پتانسیل پروبیوتیکی جداشده از شیر الاغ، شتر و سویه استاندارد پروبیوتیک LGG بر دو رده سلولی HT-29 و HEK-293 به تنهایی یا در ترکیب با 5-FU با روش MTT ارزیابی شدند. برای تحلیل آماری داده ها از آنالیز واریانس استفاده گردید و اختلاف معنی دار میان میانگین ها با استفاده از آزمون تعقیبی توکی بررسی شد. محاسبات آماری با استفاده از نرم افزارMinitab vol.20  انجام گردید. P≤ 0.05 به لحاظ آماری معنی دار تعیین شد.

    یافته های پژوهش:

     همه سویه های لاکتوباسیلوس مطالعه شده خواص پتانسیل پروبیوتیکی را نشان دادند. ترکیب عصاره سلولی سویه های لاکتوباسیلوس به همراه 5-فلورواوراسیل به طور موثر میزان زنده ماندن سلول های HT-29 را کاهش داد؛ اما عصاره سلولی سویه های لاکتوباسیلوس به همراه 5-فلورواوراسیل می تواند اثر سیتوتوکسیک 5-فلورواوراسیل بر میزان زنده مانی سلول های HEK-293 را کاهش دهد و درنتیجه، بر میزان زنده مانی بیفزاید.

    بحث و نتیجه گیری

    این یافته ها نشان می دهند، عصاره سلولی سویه های لاکتوباسیلوس ممکن است به عنوان یک درمان کمکی بالقوه ضدسرطان عمل کند. بااین حال، برای بررسی سویه های لاکتوباسیلوس به عنوان راهبرد درمان کمکی سرطان، مطالعات بیشتری لازم است.

    کلید واژگان: سرطان کولورکتال، لاکتوباسیلوس، پروبیوتیک، 5-فلورواوراسیل، فعالیت ضدسرطانی
    Sanaz Salek, Elham Moazamian*, Afshin Mohammadi Bardbori, Seyedeh Azra Shamsdin
    Introduction

     The efficacy of 5-fluorouracil (5-FU) as a chemotherapy drug for colorectal cancer (CRC) is well-established. However, due to resistance to 5-FU and its associated complications, it is necessary to search for adjuvant therapies against CRC. Considering the anticancer potential of probiotic metabolites, this study assessed the anticancer effects of potential probiotic strains isolated from mule milk, camel milk, and the standard probiotic strain Lactobacillus rhamnosus GG (LGG), used alone and in combination with 5-FU, against the human colon cancer cell line (HT-29) and normal human embryonic kidney (HEK-293).

    Materials & Methods

    Biochemical and molecular techniques were implemented to identify the strains isolated from mule and camel milk. The MTT assay was also employed to assess the anticancer effects of the probiotic strains of Lactobacillus isolated from mule milk and camel milk and of LGG, used alone and in combination with 5-FU, on the two cell lines HT-29 and HEK-293. The data were statistically analyzed using analysis of variance, and significant differences between means were assessed using Tukey's post hoc test. Minitab 20 software performed all statistical calculations in the level of significance less than 0.05.

    Results

    The results demonstrated the potential probiotic properties of all the studied Lactobacillus strains. The combination of cell extracts from Lactobacillus strains with 5-FU effectively reduced the viability of HT-29 cells.  Nonetheless, this combination can reduce the cytotoxic effects of 5-FU on the viability of HEK-293 cells, thereby increasing their viability.

    Conclusion

    These results point to the possibility of using Lactobacillus strain cell extracts as an adjuvant therapy for cancer treatment

    Keywords: Colorectal Cancer, Lactobacillus, Probiotic, 5-Fluorouracil, Anticancer Activity
  • Mehran Dorostghoal, Mohammadreza Dayer, Narges Biabi
    Background

    Chemotherapy involves the use of chemical agents to kill cancer cells, but it can also harm healthy, rapidly growing cells in the body. 5-fluorouracil (5-FU) induces tissue damage through oxidative stress and impaired male reproductive activity. The use of antioxidants appears to mitigate the harmful effects caused by 5-FU.

    Objectives

    This study evaluated the potential protective effects of taurine (TAU) against 5-FU-induced testicular toxicity in male rats.

    Methods

    Thirty-five healthy adult male Wistar rats (200 - 250 g, 6 - 8 weeks old) were randomly divided into five groups: Control, 20 mg/kg 5-FU, and 50, 100, and 200 mg/kg of TAU co-administered with 20 mg/kg 5-FU. Treatments were administered intraperitoneally for 14 consecutive days. Serum endocrinological analyses, as well as testicular biochemical and histomorphometric studies, were performed on the different groups.

    Results

    Testis and epididymis weights significantly decreased (P < 0.001) in male rats treated with 5-FU. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T4) were significantly lower (P < 0.05) in 5-FU-treated rats. Testicular tissue of 5-FU-treated rats exhibited significantly reduced activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) (P < 0.001) and increased levels of malondialdehyde (MDA) (P < 0.001). Co-administration of TAU significantly improved germinal epithelium height (GEH) and seminiferous tubule diameter (STD) (P < 0.001) in 5-FU-treated rats. Additionally, TAU co-administration significantly improved oxidative status and reproductive parameters in 5-FU-treated rats.

    Conclusions

    These findings suggest that TAU has the potential to prevent 5-FU-induced testicular oxidative toxicity and restore suppressed reproductive parameters in male rats.

    Keywords: 5-Fluorouracil, Taurine, Chemotherapy, Oxidative Stress, Spermatogenesis
  • زهرا بیگ زاده، فریده گل بابایی، مهدی نیکنام شاهرک، فریبرز امیدی، سید جمال الدین شاه طاهری*
    مقدمه

    داروهای آنتی نئوپلاستیک که برای درمان سرطان استفاده می شوند به دلیل عملکرد غیرانتخابی، علاوه بر سلول های سرطانی، سلول های سالم را نیز تحت تاثیر قرار می دهند و پیامدهای نامطلوبی برای سلامتی دارند. با توجه به خطرات بالقوه، ارزیابی و کنترل آلودگی محیطی این داروها در محیط های شغلی ضروری است. این مطالعه به بررسی کارایی Wipeهای تجاری موجود برای نمونه برداری از داروی آنتی نئوپلاستیک 5-فلورواوراسیل از سطوح مختلف می پردازد.

    روش کار

    این مطالعه کارایی پنج نوع Wipe تجاری (فیلتر سلولزی Whatman، سواپ پنبه ای، فیلتر MilliporeTM، پد گاز استریل و پد الکلی) را برای نمونه برداری از داروی 5-فلورواوراسیل از سطوح مختلف (استیل، وینیل و سرامیک) بررسی کرده است. محل نمونه برداری با استفاده از قاب های یک بار مصرف مقوایی مشخص شد و 1000 میکرولیتر از محلول µg/ml 1 داروی 5-فلورواوراسیل بر روی سطح پخش گردید. فرآیند نمونه برداری و استخراج طبق الگوی توصیه شده توسط NIOSH انجام شد. ابعاد قاب مورد استفاده 10 × 10 سانتی متر بود که مساحت نمونه برداری را به 100 سانتی متر مربع محدود می کرد. آنالیز توسط کروماتوگرافی با عملکرد بالا (HPLC) انجام گرفت. نتایج با استفاده از نرم افزار Prism GraphPad نسخه 8 تحلیل شدند.  

    یافته ها

    کارایی جمع آوری انواع Wipe بر روی سطوح مختلف بین 2/11% تا 2/86% متغیر بود. کمترین بازیابی مربوط به فیلتر Millipore بر روی سطح وینیل و بیشترین بازیابی مربوط به پد الکلی بر روی سطح استیل بود. میانگین کارایی استخراج برای Wipeهای مختلف بین 8/43% تا 8/98% متغیر بود؛ که کمترین میزان بازیابی مربوط به فیلتر Millipore و بیشترین مربوط به پد الکلی بود.

    نتیجه گیری

    نتایج نشان دادند که پد الکلی نسبت به سایر Wipeها عملکرد بهتری در جمع آوری و استخراج داروی 5-فلورواوراسیل از سطوح مختلف دارد. همچنین، سطوح سخت و صاف، مانند استیل و سرامیک، مناسب ترین سطوح برای نمونه برداری به شمار می روند. این نتایج می تواند به بهبود روش های نمونه برداری و کاهش مواجهه با داروهای آنتی نئوپلاستیک کمک کند.

    کلید واژگان: Wipe، نمونه برداری از سطوح، مواجهه شغلی، 5-فلورواوراسیل، داروهای آنتی نئوپلاستیک
    Zahra Beigzadeh, Farideh Golbabaei, Mahdi Niknam Shahrak, Fariborz Omidi, Jamaleddin Shahtaheri*
    Introduction

    The use of antineoplastic drugs in cancer treatment, while essential, poses risks due to their non-selective action on both cancerous and healthy cells. Assessing and controlling environmental contamination with these drugs in workplaces is crucial. This study aimed to evaluate the efficacy of various commercial wipes in sampling the antineoplastic drug 5-fluorouracil from surfaces to develop standardized sampling methods.

    Material and Methods

    This study assessed the efficiency of commonly used commercial wipes (Whatman cellulose filter, cotton swab, Millipore™ filter, sterile gauze pad, and alcohol pad) for sampling 5-fluorouracil from different surfaces (stainless steel, vinyl, and ceramic). The sampling area was defined using disposable cardboard frames, and 1000 microliters of a 1 µg/mL 5-fluorouracil solution were applied to each surface. Sampling and extraction were conducted following NIOSH guidelines. The frame dimensions were 10 × 10 cm, limiting the sampling area to 100 square centimeters. Analysis was performed using high-performance liquid chromatography (HPLC), and results were analyzed using Prism GraphPad software, version 8.

    Results

    The sampling efficiency varied across wipes and surfaces, ranging from 11.2% to 86.2%. Alcohol pads showed the highest efficiency on stainless steel surfaces, while the Millipore™ filter had the lowest efficiency across all surfaces. Extraction efficiency ranged from 43.8% to 98.8%, with alcohol pads providing the highest recovery. Sample stability was maintained over 15 days.

    Conclusion

    Alcohol pads were most effective in collecting and extracting 5-fluorouracil, particularly from hard, smooth surfaces such as stainless steel and ceramic. These findings may improve sampling methods, thereby reducing occupational exposure to antineoplastic drugs. Further research on different wipes and extraction parameters could refine drug analysis techniques.

    Keywords: Wipes, Surface Sampling, Occupational Exposure, 5-Fluorouracil, Antineoplastic Drugs
  • Omid Rahbar Farzam, Behzad Baradaran, Bahman Akbari *, Soozan Najafi, Mohammad Amini, Amirhossein Yari, Reza Dabbaghipour, Vahid Pourabdollah Kaleybar Pourabdollah Kaleybar, Shiva Ahdi Khosroshahi
    Objective(s)
    Colorectal cancer (CRC) remains a major health concern worldwide due to its high incidence, mortality rate, and resistance to conventional treatments. The discovery of new targets for cancer therapy is essential to improve the survival of CRC patients. Here, this study aims to present a finding that identifies the STAT6 oncogene as a potent therapeutic target for CRC.
    Materials and Methods
    HT-29 CRC cells were transfected with STAT6 siRNA and treated with 5-fluorouracil (5-FU) alone and combined. Then, to evaluate cellular proliferation and apoptosis percentage, MTT assay and annexin V/PI staining were carried out, respectively. Moreover, the migration ability of HT-29 cells was followed using a wound-healing assay, and a colony formation assay was performed to explore cell stemness features. Gene expression was quantified via qRT-PCR. Afterward, functional enrichment analysis was used to learn in-depth about the STAT6 co-expressed genes and the pathways to which they belong.
    Results
    Our study shows that silencing STAT6 with small interfering RNA (siRNA) enhances the chemosensitivity of CRC cells to 5-FU, a commonly used chemotherapy drug, by inducing apoptosis, reducing proliferation, and inhibiting metastasis. These results suggest that combining 5-FU with STAT6-siRNA could provide a promising strategy for CRC treatment.
    Conclusion
    Our study sheds light on the potential of STAT6 as a druggable target for CRC cancers, the findings offer hope for more effective treatments for CRC patients, especially those with advanced stages that are resistant to conventional therapies.
    Keywords: 5-fluorouracil, Chemosensitivity, Colorectal cancer, siRNA, STAT6
  • Souzan Najafi, Zohreh Rahimi, Behzad Mansoori, Ali Mohammadi, Fatemeh Mohammadnejad, Mohammad Amini, Ahad Mokhtazadeh, Zahra Asadzadeh, William Chi-Shing Cho *, Behzad Baradaran
    Purpose

    CD44 plays a pivotal role through tumorigenesis by regulating cancer cell metastasis, stemness, and chemosensitivity and is considered a promising therapeutic target for human cancers, including colorectal cancer (CRC). Therefore, the present research aimed to examine the simultaneous therapeutic effect of CD44 silencing and 5-fluorouracil (5-FU) on in vitro tumorigenesis of CRC cells.

    Methods

    CD44 expression was initially evaluated in TCGA datasets and CRC tissues. Furthermore, functional analysis was performed on HT-29 CRC cells overexpressing CD44. The cells were transfected with CD44 siRNA and then treated with 5-FU. Consequently, to explore the combination therapy effect on cell viability, migration, apoptosis, and chromatin fragmentation, we performed MTT assay, scratch assay, Annexin V/PI staining and DAPI staining assays, respectively. The spheroid and colony formation assays were further employed to investigate stemness features. The gene expression at protein and mRNA levels were explored using western blotting and qPCR.

    Results

    Our findings illustrated that CD44 was significantly overexpressed in CRC tissues compared to normal samples. The suppression of CD44 considerably promoted the chemosensitivity of HT-29 cells to 5-FU by apoptosis induction. Also, the combination therapy led to overexpression of apoptotic genes, including P53, caspase-3, and caspase-9, as well as downregulation of AKT1 expression. Furthermore, CD44 suppression, separately or combined with 5-FU, hindered stemness properties in HT-29 cells via downregulation of Sox2 and Nanog expression. Besides, the combination therapy remarkably downregulated MMPs and suppressed CRC cell migration.

    Conclusion

    Considering its involvement in chemosensitivity to 5-FU, CD44 could be suggested as a potential target for improving the efficiency of CRC chemotherapy.

    Keywords: CD44, 5-Fluorouracil, Colorectal cancer, Chemosensitivity, Cell migration
  • Bonnie Yudistha Anggawirya, Putri Hendria Wardhani, Diah Mira Indramaya, Muhammad Yulianto Listiawan *
    Introduction

    Benign fibroproliferative scars that are larger than the initial lesion are called keloids. Keloids treatment in clinical practice is still difficult. Although there are various therapy choices, none is embraced by everyone or is relapse-free. Various treatment modalities such as intralesional corticosteroid injection with 5-fluorouracil (5-FU), fractional Er:YAG laser, pulsed dye laser (PDL), and others can be used either as monotherapies or combined therapies. Therefore, efforts should be made to select the treatment that will provide the best results.

    Case Presentation

    A 6-year-old boy with keloids on the lower lips extending to the chin was successfully treated with a 2940-nm fractional Er:YAG laser alternated with a 595-nm long-PDL followed by the combined intralesional injection of corticosteroid and 5-FU. The patient was followed up for 1 year with no lesion recurrence.

    Conclusion

    Our case supports a combined therapy to successfully treat a patient with a keloid on the chin. Therapy using a combination of these four modalities seems safe and effective and may have a synergistic effect with minimal downtime.

    Keywords: 5-Fluorouracil, Er:YAG laser, Intralesional, Keloid, Pulsed dye laser
  • Kevin Nischay Gangavarapu*, Nandini Shyamali Bora, Srinivas Maddali, Qurratulain Hasan
    Background

    Cancer treatment using drugs metabolized by the enzymes dihydropyrimidine dehydrogenase (DPYD) and UDP-glucuronosyltransferase 1A1 (UGT1A1) results in adverse effects for some patients. This is frequently reported in cancer patients undergoing therapy with 5-fluorouracil, capecitabine, and irinotecan who have polymorphisms in the genes coding for DPYD and UGT1A1. The present study assessed the DPYD*2A and UGT1A1*28 polymorphisms in cancer patients before starting chemotherapy to identify the individuals at risk of developing an adverse drug reaction.

    Methods

    Genomic DNA was isolated from patients and subjected to PCR amplification using specific primers to study DPYD*2A and UGT1A1*28 polymorphisms. The PCR products were assessed by Sanger sequencing for establishing the genotype.

    Results

    Of 75 cancer patients requiring treatment with drugs metabolized by DPYD and UGT1A1, 2 (2.66%) and 12 (29.27%) were likely to have adverse reactions based on DPYD*2A and UGT1A1*28 genotyping, respectively.

    Conclusion

    Our findings indicate that carrying out genotyping for these two polymorphisms will help a large number of patients requiring treatment with 5-fluorouracil, irinotecan, and capecitabine.

    Keywords: Neoplasms, Chemotherapy, Drug therapy, Pharmacogenetics, 5-Fluorouracil, Irinotecan, Enzyme
  • Marziyeh Babazadeh, Mozhdeh Zamani, Parvaneh Mehrbod, Pooneh Mokarram *
    Background

    Aberrant activation of the WNT/β-catenin signaling pathway is involved in various types of cancers, particularly colorectal cancer (CRC), which is a prevalent malignancy. Targeting the Wnt signaling pathway has gained a reputation as an attractive therapeutic strategy, mainly because of its potential for regulating cell proliferation, migration, differentiation, angiogenesis, and apoptosis.

    Objectives

    The aim of the current research was to investigate the effects of 5-Fluorouracil (5-FU) and bovine alpha-lactalbumin made lethal to tumor cells (BAMLET), a complex of oleic acid with bovine α-lactalbumin protein, on colon cancer cells focusing on the Wnt signaling pathway.

    Methods

    For this purpose, HT-29 and HCT116 cells were treated with 5-FU and BAMLET, and the expression levels of Wnt signalingrelated proteins (β-catenin andE-cadherin) andVEGF as angiogenesis regulators were evaluated by quantitative real-time polymerase chain reaction (RT-qPCR) and Western Blot analysis.

    Results

    Bovine alpha-lactalbumin made lethal to tumor cells (BAMLET) treatment down-regulated the expression of β-catenin and up-regulated the expression of E-cadherin significantly compared to the 5-FU (P < 0.0001). The reduced mRNA levels of VEGF in treated cells revealed the effectiveness of 5-FU and BAMLET on angiogenesis.

    Conclusions

    Bovine alpha-lactalbumin made lethal to tumor cells (BAMLET) can be considered for targeting the Wnt signaling pathway and angiogenesis. It is amenable to further investigation in the development of CRC treatment.

    Keywords: Wnt Signaling Pathway, Lactalbumin, Oleic Acid, 5-Fluorouracil, Colorectal Neoplasms
  • Hadeia Mashaqbeh, Rana Obaidat*, Nizar A. Al-Shar’i, Tamam El-Elimat, Soraya Alnabulsi
    Background and purpose

    Several pharmaceutical formulations were investigated to improve the solubility of 5-fluorouracil to enhance bioavailability and therapeutic efficacy. This study aimed to examine the potential use of cyclodextrin-based nanosponges for the incorporation of 5-fluorouracil and to investigate the use of different crosslinking agents on the properties of the resulting drug carrier. 5-Fluorouracil complexation with β-cyclodextrin was also studied to explain the unexpected results of weak 5-fluorouracil incorporation in nanosponge.

    Experimental approach

    Nanosponges were synthesized by crosslinking β-cyclodextrin with two different crosslinkers; diphenyl carbonate and ethylenediaminetetraacetic dianhydride. The incorporation of 5- fluorouracil into β-cyclodextrin and the prepared nanosponges were assessed by NMR, FTIR, PXRD, DSC, and TGA. In addition, an in vitro release study was carried out to evaluate the potential use of β-cyclodextrinbased nanosponges as pharmaceutical formulations for 5-fluorouracil. Findings /

    Results

    Physicochemical characterization of the dried formulations indicated the complexation of 5-fluorouracil with the β-cyclodextrin polymer. Despite that, no clear manifestation of 5-fluorouracil encapsulation in the prepared β-cyclodextrin-based nanosponge was detected. Furthermore, no significant differences were observed in the release profiles of 5-fluorouracil, β-cyclodextrin complex, and βcyclodextrin-based nanosponge, suggesting weak complexation and instability in aqueous solutions. EDTAcrosslinked β-cyclodextrin-based nanosponge showed a slight improvement in 5-fluorouracil solubility with a faster initial rate of 5-fluorouracil release.

    Conclusion and implications

    This study suggested weak complexation between 5-fluorouracil and the βcyclodextrin polymer or nanosponges. Crosslinking of β-cyclodextrin with EDTA dianhydride crosslinker showed an enhancement in 5-fluorouracil saturation solubility combined with a faster initial rate of drug release.

    Keywords: β-Cyclodextrin-based nanosponges, Complexation, Crosslinking agent, 5-Fluorouracil
  • انیسه علی آبادی، سارا صبوری راد، صادق وهابی املشی، محمودرضا جعفری، علی هادیانفر
    مقدمه

     ویتیلیگو، یک بیماری پوستی اکتسابی با علت ناشناخته است که یکی از چالش های بزرگ درماتولوژی محسوب می شود. هدف از طراحی و اجرای این مطالعه، ارزیابی اثر Microneedling در ترکیب با فرم لیپوزومال موضعی 5-فلویورویوراسیل 5 درصد در درمان ویتیلیگو بود.

    روش ها

    این مطالعه به صورت کارآزمایی بالینی تصادفی سازی شده بر روی 25 بیمار مبتلا به ویتیلیگوی مراجعه کننده به کلینیک پوست بیمارستان قایم (عج) و امام رضای (عج) شهر مشهد انجام شد. از هر بیمار، سه ضایعه انتخاب شد و به صورت تخصیص تصادفی بر روی یکی از آن ها Microneedling با فرم لیپوزومال 5-فلویورویوراسیل 5 درصد و در دیگری، تنها Microneedling انجام شد. ضایعه ی سوم، به عنوان شاهد بدون هر گونه مداخله در نظر گرفته شد. این فرایند، هر دو هفته تا سه ماه ادامه یافت و میزان بهبودی بعد از 6 ماه ارزیابی شد.

    یافته ها

    در ضایعات تحت درمان با Microneedling به همراه 5-فلویورویوراسیل، 68 درصد از بیماران (17 نفر) بهبودی قابل توجهی نشان دادند که از این میان، 12 درصد بهبودی 50-25 درصد و 56 درصد بهبودی حداکثر تا 25 درصد را نشان دادند. این در حالی است که در ضایعات تحت درمان با Microneedling به تنهایی، درصد پاسخ به درمان ضایعات 32 درصد (4 درصد بهبودی 50-25 درصد و 28 درصد بهبودی حداکثر تا 25 درصد) بود. واکاوی آماری داده ها به روش معادلات برآوردی تعمیم یافته نشان داد که از نظر پاسخ به درمان، ضایعات تحت درمان هم زمان Microneedling با 5-فلویورویوراسیل، دارای تفاوت معنی داری با Microneedling به تنهایی و نیز با ضایعات شاهد بودند (050/0 > P).

    نتیجه گیری

     بر اساس یافته های این مطالعه، استفاده ی هم زمان Microneedling با 5-فلویورویوراسیل موضعی، باعث بهبودی قابل توجه ضایعات مقاوم ویتیلیگو نسبت به روش Microneedling به تنهایی، می شود.

    کلید واژگان: کارایی، ویتیلیگو، 5-فلوئورویوراسیل، Needling خشک، Microneedling
    Aniseh Aliabadi, Sara Sabourirad, Sadegh Vahabi Amlashi, MahmoudReza Jaafari, Ali Hadianfar
    Background

    Vitiligo is </em>an acquired disease with unknown cause and one of the major challenges in dermatology. The aim of this study was to evaluate the therapeutic efficacy of microneedling in combination with topical liposomal form of 5-fluorouracil (5-FU) 5% in treatment of vitiligo.

    Methods

    This study was performed as a randomized clinical trial on 25 patients with vitiligo referred to the dermatology clinics of Imam Reza and Ghaem hospitals in Mashhad City, Iran. In each patient, three lesions were selected and microneedling with liposomal form of 5-FU 5% and only microneedling were performed on one of them by random allocation. The third lesion was considered as a control without any intervention. This process was done every 2 weeks for 3 months, and the rate of improvement was assessed after 6 months.

    Findings

    68% of lesions (17 persons) treated with microneedling and 5-FU had significant repigmentation, 12% with 25%-50% improvement and 56% with improvement up to 25%. However, response rate of lesions treated with microneedling alone was 32%, 4% with 25%-50% improvement and 28% with improvement up to 25%. Statistical analysis of data with generalized estimating equation (GEE) method showed that in terms of response to treatment, the lesions treated with microneedling and 5-FU had a significant difference with microneedling alone and also with control lesions (P < 0.050).

    Conclusion

    According to our findings, the combined use of microneedling with topical 5-FU significantly improves resistant vitiligo lesions compared to microneedling method alone.

    Keywords: Efficiency, Vitiligo, 5-fluorouracil, Dry needling, Skin diseases
  • هادی منجی، حمید زند، آرمان قربانی، کتایون پورولی*
    سابقه و هدف

    بروز سرطان در دوران جنینی بسیار نادر است. با این حال، هنوز عواملی که مانع ایجاد و یا باعث کنترل روند تومورزایی در محیط جنینی شوند به درستی شناسایی نشده اند. از سوی دیگر، سلول های بنیادی تومور، با ویژگی هایی مشابه سلول های بنیادی جنینی، در پیشرفت و مقاومت به درمان سرطان دخالت دارند. هدف از این مطالعه بررسی اثر سفیده تخم مرغ نابارور، به عنوان یک محیط شبه جنینی، بر خصوصیات تکثیر، آپوپتوز، خودنوزایی، بنیادینگی و قدرت مهاجرت سلول های سرطانی کولون رده SW480 و زیرگروهی مقاوم به داروی 5-فلورواوراسیل (5FU) است.

    مواد و روش ها

    سلول های SW480 و5FU-SW480 ، با غلظت 10% حجمی سفیده تخم مرغ نابارور تیمار شدند. میزان زنده مانی سلول ها با روش MTT، بررسی سیکل سلولی با فلوسایتومتری، خودنوزایی با روش تشکیل کولونی و تشکیل اسفرویید و مهاجرت سلولی با روش ترمیم زخم سنجیده شدند. همچنین، بیان ژن های c-Myc، Nanog، Ndrg1 و E-cadherin  با روش Real time-PCR بررسی شد.

    یافته ها

    سفیده تخم مرغ باعث کاهش میزان بقا، توقف سیکل سلولی در فاز G0/G1، کاهش تشکیل کولونی و اسفرویید و مهار مهاجرت در هر دو گروه سلولی در مقایسه با گروه کنترل شد. همچنین در سلول های SW480 منجر به کاهش بیان ژن c-Myc و Nanog و افزایش بیان ژن های Ndrg1 و E-cadherin شد. در حالی که، افزایش بیان ژن c-Myc، کاهش بیان ژن Nanog و Ndrg1 در سلول های مقاوم به دارو مشاهده شد.

    نتیجه گیری

    به نظر می رسد سفیده تخم مرغ نابارور از طریق مکانیسم های متفاوتی باعث جلوگیری و یا کنترل روند تومورزایی می شود. مطالعات بیشتری نیاز است تا دقیقا عواملی که به صورت خاص بر بنیادینگی و تهاجم پذیری سلول های سرطانی به خصوص در سلول های بنیادی سرطانی موثرند، را شناسایی کند.

    کلید واژگان: SW480، 5-فلورواوراسیل، سرطان روده، محیط جنینی، سفیده تخم مرغ، خرد زیست محیط تومور
    H Monji, H Zand, A Ghorbani, K Pourvali*
    Background and Objectives

    Embryonic cancers are very rare. However, the exact components preventing cancer development or progression in embryonic microenvironment are largely unknown. On the other hand, cancer stem cells with characteristics similar to embryonic stem cells are involved in cancer progression and resistance to treatment. The aim of this study was to investigate effects of unfertilized egg white, as an embryonic microenvironment model, on proliferation, self-renewal, stemness and migration of SW480 colon cancer cells and 5-fluorouracil (5FU) resistant subgroup.

     Materials & Methods

    In brief, SW480 and 5FU-SW480 cells were exposed to 10% (v/v) egg white. To assess viability, self-renewal and stemness characteristics and migratory capacity of the colon cancer cells, MTT, flow PI staining and flow cytometry, colony formation, spheroid and wound healing assays were used, respectively. Furthermore, expression levels of c-Myc, Nanog, Ndrg1 and E-cadherin genes were quantified using real-time polymerase chain reaction.

    Results

    Findings showed that 10% volume of unfertilized egg white significantly decreased cell survival, inhibited cell cycle in G0/G1, decreased colony formation and sphere formation and inhibited migration ability in the two cell groups, compared to the control. Moreover, expression of c-Myc and Nanog decreased while expression of Ndrg1 and E-cadherin increased in SW480 cells. However, c-Myc gene expression increased in 5FU-SW480 with decreases in expression of Nanog and Ndrg1.

    Conclusion

    It seems that unfertilized egg white includes various mechanisms to control cancer development and progression. Further studies are needed to identify actual components affecting stemness and invasiveness of tumor cells, specifically cancer stem cells.

    Keywords: SW480, 5-fluorouracil, Colonic neoplasms, Embryonic microenvironment egg white, Tumor microenvironment
  • Mohammadreza Roshanazadeh, Hossein Babaahmadi Rezaei, Mojtaba Rashidi *
    Objective(s)
    Breast cancer (BC) cells’ ability to metastasize to other tissues increases mortality. The Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) facilitate cancer cell migration. 5-fluorouracil is a frequently applied chemotherapeutic agent in cancer treatment with destructive side effects on normal tissues. Hence, researchers have focused on finding a way to reduce the dose of chemotherapeutic drugs. Quercetin, a natural polyphenolic compound, has inhibitory effects on proliferation and migration of tumor cells. This study evaluated the effect of the combination of Quercetin and 5-fluorouracil  on migration of the MDA-MB-231 breast cancer cell line.
    Materials and Methods
    The effect of Quercetin, 5-fluorouracil , and their combination on MDA-MB-231 breast cancer cell proliferation was investigated through MTT assay. Inhibition of tumor cell migration was examined by wound healing assay. Finally, the effect of treatments on gene expression of MMP-2 and MMP-9 was evaluated by quantitative real-time PCR.
    Results
    The IC50 values for Quercetin and 5-fluorouracil  after 48 hr treatment were 295 μM and 525 μM, respectively. The combination index (CI) for Quercetin and 5-fluorouracil  was <1, indicating synergy between them. The combination of Quercetin plus 5-fluorouracil  resulted in a significant reduction in migration rate and MMP-2 and MMP-9 gene expressions of MDA-MB-231 cancer cells compared with the individual application of 5-FU.
    Conclusion
    Quercetin enhances the suppressory effect of 5-fluorouracil  on migration of BC cells. The combination of Quercetin and 5-fluorouracil  can be an attractive field for future studies.
    Keywords: 5-fluorouracil, Anti-metastatic effect, Breast Cancer, Quercetin, Synergism
  • Alaba Tolulope Agbele, Sedigheh Marjaneh Hejazi*, Ahmad Reza Dehpour, Razieh Mohammad Jafari, Arash Elyassi, Mahmoud Bagheri, Mojtaba Seydi
    Introduction

    The most important side effect after non-surgery cancer treatment (NSCT) is oral mucositis (OM) which degrades the quality of life. Using photobiomodulation (PBM), formerly known as low-level laser therapy (LLLT), in the prevention of NSCT-induced OM was widely studied. Hence, this review evaluates the efficacy of optical treatment parameters behind the working process of PBM in preventing NSCT-induced OM in preclinical studies.

    Methods

    Using the PubMed, Scopus and Embase databases, the present study systematically reviewed existing preclinical studies for optical treatment parameters of PBM in preventing NSCT-induced OM in experimental models without restriction on the year of publication.

    Results

    In total, 51 articles were recognized during the search of the literature, and only 16 research papers were included in this review, taking into consideration the inclusion as well as exclusion benchmarks. The reviewed studies showed that a consensus has yet to be reached on the optimal PBM treatment parameters in preventing NSCT-induced OM. However, a wavelength of 660 nm, a power density of 40 mW as well as fluence which ranged between 2 and 6 J/cm2 were mostly utilized in the included studies. Furthermore, the severity of NSCT-induced OM was reduced following PBM application with no reported severe side effects.

    Conclusion

    The efficacy of PBM with the associated optical parameters is a promising strategy in preventing NSCT-induced OM. However, the optimal parameters of PBM need to be investigated.

    Keywords: Low-level laser therapy (LLLT), Photobiomodulation (PBM), Oral mucositis, 5-Fluorouracil, NSCT-induced oral mucositis
  • Elias Adikwu, Nelson Clemente Ebinyo*
    Background

    The hepatotoxic effect of 5-fluorouracil (5-FU) can deprive cancer patients of its maximum therapeutic benefits. Selenium (Se) is a trace element with potential benefits in some animal models of diseases.

    Objectives

    This study assessed the ability of Se to nullify the hepatotoxic effect of 5-FU in albino rats. 

    Methods

    In this study, 40 adult male albino rats were grouped into A to D (each 5 rats). Rats in group A (control) were treated intraperitoneally (IP) with normal saline (0.2 mL) daily for 5 days. Rats in groups B1 to B3 were treated IP with Se (0.125, 0.25, and 0.50 mg/kg) daily for 5 days, respectively. Rats in group C were treated IP with 5-FU (20 mg/kg) daily for 5 days. Rats in groups D1to D3 were treated IP with Se with 0.125, 0.25, and 0.50 mg/kg before treatment with 5-FU (20 mg/kg) daily for 5 days, respectively. After treatment, the rats were euthanized, and their blood samples were collected and evaluated for serum liver function. Liver samples were evaluated for biochemical and histological parameters.

    Results

    Liver and serum aminotransferases, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and conjugated bilirubin levels were significantly (P<0.001) high in 5-FU-treated rats in comparison to the control group. Liver glutathione peroxidase, superoxide dismutase (SOD), catalase, and glutathione levels were significantly (P<0.001) low whereas the malondialdehyde level was significantly (P<0.001) high in 5-FU-treated rats compared with the control group. Moreover, hepatocyte necrosis was observed in 5-FU-treated rats. 

    Conclusion

    Nonetheless, 5-FU-induced hepatotoxicity was significantly nullified in rats supplemented with Se (0.125 mg/kg, P<0.05; 0.25 mg/kg, P<0.01, and 0.5 mg/kg, P<0.001) in a dose-dependent fashion in comparison to 5-FU-treated rats. Thus, Se may have a clinical benefit in 5-FU-induced hepatotoxicity

    Keywords: 5-Fluorouracil, Liver chemotherapy, Toxicity, Selenium, Protection, Antioxidant
  • Negin Nokhandani, Mahdieh Naghavi Alhosseini, Ali Memarian, Homa Davoodi *

    Several studies have been conducted to find suitable combinations of drugs to increase the efficacy of chemotherapy and reduce the resistance of tumor cells to treatment. Lipopolysaccharide (LPS), as a ligand for Toll-like receptor 4 (TLR-4), can modify immune responses in different cancers. Although multiple studies have been performed in this area, the effect of LPS on tumor cells remains controversial. In the present study, the cytotoxic effects of 5-fluorouracil (5-FU), with or without LPS, were evaluated in human breast cancer cell line (MCF-7) on apoptosis and gene expression in downstream signaling pathways. MCF-7 was obtained from the Pasteur Institute of Iran. The effects of LPS and 5-FU on cytotoxicity, apoptosis, and gene expression in NF-κB, ERK, and AKT signaling pathways were evaluated by MTT assay, Annexin V/propidium iodide (PI) apoptosis assay, and qRT-PCR, respectively. Our findings showed that LPS alone did not significantly affect cytotoxicity or apoptosis, compared to the control cells (untreated cells), while combined with 5-FU, it caused a significant increase in the apoptosis of cancer cells and decreased cell viability. It was also concluded that LPS in combination with 5-FU increased TLR-4 expression and down-regulated gene expression in NF-κB, ERK, and AKT pathways (p=0.001). Although the role of LPS in tumor inhibition or progression remains controversial, our findings suggest that LPS can be considered a novel complementary approach intranslational oncology research of breast cancer therapy.

    Keywords: Breast cancer, Cytotoxicity, Lipopolysaccharides, Toll-like receptor 4, 5-Fluorouracil
  • Luana Campos, Claudia Carrara Cotomacio, Victor Elias Arana Chavez, Alyne Simões*
    Introduction

    Oral mucositis (OM) has been considered one of the most feared collateral effects of oncological treatments. Some therapies have been used, such as light-emitting diode (LED), with promising results, but with no sufficient evidence in the literature.

    Objective

    Our study aimed to evaluate, by clinical and histological analysis, the effect of LED on the treatment of chemotherapy-induced OM (CIOM) in an animal model.

    Methods

    Twenty male hamsters were equally distributed to two groups: control (C), which received anesthesia and CIOM induction; and LED (L), which received anesthesia, CIOM induction, and LED treatment (635 nm, 120 mW, 0.48 J). The clinical analysis was performed through two specific scales for OM analysis on days 5, 7 and 10 of the experiment. In addition, the injured area of all hamsters check pouch mucosa was removed and processed for histological analysis on the last experimental day.

    Results

    After statistical analysis, group L showed less severity of OM when compared with the C group (P < 0.05); beyond that, both healed completely on day 10.

    Conclusion

    Our results suggested that the phototherapy with LED had a positive effect on accelerating repair, reducing the severity of CIOM.

    Keywords: Chemotherapy, Oral mucositis, Phototherapy, LED, 5-Fluorouracil
  • Mohammad Hadi Abbasian, Nafiseh Ansarinejad, Bahareh Abbasi Masoud Iravani, Tayeb Ramim, Fahime Hamedi, Ali M. Ardekani *
    Background

    The fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Pharmacogenetics research could be useful for the identification of predictive markers in chemotherapy treatment. The aim of the study was to investigate the role of five genetic polymorphisms within two genes (DPYD, TYMS) in toxicity and efficacy of fluoropyrimidine-based chemotherapy.

    Methods

    Total genomic DNA was extracted from 83 cancer patients treated with fluoropyrimidine-based chemotherapy. In this study, three polymorphisms were genotyped in dihydropyrimidine dehydrogenase gene c.1905+1 G>A (DPYD*2A; rs3918290), c.1679 T>G (I560S; DPYD*13; rs55886062), and c.2846A>T (D949V; rs67376798) and two polymorphisms, besides the Variable Number of Tandem Repeat (VNTR) polymorphism and 6-bp insertion/deletion polymorphism in thymidylate synthase gene. The analysis of polymorphisms for rs3918290, rs55886062, rs67376798 and 6-bp insertion/ deletion in TYMS was done by Polymerase Chain Reaction-restriction Fragment Length Polymorphism (PCRRFLP) TYMS VNTR analysis. 5-FU-related toxicities such as anemia, febrile neutropenia, neurotoxicity, vomiting, nausea, and mucositis were evaluated according to NCI-CTC criteria version 4.0. T-test and chi-square were used and p-values less than 0.05 were considered statistically significant.

    Results

    DPYD gene polymorphisms were not observed in this study. The frequency of the TYMS +6 bp allele was 40.35% and the -6 bp allele was 59.65% in this study. The frequency of VNTR 2R allele was 48.75% and 3R allele was 51.15%. Toxicity grade II diarrhea, mucositis, nausea, vomiting, and neurotoxicity was 2.2, 24.1, 15.7, 6, and 51.8%, respectively. Thymidylate synthase ins/del polymorphisms were associated with increased grade III neurotoxicity (p=0.02). Furthermore, anemia grade III was significantly associated with 2R/2R genotype (0.009).

    Conclusion

    Thymidylate synthase gene polymorphisms may play a key role in fluoropyrimidne -based chemotherapy. Although rare DPYD polymorphisms were not observed in our study, according to large population studies, DPYD gene polymorphisms could be used as a predictive biomarker for patient treatments.

    Keywords: 5-fluorouracil, Dihydropyrimidine dehydrogenase, Fluoropyrimidines, Pharmacogenetics, Thymidylate synthase
نکته
  • نتایج بر اساس تاریخ انتشار مرتب شده‌اند.
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