Vadimezan (also known as or ASA404[1] and dimethylxanthenone acetic acid or DMXAA) is a tumor-vascular disrupting agent (tumor-VDA) that attacks the blood supply of a cancerous tumor to cause tumor regression.[2]
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| Other names | ASA404, DMXAA |
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| ECHA InfoCard | 100.107.097 |
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| Formula | C17H14O4 |
| Molar mass | 282.295 g·mol−1 |
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Clinical trials
editNon-small cell lung cancer
editDespite positive results at the preclinical stage, vadimezan failed in human clinical trials. Studies have demonstrated the reason for the inefficacy. Vadimezan was shown to target the STING pathway,[3] however, this effect is mouse specific; it has no effect on human STING.[4] A single amino acid difference at position 162 (S162A) of the cyclic-dinucleotide-binding site of STING makes mouse STING sensitive to the drug, whereas human STING remains insensitive.[5]
Vadimezan had been studied in combination with chemotherapy in at least two Phase II trials for advanced non-small cell lung cancer (NSCLC) and showed survival extensions of around 5 months when compared to chemotherapy alone (14.0 months compared to 8.8 months).[6] [7] In April 2008, a Phase III trial started. In March 2010, the phase III trial of use as a first line therapy for NSCLC gave poor results.[8] Interim results on another phase III trial as second-line therapy for NSCLC were completed in 2011. In November 2010, the second trial also gave poor interim results.[9]
Other cancers
editVadimezan has also been studied for the treatment of prostate cancer[7] and HER2-negative metastatic breast cancer.[1][10]
History
editVadimezan was discovered by Bruce Baguley and William Denny and their teams at the Auckland Cancer Society Research Centre at the University of Auckland in New Zealand.[10] It was licensed to Antisoma in 2001. Novartis acquired the worldwide rights for it in 2007 and it underwent development by Antisoma and Novartis.[7][10] In 2020 CRM Therapeutics, a Dutch drug-development company, initiated research for re-developing Vadimezan in combination with its proprietary targeted delivery platform. Since January 2021, Vadimezan is a registered trademark of CRM Therapeutics B.V., Rotterdam.[citation needed]
References
edit- ^ a b "New Zealand drug tested for breast-cancer fight". The New Zealand Herald. 14 February 2009. Retrieved 13 February 2009.
- ^ ASA404, A Novel Cancer Agent, Begins Pivotal Trial To Explore New Approach In Treating Lung Cancer, The Leading Cause Of Cancer Death, Medical News Today, 14 April 2008
- ^ Prantner D, Perkins DJ, Lai W, Williams MS, Sharma S, Fitzgerald KA, Vogel SN (November 2012). "5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential". The Journal of Biological Chemistry. 287 (47): 39776–88. doi:10.1074/jbc.M112.382986. PMC 3501038. PMID 23027866.
- ^ Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, et al. (May 2013). "Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid". Journal of Immunology. 190 (10): 5216–25. doi:10.4049/jimmunol.1300097. PMC 3647383. PMID 23585680.
- ^ Chang J, Hou S, Yan X, Li W, Xiao J (2023). "Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA". Molecules. 28 (7): 2906. doi:10.3390/molecules28072906. PMC 10095708. PMID 37049669.
- ^ McKeage MJ, Von Pawel J, Reck M, Jameson MB, Rosenthal MA, Sullivan R, et al. (December 2008). "Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer". British Journal of Cancer. 99 (12): 2006–12. doi:10.1038/sj.bjc.6604808. PMC 2607218. PMID 19078952.
- ^ a b c ASA404 Vascular Disrupting Agent for Solid Tumours, drugdevelopment-technology.com
- ^ "Antisoma and Novartis Ditch ASA404 After Second Phase III NSCLC Trial Bombs". 11 November 2010.
- ^ a b c "ASA404 to be developed in breast cancer". Antisoma. 12 February 2009. Archived from the original on 20 February 2012. Retrieved 13 February 2009.