Enhanced Therapeutic Efficacy of the Nanoscale Fluoropyrimidine Polymer CF10 in a Rat Colorectal Cancer Liver Metastasis Model

Abstract

Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (~90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.

Phenethyl isothiocyanate inhibits the carcinogenic properties of hepatocellular carcinoma Huh7.5.1 cells by activating MAPK/PI3K-Akt/p53 signaling pathways

“…Future research needs to delve into the therapeutic effectiveness and safety of PEITC in vivo , including validating its anti-tumor activity via preclinical animal models and conducting preliminary human clinical trials to assess its efficacy and safety in humans. Simultaneously, in view of the bioavailability and metabolic characteristics of PEITC, developing innovative and effective delivery systems, such as nanoscale fluoropyrimidine polymer CF10 ( Okechukwu et al., 2024 ), is also a focus of future research to enhance therapeutic efficacy in HCC. To sum up, while our research provides promising preliminary data for the application of PEITC in the treatment of HCC, more studies are needed to fully understand its potential and limitations in clinical therapy.…”

CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer

“…Cells were placed on ice and washed twice with ice-cold PBS, and cell lysates were collected using either cytoskeletal (CSK) buffer as described previously [ 71 , 72 ], (10 mM PIPES at pH 6.8, 100 mM NaCl, 300 mM sucrose, 3 mM MgCl 2 , 1 mM EGTA, 0.1 mM ATP, 0.1% Triton X-100 freshly supplemented with 1 mM dithiothreitol, 1× protease and phosphatase inhibitors with EDTA) or RIPA buffer (50 mM Tris-HCl at pH 7.4, 150 mM NaCl, 1% Triton X-100 or NP-40, 0.5% Sodium deoxycholate, 0.1% SDS, 1 mM EDTA, 10 mM Naf with freshly supplemented with 1× protease and phosphatase inhibitors). Either Bradford reagent for CSK, or DC reagent for RIPA were used to estimate protein content, and the proteins were equilibrated using either CSK buffer or ddH 2 O with 6× Laemmli buffer and heated at 100 °C for 15 min.…”