Gimeracil CAS 103766-25-2

(1) Treatment of gastrointestinal tumors
Gastric cancer: As the core component of Tegio capsule (TS-1), gemostat combined with tegafur and ateiracile is used for first-line treatment of advanced gastric cancer. The JCOG9912 trial showed that the median survival time of the Tegio group was 12.5 months, which was better than the 10.1 months of the 5-FU monotherapy group.
Colorectal cancer: As a DPD modulator in the FOLFOXIRI regimen, combined with irinotecan and oxaliplatin, phase III studies have shown an objective response rate (ORR) of 65%, which is 18% higher than traditional regimens.

(2) Application of pancreatic cancer
In the combination therapy of gemcitabine and tigio (GS therapy), gemcitabine enhances the synergistic effect by maintaining an effective concentration of 5-FU. The Japanese GEST study confirmed that the 1-year survival rate of locally advanced pancreatic cancer increased from 42% to 63%.
(3) Exploration of other solid tumors
In phase II clinical trials of breast cancer and non-small cell lung cancer, gemcitabine combined with capecitabine showed a disease control rate (DCR) of 72%, especially for patients with high DPD activity.

(1) Collaborative design of Tigio capsules
Tigafur (FT): As a prodrug of 5-FU, it is converted into an active ingredient under the action of liver microsomal CYP2A6.

Jimost: Maintaining plasma {{0}}FU concentration through DPD inhibition, achieving a balance between efficacy and toxicity with a three component molar ratio of 1:0.4:1.

(2) Example of Combination Chemotherapy Protocol
S-1+Cisplatin (SP regimen): In neoadjuvant chemotherapy for gastric cancer, the ORR reaches 58% and the pathological complete response rate (pCR) is 12%, significantly better than the ECF regimen.
S-1+paclitaxel: For HER2 negative gastric cancer, the median progression free survival (PFS) reported in phase I/II studies is 6.8 months, which is better than the 4.2 months of paclitaxel monotherapy.
(3) Individualized drug delivery strategy
Predicting enzyme activity by detecting DPD gene polymorphism (such as 2A/2A type) in patients, and guiding the adjustment of Giemster dosage. The UMIN000002345 experiment showed that the incidence of grade III-IV toxicity in the genotype group decreased from 42% to 23%.

For patients aged 75 years or older, the dose of Tegio is adjusted to 40mg/m ² bid, and Gimostat compensates for metabolic slowdown by prolonging the action time of 5-FU. The JGCOG1213 study confirmed that the efficacy of this regimen is equivalent to the standard dose in elderly patients with advanced gastric cancer, but the incidence of neutropenia is reduced by 15%.

In liver metastasis of colorectal cancer, the combination of Tegio and Bevacizumab is used as a translational chemotherapy regimen, while Gismost promotes tumor regression by maintaining drug exposure. A retrospective study showed that the R0 resection rate increased from 18% to 34%.

For advanced esophageal cancer, Tegio can significantly improve swallowing difficulties and increase the quality of life score (EORTC QLQ-OES18) by 27 points, which is superior to optimal supportive treatment.

Co loading Gimostat and 5-FU onto mesoporous silica nanoparticles (MSN) enhances tumor targeting through EPR effect. Animal experiments showed that the drug concentration at the tumor site increased by 6.8 times, and the cardiotoxic indicator troponin I level decreased by 45%.

Jimost enhances M1 polarization of tumor associated macrophages (TAMs) by prolonging the action time of 5-FU, and when combined with PD-1 inhibitors, it can increase cytotoxic T lymphocyte infiltration. The preclinical model showed that the tumor growth inhibition rate of the combination group reached 78%, which was 42% higher than that of the monotherapy group.

In vitro experiments have found that gemostat has inhibitory effects on Zika virus (ZIKV) NS5 polymerase, with a half maximal inhibitory concentration (IC50) of 12.7 μ M, and shows synergistic antiviral effects when combined with sofosbuvir.

For drug-resistant Staphylococcus aureus, Gimostat exerts antibacterial effects by inhibiting dihydropteroate synthase (DHPS), with a MIC value of 64 μ g/mL. Although higher than the clinical drug concentration, it provides a new target for structural optimization.

Preliminary studies have shown that gemostat can cross the blood-brain barrier and improve cognitive function in Alzheimer's disease model mice by regulating thymine metabolism. The specific mechanism is still under investigation.

Perioperative treatment of gastric cancer (JCOG1301 trial)
Solution: Ceio 80mg/m ² bid d1-14+Cisplatin 60mg/m ² d8q3w x 3 cycles
Result: R0 resection rate was 83%, 3-year DFS rate was 62%, and compared with the postoperative adjuvant chemotherapy group, it increased by 11%
Toxicity management: By adjusting the dosage of Giemster, the hematological toxicity of grade III or above was reduced from 52% to 38%

Solution: FOLFOXIRI (irinotecan+oxaliplatin+fluorouracil)+gemcitabine 9mg bid

Result: Objective response rate (ORR) of liver metastases was 69%, R0 resection rate was 34%, and median OS was 33 months

Innovation point: Jimos envoy extends the duration of action of 5-FU to 48 hours, enhancing its synergistic effect with oxaliplatin

Neoadjuvant therapy for pancreatic cancer (PREOPANC-1 trial)
Scheme: Gemcitabine 1000mg/m ² d1,8,15+Tegio 30mg/m ² bid d1-28 q4w × 3 cycles
Result: The R0 resection rate was 42%, which was 18% higher than the simple surgery group, and the median OS was prolonged by 6.3 months
Mechanism: Gemcitabine enhances the DNA damage effect of gemcitabine by maintaining the concentration of 5-FU in tumor tissue

Renal insufficiency: When creatinine clearance rate is less than 50mL/min, the dose of Tegio is reduced by 20%
Liver dysfunction: Child Pugh class B patients with a 35% increase in Gimostat AUC require close monitoring

Hematological toxicity: Prophylactic administration of G-CSF (PEG rhG CSF 6mg d2) can reduce the incidence of grade IV neutropenia from 32% to 8%
Gastrointestinal reactions: Combined with the triple antiemetic regimen of aripipitan, the incidence of CINV decreased from 68% to 41%

CYP2A6 inhibitors (such as ciprofloxacin): increase the conversion of tegafur and require monitoring of 5-FU related toxicity

Developing pH sensitive nanoparticles and utilizing the pH gradient of the tumor microenvironment to achieve programmed release of gemcitabine at the tumor site. Animal experiments have shown a tumor/plasma drug concentration ratio of 12:1.

in enhancing CAR-T cell therapy. In vitro experiments showed a 2.3-fold increase in tumor killing efficiency.