Orally Administrated Glutamate Restored EAAT1 and 3 Expression Levels Suppressed in 5-Fluorouracil-damaged Intestinal Epithelial Cells.

BACKGROUND/AIM: 5-Fluorouracil (5-FU) treatment induces intestinal mucositis, with diarrhea as the primary symptom. Mucositis significantly reduces patients' quality of life (QOL). Amino acids such as glutamate are beneficial for treating gastrointestinal disorders; however, the underlying mechanism remains unclear. Therefore, this study aimed to clarify the role of excitatory amino acid transporters (EAATs) in 5-FU-induced intestinal injury. MATERIALS AND METHODS: The rat intestinal epithelial cell line (IEC-6) was used to evaluate whether the EAAT inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) affects 5-FU-induced cytotoxicity. Mice with 5-FU-induced mucositis were used to determine the effects of glutamate on EAATs expression levels. RESULTS: Treatment with L-trans-PDC suppressed IEC-6 cell growth. It also exacerbated the 5-FU-induced cell growth suppression and increased inflammatory cytokine expression. In addition, mice treated with 5-FU+Glutamate showed higher EAAT1,3 expression than 5-FU only-treated mice. CONCLUSION: Decreased EAAT levels worsen intestinal cell damage caused by 5-FU, suppress cell growth, and induce inflammation. This study contributes to the understanding EAAT and its relationship with intestinal mucositis, which can aid in the development of novel preventive strategies for cancer chemotherapy.

Translational PK-PD/TD modeling of antitumor effects and peripheral neuropathy in gemcitabine and nab-paclitaxel chemotherapy from xenograft mice to patients for optimal dose and schedule.

PURPOSE: Gemcitabine and nab-paclitaxel (GnP) treatment, the standard first-line chemotherapy for unresectable pancreatic cancer, often causes peripheral neuropathy (PN). To develop alternative dosing strategies to avoid severe PN, understanding the relationship between pharmacokinetics (PK) and pharmacodynamics/toxicodynamics (PD/TD) is necessary. We established a PK-PD/TD model of GnP treatment to develop an optimal dose schedule. METHODS: A mouse xenograft model of human pancreatic cancer was generated to measure drug concentrations in the plasma and tumor, antitumor effects, and PN after GnP treatment. The Simeoni tumor growth inhibition model with tumor concentrations and empirical indirect response models were used for the PD and TD models, respectively. Clinical outcomes were predicted with reported population estimates of PK parameters in cancer patients. RESULTS: The PK-PD/TD model simultaneously described the observed tumor volume and paw withdrawal frequency in the von Frey test. For the standard GnP regimen, the model predicted clinical overall response (75.1%), which was overestimated compared to that in a recent phase II study (42.1%) but lower than the observed disease control rate (96.5%). Model simulation showed that dose reduction to less than 40% GnP dose was not effective; a change of dose schedule from every week for 3 weeks to every 2 weeks was a more favorable approach than dose reduction to 60% every week. CONCLUSION: The PK-PD/TD model-based translational approach provides a guide for optimal dose determination to avoid severe PN while maintaining antitumor effects during GnP chemotherapy. Further research is needed to enhance its applicability and potential for combination chemotherapy regimens.

Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer.

Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1-2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1-2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.