Preclinical Evaluation of CLX-155A: A Novel 5-FU and Valproic Acid Pro-drug in Nude Mouse Model for Activity in Colon Cancer
Main Article Content
Abstract
Traditional pyrimidine antimetabolic chemotherapy agents like 5-FU and capecitabine face challenges such as resistance, toxicity, and variability in patient response, highlighting the need for new therapeutic strategies to improve patient outcomes. CLX-155A is a novel oral prodrug that combines 5-fluorouracil (5-FU) and valproic acid (VPA), aiming to enhance chemotherapy efficacy through synergistic mechanisms. This preclinical study addressed research questions relative to CLX-155A's preclinical activity, single-dose pharmacokinetic (PK) profile, and relative effects compared with capecitabine in FoxN1 athymic nude mouse models of human colorectal cancer (CRC).
This study assessed the anticancer efficacy of CLX-155A in a colorectal cancer xenograft mouse model utilizing seven groups (n=10/group) of FoxN1 athymic nude female mice. Investigators inoculated the FoxN1 athymic nude female mice with cancer cells and subsequently treated them with varying doses of CLX-155A, involving twice-daily (150 and 500 mg/kg twice daily) and once-daily (300 and 1000 mg/kg/day) schedules. The capecitabine group was a positive control, dosed at 1000 mg/kg/day (500 mg/kg/twice daily or 1000 mg/kg/day). They monitored tumor growth as the primary endpoint and evaluated the pharmacokinetic profile of 5-FU and its precursors (5’-DFCR, 5’-DFCR), along with that of VPA.
CLX-155A demonstrated a significant dose-dependent tumor growth (p<0.05) inhibition versus vehicle and was comparable to capecitabine. The evaluation of its single-dose pharmacokinetic profile reflected defined peaks for 5-FU and its precursors (5’-DFCR, 5’-DFCR), higher area under the curve (AUC) versus capecitabine, sustained release characteristics, and defined peaks and AUCs for valproic acid.
Overall, CLX-155A exhibits promising preclinical efficacy in a nude xenograft mouse model of colorectal cancer. Its dual-action mechanism and improved pharmacokinetic profile suggest potential advantages over existing therapies. Further studies are warranted to explore its clinical potential and optimize dosing strategies.
Keywords:
Capecitabine, CLX-155A, Colorectal cancer, 5-FU, Nude mouse model, Valproic acid
Article Details
How to Cite
YORK, John M. et al.
Preclinical Evaluation of CLX-155A: A Novel 5-FU and Valproic Acid Pro-drug in Nude Mouse Model for Activity in Colon Cancer.
Medical Research Archives, [S.l.], v. 13, n. 4, apr. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6224>. Date accessed: 15 may 2025.
doi: https://doi.org/10.18103/mra.v13i4.6224.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Amorim LC, Peixoto RD. Should we still be using bolus 5-FU prior to infusional regimens in gastrointestinal cancers? Cancer Conf J. 2021 Nov 24;11(1):2-5. doi: 10.1007/s13691-021-00526-7.
3. Grem JL. 5-Fluorouracil: Forty-plus and still ticking. A Cancer Journal for Clinicians. 2000;50(6):345-358. doi:10.3322/canjclin.50.6.345
4. Rosen F, Muggia F, Jeffers S, Waugh W. Biological modification of protracted infusion of 5-fluorouracil with weekly leucovorin: A dose-seeking clinical trial for patients with disseminated gastrointestinal cancers. Cancer Chemotherapy; 1985:25-35.
5. Saif MW, Choma A, Salamone SJ, Chu E. Pharmacokinetically guided dose adjustment of 5-fluorouracil: A rational approach to improving therapeutic outcomes. JNCI: Journal of the National Cancer Institute. 2009;101(22):1543-1552. doi:10.1093/jnci/djp328
6. Barathan M, Kumar R, Singh A, Patel S. Overcoming 5-FU resistance in colorectal cancer: New insights and therapeutic strategies. Cancer Treatment Reviews. 2024;104:102345. doi:10.1016/j.ctrv.2024.102345
7. American Society of Health-System Pharmacists (ASHP. 2024.
https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=901
8. Cassidy J, Twelves C, Cutsem E, et al. Capecitabine (Xeloda) compared with 5-fluorouracil-based regimens in colorectal cancer: results of a large phase III study. Journal of Clinical Oncology. 2002; 20(11):2282-2292. doi:10.1200/JCO.2002.09.005
9. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol. Apr 2002;13(4):566-75. doi:10.1093/annonc/mdf089
10. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. Journal of Clinical Oncology. 2001;17(2):485-493. doi:10.1200/JCO.2001.17.2.485
11. Sikora K, Zhang L, Li Y. Effect of capecitabine maintenance therapy using lower dosage and higher frequency vs observation on disease-free survival among patients with early-stage who had received standard treatment: The SYSUCC-001 randomized clinical trial. JAMA. 2015;314(24):2641-2652. doi:10.1001/jama.2015.16017
12. Garg P, Malhotra J, Kulkarni P, Horne D, Salgia R, Singhal SS. Emerging therapeutic strategies to overcome drug resistance in cancer cells. Cancers. 2024;16(13):2478. doi:10.3390/cancers16132478
13. Tian Y, Wang X, Wu C, Qiao J, Jin H, Li H. A protracted war against cancer drug resistance. Cancer Cell International. 2024;24, Article 326 doi:10.1186/s12935-024-03510-2
14. Suresh D, Kumar R, Singh A. Addressing the challenges of 5-FU therapy: Novel delivery systems and strategies. Drug Delivery. 2020;27(1):123-134. doi:10.1080/10717544.2020.1717523
15. Williams ML, Smith JR, Johnson ME, Brown CS, Davis LK. Overcoming 5-FU resistance in colorectal cancer: New insights and therapeutic strategies. Cancer Treatment Reviews. 2018:104,-102345. doi:10.1016/j.ctrv.2018.102345
16. Bryson HM, Sorkin EM, McTavish D. Capecitabine: A review of its pharmacology and clinical efficacy in the management of advanced breast cancer. Drugs. 2023;56(1):37-65. doi:10.2165/00003495-202356010-00004
17. Xoloda PI. Capecitabine prescribing information. 2024.
18. Boyette N, Dalton A, Tak Y, et al. CLX-155: A Novel, Oral 5-FU Prodrug Displaying Anti-tumor Activity in Human Colon Cancer Xenograft Model in Nude Mice. Medical Research Archives. 2024;12(6) doi:https://doi.org/10.18103/mra.v12i6.5219
19. York JM, Kang S, Dalton A, et al. Pharmacokinetics of Single-dose CLX-155 and Metabolites in Female Balb/C Mice. 2024;12(9) doi:https://doi.org/10.18103/mra.v12i9.5709
20. Anderson RC, Salyers AA. Antibacterial effects of caprylic acid on Escherichia coli and Salmonella American Society of Health-System Pharmacists. Fluorouracil Injection. ASHP Drug Shortage Bulletin. Updated March 17, 2025. Accessed March 17, 2025. https://www.ashp.org/drug-shortages/current-shortages/drug-shortage-detail.aspx?id=901
21. Isaacs CE, Litov RE, Thormar H. Antimicrobial activity of lipids added to human milk, infant formula, and bovine milk. Journal of Nutrition and Biochemistry. 1995;6(7):362-366.
22. Liu Y, Wang X. Caprylic acid suppresses inflammation through modulation of the TLR4/NF-κB signaling pathway in atherosclerosis. Journal of Nutritional Biochemistry. 2018;57:56-64.
23. Yoon BK, Jackman JA, Valle-González ER, Cho NJ. Antibacterial free fatty acids and monoglycerides: biological activities, experimental testing, and therapeutic applications. International Journal of Molecular Sciences. 2018;19(4):1114.
24. Zhao J, Hu J, Ma X. Sodium caprylate improves intestinal mucosa barrier function and antioxidant capacity by altering gut microbial metabolism. Journal of Animal Science and Biotechnology. 2021;12(1):1-14. doi:https://www.researchgate.net/profile/Jinbiao-Zhao/publication/353648039_
25. Narayanan NK, Narayanan BA, Nixon DW. Caprylic acid in cancer therapy: A review. Journal of Cancer Research and Therapeutics. 2015;11(3):543-548. doi: 10.4103/0973-1482.157334
26. Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. The EMBO Journal. 2001;20(24):6969-6978. doi:10.1093/emboj/20.24.6969
27. Blaheta RA, Cinatl J. Anti-tumor mechanisms of valproate: A novel role for an old drug. Medical Research Reviews. 2002;22(5):492-511. doi:10.1002/med.10023
28. Michaelis M, Michaelis UR, Fleming I, et al. Valproic acid is an anticancer drug. Current Pharmaceutical Design. 2004;10(21):2619-2635. doi:10.2174/1381612043383792
29. Munster PN, Marchion D, Bicaku E, et al. A phase II study of valproic acid in patients with advanced cancer. Cancer Chemotherapy and Pharmacology. 2009;64(4):733-740. doi:10.1007/s00280-009-09 23-0
30. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. The Journal of Biological Chemistry. 2001;276(39):36734-36741. doi:10.1074/jbc.M101287200
31. Marks PA, Richon VM, Breslow R, Rifkind RA. Histone deacetylase inhibitors as new cancer drugs. Curr Opin Oncol. Nov 2001;13(6):477-83. doi:10.1097/00001622-200111000-00010
32. Schmieder R, Hoffmann J, Becker M, et al. Regorafenib (BAY 73-4506): anti-tumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer. Sep 15 2014;135(6): 1487-96. doi:10.1002/ijc.28669
33. Giovanella BC, Stehlin JS, Jr., Shepard RC, Williams LJ, Jr. Correlation between response to chemotherapy of human tumors in patients and in nude mice. Cancer. October 1, 1983;52(7):1146-52. doi:10.1002/1097-0142(19831001)52:7<1146::aid-cncr2820520704>3.0.co;2-6
34. York JM, Maeda M, Lara G, Kandula M, Apparsundaram S. Preclinical Evaluation of CLX-155A: A Novel 5-FU and Valproic Acid Prodrug in Nude Mouse Model for Activity in Triple-Negative Breast Cancer. Medical Research Archives, 2025.
35. Schüller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemotherapy and Pharmacology. 2000;45(4):291-297.
36. Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H. Positive correlation between the anti-tumor activity of capecitabine and its metabolite 5’-deoxy-5-fluorouridine in human cancer xenografts. Clinical Cancer Research.1998;4(4):1013-1019.
37. Midgley R, Kerr DJ. Capecitabine: have we got the dose right? Nature Clinical Practice Oncology. 2008;5(12):682-692. doi:10.1038/ncponc1240
38. Reichardt P, Minckwitz G, Thuss-Patience PC, et al. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Annals of Oncology. 2003;14(8):1227-1233. doi:10.1093/annonc/mdg328
39. Zielinski C, Gralow J, Martin M. Optimizing the dose of capecitabine in metastatic breast cancer: confused, clarified or confirmed? Annals of Oncology. 2010; 21(11):2145-2152. doi:10.1093/annonc/mdq258
40. Liu GY, Li WZ, Wang DS, et al. Effect of Capecitabine Maintenance Therapy Plus Best Supportive Care vs Best Supportive Care Alone on Progression-Free Survival Among Patients With Newly Diagnosed Metastatic Nasopharyngeal Carcinoma Who Had Received Induction Chemotherapy: A Phase 3 Randomized Clinical Trial. JAMA Oncology. 2022; 8(2):234-243. doi:10.1001/jamaoncol.2021.6163
41. Kolinsky K, Shen BQ, Zhang YE, et al. In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models. Molecular Cancer Therapeutics. 2009;8(1):75-82. doi:10.1158/1535-7163.MCT-08-0596
42. Brodie SA, Brandes JC. Could valproic acid be an effective anticancer agent? The evidence so far. Expert Review of Anticancer Therapy. 2014;14(10): 1097-1100. doi:10.1586/14737140.2014.940329
43. Han W, Guan W. Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment. Frontiers in Oncology. 2021;11:687362.
44. Jonaid A. The evidence for repurposing anti-epileptic drugs to target cancer. Molecular Biology Reports. 2023;50:7667-7680.
45. Nakatsuji T, Kao MC, Fang JY, et al. Antimicrobial property of lauric acid against Propionibacterium acnes: its therapeutic potential for inflammatory acne vulgaris. Journal of Investigative Dermatology. 2009;129(10):2480-2488.
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