CLX-155: A Novel, Oral 5-FU Prodrug Displaying Antitumor Activity in Human Colon Cancer Xenograft Model in Nude Mice

Main Article Content

Natasha Boyette Ava Dalton Yearam Tak Sophie Kang Subbu Apparsundaram Mahesh Kandula John York

Abstract

Introduction: Capecitabine is an oral prodrug of 5-FU, which interpatient pharmacokinetic (PK) variability related to liver function and severe adverse events (e.g., hand-foot syndrome, myelosuppression, and neurotoxicity) limits. CLX-155 is a novel oral 5’-DFCR prodrug involving 5’-DFCR as an intermediate for generating 5-FU, unlike capecitabine, which the liver does not metabolize. This study addresses the following research question: what is the activity of CLX-155 in a human colon cancer xenograft model in nude mice?


Methods: This study involved 50 Foxn1 athymic nude female mice implanted with the human colon cancer cell line HCT116 (5 million cells per site). Investigators randomized animals into five treatment groups (N = 10): vehicle control, CLX-155 at doses of 125, 250, and 500 mg/kg/day, or capecitabine 1000 mg/kg/day. Animals received oral treatment once daily for five days a week with two days off for a total of three consecutive weeks. Investigators evaluated treatment toxicity based on body weight loss. Calculations for tumor growth inhibition involved comparing changes in tumor volume on a given day to tumor volumes on Day 1.


Results: CLX-155 demonstrated statistically significant, dose-dependent tumor growth inhibition at all doses compared to vehicle control (p<0.0001). Tumor growth inhibition at Day 15 for CLX-155 treatment groups of 125, 250, and 500 mg/kg/day was 57.8%, 70.4%, and 90.6% respectively. Two animals in the CLX-155 500 mg/kg/day treatment group experienced complete tumor regression, and all animals in the CLX-155 treatment groups survived. Two animals in the CLX-155 250 and 500 mg/kg/day dosing groups experienced a decrease in body weight. In contrast, two mice in the capecitabine group exhibited clinical signs of hunchback and scaly skin, progressive weight loss, and eventual death.


Conclusion: CLX-155 demonstrated comparable tumor growth inhibition to capecitabine but at a lower dose, suggesting increased potency. In addition, CLX-155 exhibited improved tolerability and fewer adverse effects. These promising results support further investigation in Phase 1 clinical trials for managing colon cancer.

Keywords: Colon cancer, CLX-155, 5-FU prodrug, Xenograft, Preclinical activity, Antimetabolite

Article Details

How to Cite
BOYETTE, Natasha et al. CLX-155: A Novel, Oral 5-FU Prodrug Displaying Antitumor Activity in Human Colon Cancer Xenograft Model in Nude Mice. Medical Research Archives, [S.l.], v. 12, n. 6, june 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5219>. Date accessed: 22 july 2024. doi: https://doi.org/10.18103/mra.v12i6.5219.
Section
Research Articles

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