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| ID | Type | Description | Link |
|---|---|---|---|
| NMRR ID-24-01879-TSI | Other Identifier | National Medical Research Registration, Malaysia |
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| Name | Class |
|---|---|
| Clinical Research Malaysia | UNKNOWN |
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TThis study evaluates the safety and effectiveness of pre-operative artesunate, given orally once a day for 14 days prior to surgery, in patients with Stage II/III colorectal cancer.
Artesunate is an established antimalarial drug with an excellent safety profile. It is well tolerated, affordable, and widely available. Several laboratory studies and one small pilot clinical study in patients with colorectal cancer have shown that artesunate can reduce the proliferation and growth of cancer cells.
One hundred patients diagnosed with Stage II/III operable colorectal cancer will be randomly allocated to receive oral artesunate 200 mg daily or a matching placebo for 14 days prior to surgery. Patients will then be followed closely for 5 years to determine whether pre-operative artesunate reduces the risk of cancer recurrence after surgery.
Artesunate is an established antimalarial drug belonging to the artemisinin class of drugs, has an excellent safety profile, is well tolerated and affordable. In last two decades, artemisinins have shown potent and broad anticancer properties in a range of cell lines and animal models, supporting the hypothesis that artemisinins have the potential to be an effective anti-cancer therapy. Multiple potential mechanisms of action include anti-proliferative effects through cell-cycle disruption, reactive oxygen species (ROS) -induced DNA damage, induction of apoptosis, anti-angiogenesis, immunomodulation and induced radiosensitivity.
Despite a multi-modality treatment approach to colorectal cancer, 5 year overall survival does not currently exceed 60%. Neoadjuvant pre-operative therapy may be more effective at eradicating micrometastases compared to adjuvant therapy delivered following the delay and immunological stress of surgery. However current neoadjuvant chemotherapy regimens are often associated with significant side effects and may result in a delay in surgery whilst patients recover. A well tolerated, affordable, novel anticancer agent that could be given to patients whilst they wait for surgery, without causing a surgical delay due to treatment related toxicity, would have a significant clinical impact on patient care.
The NeoART trial is a phase II multicentre randomised, double blind, placebo controlled trial (RCT) for patients undergoing primary surgery for Stage II/III colorectal cancers. Patients are randomised (1:1 ratio) to receive either a two week course of neoadjuvant artesunate 200mg once daily or matching placebo. Both patients and health care professionals are blinded to treatment allocation arm to minimise outcome-reporting bias. The primary endpoint of the trial is recurrence free survival two years after surgery. Secondary endpoints include 2 and 5 year overall survival, treatment related toxicity, tolerability and patient quality of life. A translational sub-study looking at predictive and prognostic biomarkers is also planned.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Artesuante | Experimental | Artesunate 200mg oral tablets once daily for 14 days. |
|
| Artesunate matching placebo | Placebo Comparator | Matching placebo oral tablets once daily for 14 days. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Artesunate | Drug | Artesunate 200mg PO OD for 14 days prior to colorectal resection surgery |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Recurrence-Free Survival (RFS) at 2 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation | RFS is defined as the time from randomisation to the first documented recurrence of colorectal cancer (local or distant) or death from any cause, whichever occurs first. Recurrence will be assessed using standard CT scans of the chest, abdomen, and pelvis, clinical examination and measuring carcinoembryonic antigen (CEA). Confirmation of recurrence may include histological evidence where clinically indicated. Unit of Measure: Months | 2 years following study randomisation. |
| Measure | Description | Time Frame |
|---|---|---|
| Recurrence-Free Survival at 5 Years Post-Randomisation Assessed by Radiological and Clinical Evaluation | RFS is defined as the time from randomisation to the first documented recurrence of colorectal cancer (local or distant) or death from any cause, whichever occurs first. Recurrence will be assessed using standard CT scans of the chest, abdomen, and pelvis, clinical examination and CEA . Histological confirmation of recurrence will be obtained where clinically indicated. Unit of Measure: Months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dr Yolanda Augustin | Contact | +442087250446 | yagustin@cadt.org.uk | |
| Dr Nafeesa Mat Ali | Contact | nmatali@cadt.org.uk |
| Name | Affiliation | Role |
|---|---|---|
| Emeritus Professor Sanjeev Krishna, FRCP, ScD, FMedSci | Centre for Affordable Diagnotics and Therapeutics | Study Chair |
| Dr Yolanda Augustin | Centre for Affordable Diagnotics and Therapeutics | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Sultanah Bahiyah | Alor Star | Kedah | 05460 | Malaysia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26137537 | Background | Krishna S, Ganapathi S, Ster IC, Saeed ME, Cowan M, Finlayson C, Kovacsevics H, Jansen H, Kremsner PG, Efferth T, Kumar D. A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine. 2014 Nov 15;2(1):82-90. doi: 10.1016/j.ebiom.2014.11.010. eCollection 2015 Jan. | |
| 15262108 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 6, 2024 | Jul 23, 2025 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| ID | Term |
|---|---|
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000077332 | Artesunate |
| ID | Term |
|---|---|
| D037621 | Artemisinins |
| D017382 | Reactive Oxygen Species |
| D005609 | Free Radicals |
| D007287 | Inorganic Chemicals |
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This is a Phase II randomised, placebo-controlled, double-blind trial of neoadjuvant oral artesunate 200 mg once daily for 14 days in patients with histologically confirmed colorectal cancer (CRC) Stage II/III awaiting surgical treatment with curative intent. The study null hypothesis is that there is no difference in survival outcomes between patients with Stage II/III colorectal cancer who receive neoadjuvant artesunate 200 mg once daily for 14 days prior to surgery and those receiving a matching placebo tablet. A randomised, placebo-controlled, double-blind design has been chosen to minimise potential researcher bias. A placebo arm is included as there is currently no standard neoadjuvant treatment in Stage II/III colon cancer.
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| Artesunate matching Placebo |
| Drug |
Matched placebo PO OD for 14 days prior to colorectal resection surgery |
|
| 5 years from study randomisation |
| Overall Survival (OS) at 2 and 5 Years Post-Randomisation | Survival status will be determined through clinical follow-up, hospital records, and national death registries where available. Unit of Measure: Months | 2 years and 5 years following study randomisation. |
| Colon Cancer-Specific Mortality at 2 and 5 Years Post-Randomisation | 2 years and 5 years following study randomisation. |
| Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one artesunate-related adverse event, by CTCAE grade. | Assessment at Day 7 following initiation of study intervention (artesunate or matching placebo). |
| Incidence of Artesunate-Related Toxicity Assessed by Common Terminology CTCAE v5.0 | The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Causality will be assessed by the site investigator and confirmed by the clinical trial safety team. Adverse events will be coded and reported by type and severity. | Assessment at Day 14 following initiation of study intervention (artesunate or matching placebo). |
| Incidence of Artesunate-Related Toxicity Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | The number of participants experiencing adverse events considered related to artesunate will be recorded and graded using the CTCAE. Causality will be assessed by the site investigator and confirmed by the clinical trial safety team. Adverse events will be coded and reported by type and severity. Unit of Measure: Number of participants with at least one artesunate-related adverse event, by CTCAE grade. | Assessment at Day 42 following initiation of study intervention (artesunate or matching placebo). |
| Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. | Assessment at Day 7 following administration of study intervention (artesunate or matching placebo). |
| Incidence Adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Day 14 | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. | Assessment at Day 14 following study intervention |
| Incidence of adverse events affecting patients as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | The number and proportion of participants experiencing any adverse events (AEs), regardless of causality, will be recorded and graded using the CTCAE. Unit of Measure: Number of participants with at least one adverse event, categorised by CTCAE grade. | Assessment at Day 42 following study intervention |
| Pathological assessment of tumour regression post intervention | Tumour regression will be assessed by histopathological examination of the surgical resection specimen. The assessment will include:
Unit of Measure: Number and proportion of participants with positive lymph nodes, serosal involvement, and positive resection margins. | Post surgical pathology review (following Day 14 of study intervention) |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires at Baseline | Quality of life will be assessed using validated, self-administered questionnaires:
These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. | Assessment at Day 1 of study intervention (baseline assessment) |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires | Quality of life will be assessed using validated, self-administered questionnaires:
These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. | Assessment at Day 7 of study intervention |
| Patient-Reported Quality of Life (QoL) Assessed by Validated Questionnaires post intervention | Quality of life will be assessed using validated, self-administered questionnaires: 1. EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30) 2. EORTC QLQ-CR29 (Colorectal Cancer-Specific Module) These instruments evaluate global health status/QoL, functional scales (physical, role, emotional, cognitive, social), and symptom scales. Scores for each scale range from 0 to 100. For functional and global health status scales, higher scores indicate better QoL. For symptom scales, higher scores indicate worse symptoms. Unit of Measure: Mean scores for each scale/domain of the EORTC QLQ-C30 and QLQ-CR29 questionnaires. | Assessment at Day 14 of study intervention |
| Incidence of Surgery-Related Adverse Events Assessed by CTCAE v5.0 | The number and proportion of participants experiencing surgery-related adverse events (AEs) will be recorded. Events will be graded using the CTCAE version 5.0, with severity classified from Grade 1 (mild) to Grade 5 (death related to AE). Events of interest include, but are not limited to, surgical site infection, anastomotic leak, wound dehiscence, postoperative bleeding, and thromboembolic events. Unit of Measure: Number of participants with at least one surgery-related AE, categorised by CTCAE grade. | From time of surgery up to 3 months post surgery |
| Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy | Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL) | Day 1 of study intervention (baseline assessment). |
| Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy | Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL) | Assessment at Day 7 of study intervention |
| Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy | Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL) | Assessment at Day 14 of study intervention |
| Predictive value of tumour marker Carcinoma Embryonic Antigen (CEA) kinetics in terms of predicting response to artesunate therapy | Carcinoembryonic Antigen (CEA) levels will be measured in blood samples and their predictive value for response to artesunate therapy. he predictive value will be evaluated by correlating CEA with pathological tumour regression grade and recurrence-free survival. Unit of Measure: Change in serum CEA levels (ng/mL) | Assessment at Day 42 of study intervention |
| Immunohistochemical analyses of paraffin-embedded tumour sections to assess Kirsten rat sarcoma viral oncogene homolog (Kras) mutation status | KRAS mutation status will be assessed in tumour tissue sections obtained from pre-intervention (diagnostic biopsy, Day 0) and post-intervention (surgical resection, Day 15) samples. Immunohistochemistry (IHC) will be performed. Comparisons will be made to evaluate changes in mutation status and association with response to artesunate therapy. Unit of Measure: Number and proportion (%) of participants with KRAS mutant tumours at each time point. | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Immunohistochemical analyses of paraffin-embedded tumour sections to assess Mismatch Repair (MMR) status | Mismatch Repair (MMR) status will be assessed in tumour tissue sections obtained from pre-intervention (diagnostic biopsy, Day 0) and post-intervention (surgical resection, Day 15) samples. Immunohistochemistry (IHC) will be performed. Unit of Measure: Number and proportion (%) of participants with MMR-deficient tumours at each time p | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Immunohistochemical analyses of paraffin-embedded tumour for v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation status | Number of patients with BRAF mutant tumours | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Immunohistochemical analyses of paraffin-embedded tumour for Platelet derived growth factor (PDGF) expression | Number of patients whose tumours show PDGF upregulation/downregulation following treatment intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Immunohistochemical analyses of paraffin-embedded tumour for Vascular endothelial Growth Factor (VEGF) expression | Number of patients whose tumours show VEGF upregulation/downregulation following study intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Immunohistochemical analyses of paraffin-embedded tumour on Vascular endothelial Growth Factor Receptor (VEGFR) expression | Number of patients whose tumours show VEGFR upregulation/downregulation following study intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Determination of proliferative activity (Ki-67 staining, Cluster of Differentiation 31 protein (CD31) staining) | Number of patients whose tumours show an increase or reduction in proliferation markers Ki67 and CD31 following study intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Determination of activation of the Deoxyribonucleic acid damage response (DDR) pathway | Number of patients whose tumour samples show activation of the DDR pathway following study intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Wnt/β-catenin proliferation pathway protein expression (e.g. c-myc and cyclinD1 proteins) | Number of patients who show an increase or a decrease in expression of proteins involved in the Wnt/β-catenin proliferation pathway (e.g. c-myc and cyclinD1 proteins) following study intervention | Pre and post intervention tumour samples from patients (Day 0 and Day 15) |
| Hospital Kuala Lumpur | Kuala Lumpur | Kuala Lumpur | 50586 | Malaysia |
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| Pusat Perubatan Universiti Malaya | Kuala Lumpur | Kuala Lumpur | 59100 | Malaysia |
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| Hospital Umum Sarawak | Kuching | Sarawak | 93586 | Malaysia |
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| Hospital Sungai Buloh | Sungai Buloh | Selangor | 47000 | Malaysia |
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| Hospital Pulau Pinang | Pulau Pinang | 10990 | Malaysia |
|
| Kremsner PG, Krishna S. Antimalarial combinations. Lancet. 2004 Jul 17-23;364(9430):285-94. doi: 10.1016/S0140-6736(04)16680-4. |
| 18752857 | Background | Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends Pharmacol Sci. 2008 Oct;29(10):520-7. doi: 10.1016/j.tips.2008.07.004. Epub 2008 Aug 25. |
| 6354290 | Background | Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983 Jun;39(2):499-503. |
| 17101767 | Background | Singh NP, Panwar VK. Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther. 2006 Dec;5(4):391-4. doi: 10.1177/1534735406295311. |
| 21156967 | Background | Steinbruck L, Pereira G, Efferth T. Effects of artesunate on cytokinesis and G(2)/M cell cycle progression of tumour cells and budding yeast. Cancer Genomics Proteomics. 2010 Nov-Dec;7(6):337-46. |
| 22560712 | Background | Reichert S, Reinboldt V, Hehlgans S, Efferth T, Rodel C, Rodel F. A radiosensitizing effect of artesunate in glioblastoma cells is associated with a diminished expression of the inhibitor of apoptosis protein survivin. Radiother Oncol. 2012 Jun;103(3):394-401. doi: 10.1016/j.radonc.2012.03.018. Epub 2012 May 3. |
| 17942255 | Background | Nakase I, Lai H, Singh NP, Sasaki T. Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation. Int J Pharm. 2008 Apr 16;354(1-2):28-33. doi: 10.1016/j.ijpharm.2007.09.003. Epub 2007 Sep 6. |
| Background | Kim SJ., Kim MS., Lee JW., Lee CH., Yoo, H., Shin, SH., et al. Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro. J Cancer Res Clin Oncol. 2006;132 :129-135. Krishna K., Ganapathi S., Ster IS., Saeed MEM., Cowan M., Finlayson C., Kovacsevics H., Jansen H., Kremsner PG., Efferth T., Kumar D. A Randomised, Double Blind,Placebo Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine 2015;2(1) :82-90 Kreeftmeijer-Vegter, A. R., P. J. van Genderen., Visser LG., Bierman WF., Clerinx J., van Veldhuizen CK., de Vries PJ. "Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium." Malar J.2012;11:102. Lai H., Nakase I., Lacoste E., Singh NP., Sasaki. Artemisinin-transferrin conjugate retards growth of breast tumors in the rat. Anticancer Res 2009;29 :3807-3810. |
| 24316259 | Background | Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014 Apr;142(1):126-39. doi: 10.1016/j.pharmthera.2013.12.001. Epub 2013 Dec 6. |
| 23017669 | Background | Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol. 2012 Nov;13(11):1152-60. doi: 10.1016/S1470-2045(12)70348-0. Epub 2012 Sep 25. |
| 3416116 | Background | Finlay IG, Meek D, Brunton F, McArdle CS. Growth rate of hepatic metastases in colorectal carcinoma. Br J Surg. 1988 Jul;75(7):641-4. doi: 10.1002/bjs.1800750707. |
| 25248945 | Background | Ericsson T, Blank A, von Hagens C, Ashton M, Abelo A. Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer. Eur J Clin Pharmacol. 2014 Dec;70(12):1453-63. doi: 10.1007/s00228-014-1754-2. Epub 2014 Sep 25. |
| 11251172 | Background | Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. The anti-malarial artesunate is also active against cancer. Int J Oncol. 2001 Apr;18(4):767-73. doi: 10.3892/ijo.18.4.767. |
| 19690861 | Background | Du JH, Zhang HD, Ma ZJ, Ji KM. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol. 2010 Apr;65(5):895-902. doi: 10.1007/s00280-009-1095-5. Epub 2009 Aug 19. |
| 16273263 | Background | Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G. Artesunate in the treatment of metastatic uveal melanoma--first experiences. Oncol Rep. 2005 Dec;14(6):1599-603. |
| 21998290 | Background | Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther. 2011 Dec;10(12):2224-33. doi: 10.1158/1535-7163.MCT-11-0534. Epub 2011 Oct 13. |
| 26153023 | Background | Beccafico S, Morozzi G, Marchetti MC, Riccardi C, Sidoni A, Donato R, Sorci G. Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells. Carcinogenesis. 2015 Sep;36(9):1071-83. doi: 10.1093/carcin/bgv098. Epub 2015 Jul 7. |
| 16432535 | Background | Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics J. 2006 Jul-Aug;6(4):269-78. doi: 10.1038/sj.tpj.6500371. Epub 2006 Jan 24. |
| D004066 |
| Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D009930 |
| Organic Chemicals |
| D012717 | Sesquiterpenes |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |