Preclinical Evaluation of CLX-155A: A Novel 5-FU and Valproic Acid Pro-drug in Nude Mouse Model for Activity in Triple-Negative Breast Cancer
Main Article Content
Abstract
New therapeutic approaches are needed to improve patient outcomes. Traditional pyrimidine antimetabolic chemotherapy agents like 5-FU and capecitabine face challenges of resistance, toxicity, and variability in patient response. CLX-155A, a novel oral prodrug, aims to enhance chemotherapy efficacy by combining 5-fluorouracil (5-FU) and valproic acid (VPA) to utilize synergistic mechanisms. This preclinical study addresses the research question: What is CLX-155A's preclinical activity in nude mouse models of triple-negative breast cancer (TNBC)?
This study assesses the anticancer efficacy of CLX-155A in TNBC nude xenograft mouse models, focusing on tumor growth inhibition and its potential effects when combined with paclitaxel. Mice inoculated with cancer cells were treated with CLX-155A at 1000 mg/kg/D either as monotherapy or in combination with paclitaxel at 15mg/kg daily. The study utilized comparisons with vehicle and capecitabine at 1000 mg/kg/D. The primary endpoint was tumor growth rate (%). Secondary assessments included survival and weight loss.
CLX-155A displayed significant antitumor activity in a TNBC model. The two CLX-155A groups (CLX-155A at 1000 mg/kg and CLX-155A at 1000 mg/kg + paclitaxel at 15 mg/kg) showed a significant effect (p<0.001) versus the vehicle control. At equal dosages to capecitabine, CLX-155A showed similar effects. It was numerically superior compared to capecitabine at equal dosages, both alone and in combination with paclitaxel. Further, CLX-155A as monotherapy showed similar effects to capecitabine with paclitaxel at 15mg/kg daily.
Overall, CLX-155A exhibits promising preclinical efficacy in CRC and TNBC models. Due to its dual-action mechanism, it may offer potential advantages over existing therapies. Additional studies are warranted to explore its clinical potential further and optimize dosing strategies.
Keywords:
Capecitabine, CLX-155A, 5-FU, Nude mouse model, Triple-negative breast cancer, 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 Triple-Negative Breast Cancer.
Medical Research Archives, [S.l.], v. 13, n. 4, apr. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6470>. Date accessed: 15 may 2025.
doi: https://doi.org/10.18103/mra.v13i4.6470.
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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25. Liu Y, Wang X. Caprylic acid suppresses inflammation through modulation of the TLR4/NF-κB signaling path-way in atherosclerosis. Journal of Nutritional Biochemi-stry. 2018;57:56-64.
26. Yoon BK, Jackman JA, Valle-González ER, Cho NJ. Antibacterial free fatty acids and monoglycerides: biological activities, experimental testing, and ther apeutic applications. International Journal of Mole cular Sciences. 2018;19(4):1114.
27. 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.
28. 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
29. York York JM, Kang S, Dalton A, Tak Y, Boyette N, Kandula M, Apparsundaram S. Pharmacokinetics of Single-dose CLX-155 and Metabolites in Female Balb/C Mice. Med Res Arch. 2024;12(9). doi:10.181-03/mra.v12i9.5709.
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32. Michaelis M, Michaelis UR, Fleming I, et al. Valproic acid is an anticancer drug. Current Pharmaceutical Design. 2004;10(21):2619-2635. doi:10.2174/138 161 2043383792
33. Munster PN, Marchion D, Bicaku E, et al. A phase II study of valproic acid in patients with advanced ca ncer. Cancer Chemotherapy and Pharmacology. 2009; 64(4):733-740. doi:10.1007/s00280-009-09 23-0
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36. Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 Breast tumor model. Curr Prot Immunology. 2001;(Chap 20 Unit 20.2) doi:https://doi.org/10.1002/04711427 35.im2002s39
37. Contreras-Zárate MJ, Ormond DR, Gillen AE, et al. Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases. Front Oncol. 2017;7:252. doi:10.3389/fonc.2017.00252
38. Pitts TM, Simmons DM, Bagby SM, et al. Wee1 Inhibition Enhances the Anti-Tumor Effects of Capecitabine in Preclinical Models of Triple-Negative Breast Cancer. Cancers (Basel). Mar 19 2020;12(3) doi:10.3390/cancers12030719
39. Rosato RR, Dávila-González D, Choi DS, et al. Evaluation of anti-PD-1-based therapy against triple-negative breast cancer patient-derived xenograft tumors engrafted in humanized mouse models. Breast Cancer Res. Sep 5 2018;20(1):108. doi:10.1186/ s13058-018-1037-4
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