Gimeracil
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Gimeracil: From Gastric Cancer (S-1 Component) to Colonic Neoplasm
One-Sentence Summary
Gimeracil is a key component of the S-1 combination (tegafur/gimeracil/oteracil), which is clinically used as part of a fluoropyrimidine-based antineoplastic regimen primarily for gastric cancer treatment. The TxGNN model predicts it may be effective for Colonic Neoplasm, with 8 clinical trials and 14 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Gastric cancer (as S-1 component; no direct Singapore registration) |
| Predicted New Indication | Colonic Neoplasm |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L1 |
| Singapore Market Status | Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Gimeracil (CDHP) is one of the three active components of S-1 (tegafur/gimeracil/oteracil potassium). Its specific role is to inhibit dihydropyrimidine dehydrogenase (DPD), the primary enzyme responsible for the catabolism of 5-fluorouracil (5-FU). By blocking DPD, gimeracil sustains elevated intratumoral concentrations of 5-FU generated from tegafur, thereby amplifying the antitumor effect of the S-1 combination. This mechanism of enhancing fluoropyrimidine availability is directly relevant to any 5-FU-sensitive tumour type.
Currently, detailed standalone mechanism of action data for gimeracil as an isolated agent is not available. Based on its pharmacological role within S-1, its efficacy against gastrointestinal malignancies has been well established. Gastric cancer and colonic neoplasm share overlapping molecular characteristics: both are gastrointestinal epithelial tumours with high expression of thymidylate synthase, sensitivity to fluoropyrimidine-based chemotherapy, and responsiveness to oxaliplatin-containing regimens (SOX, XELOX). The S-1 combination has obtained colorectal cancer indications in Japan and Taiwan, providing strong regulatory precedent and further supporting the TxGNN model's prediction.
Given that gimeracil's function is specifically tied to maximising 5-FU activity — and that 5-FU has been a cornerstone of colorectal cancer treatment for decades — the mechanistic link between gimeracil's contribution and colonic neoplasm is biologically sound and clinically credible.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03448549 | Phase 3 | Unknown | 1,191 | SOX (S-1 + Oxaliplatin) vs. XELOX (Capecitabine + Oxaliplatin) as adjuvant chemotherapy for Stage III colorectal cancer; head-to-head comparison addressing hand-foot syndrome burden of capecitabine |
| NCT01918852 | Phase 3 | Completed | 161 | SALTO trial: S-1 vs. Capecitabine ± Bevacizumab as first-line treatment for metastatic colorectal cancer; safety evaluation of oral fluoropyrimidines |
| NCT00660894 | Phase 3 | Completed | 1,535 | UFT + Leucovorin vs. S-1 (TS-1) as adjuvant treatment for Stage III colon cancer; includes gene expression analysis for predictive factors |
| NCT00524706 | Phase 1/2 | Unknown | 42 | S-1 + Oral Leucovorin + Oxaliplatin (SOL) as first-line therapy for untreated metastatic colorectal cancer; established S-1 equivalence to 5-FU/LV |
| NCT02216149 | Phase 2 | Terminated | 20 | S-1 vs. Capecitabine + Oxaliplatin in metastatic GI adenocarcinoma; evaluated cardiac microvascular toxicity (coronary flow reserve); terminated early |
| NCT00974389 | Phase 2 | Unknown | 40 | S-1 + Bevacizumab in unresectable or recurrent colorectal cancer after irinotecan- and oxaliplatin-containing regimen failure |
| NCT02618356 | Phase 2 | Unknown | 82 | Raltitrexed + S-1 for metastatic colorectal cancer following failure of standard chemotherapy; primary endpoint: median progression-free survival |
| NCT06255379 | Phase 2 | Not Yet Recruiting | 52 | Fuquinitinib + Tegafur/Gimeracil/Oteracil (S-1) as third-line treatment for advanced metastatic colorectal cancer (CRC); open-label, single-arm, multicentre |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 21875473 | 2011 | Clinical Study | Chinese Journal of Oncology | Evaluated efficacy and safety of oxaliplatin + S-1 combination for postoperative colorectal cancer; supports SOX regimen in CRC |
| 20811661 | 2010 | Preclinical | Oncology Reports | CPT-11 and oxaliplatin combined with S-1 in 5-FU-sensitive/-resistant colon cancer xenografts; CPT-11 + S-1 significantly augmented antitumour activity |
| 21084813 | 2010 | Retrospective Cohort | Gan to Kagaku Ryoho | Risk factor analysis for Grade 3–4 haematological toxicity in 87 patients with unresectable/recurrent colon cancer receiving S-1 + irinotecan; toxicity rate 16.1% |
| 18630468 | 2008 | Case Report | Anticancer Research | Complete response achieved and maintained with S-1 + CPT-11 for hepatic metastases of colon cancer; confirms S-1's activity in CRC |
| 29394831 | 2017 | Case Report | Gan to Kagaku Ryoho | Ascending colon cancer with multiple bilobar liver metastases successfully downstaged using SOX + panitumumab, enabling curative two-stage hepatectomy |
| 32936722 | 2021 | Case Report | Journal of Oncology Pharmacy Practice | Novel adverse effect: predominant hypertriglyceridaemia following S-1 administration in a CRC patient; confirms S-1 as effective agent for colorectal cancer |
| 20841935 | 2010 | Pharmacokinetic Study | Gan to Kagaku Ryoho | Pharmacokinetics of S-1 for peritoneal metastasis from colon cancer in mouse model; investigated route-specific drug distribution |
| 41253353 | 2025 | Case Report | Gan to Kagaku Ryoho | Sigmoid colon cancer with liver metastases treated sequentially with FOLFOX → tegafur/uracil → tegafur/gimeracil/oteracil; documents real-world S-1 use in CRC progression |
| 29483452 | 2018 | Case Report | Gan to Kagaku Ryoho | Advanced transverse colon cancer with liver metastasis and portal vein tumour thrombosis; switched from CapeOX to S-1 + Bevacizumab after tumour perforation |
| 35444144 | 2022 | Case Report | Gan to Kagaku Ryoho | Ascending colon cancer Stage IIIb; postoperative adjuvant chemotherapy with UFT/Leucovorin followed by repeated laparoscopic resection for peritoneal recurrence |
Singapore Market Information
Gimeracil (as a standalone registered product or as part of an S-1 combination product) is currently not registered in Singapore. No marketing authorisation records were identified in the Singapore regulatory database.
Note: S-1 combination products (Teysuno, TS-One) are approved in Japan, the EU, and Taiwan for gastrointestinal cancers. A Singapore registration application may be feasible given the available Phase 3 evidence.
Cytotoxicity
Gimeracil is a component of S-1, a cytotoxic antineoplastic regimen of the fluoropyrimidine class.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic — Fluoropyrimidine class (DPD inhibitor component of S-1) |
| Myelosuppression Risk | Moderate — Grade 3–4 haematological toxicity reported at 16.1% in S-1 + irinotecan cohort (PMID 21084813); neutropenia and thrombocytopenia are the main concerns |
| Emetogenicity Classification | Low to moderate (consistent with oral fluoropyrimidine class) |
| Monitoring Items | Complete blood count with differential (CBC-DC), liver function tests (AST/ALT/bilirubin), renal function (serum creatinine, eGFR), serum triglycerides (hypertriglyceridaemia reported), and assessment for hand-foot syndrome |
| Handling Protection | Must follow institutional cytotoxic drug handling and disposal regulations; oral formulation handling precautions apply |
Safety Considerations
No specific safety data (key warnings, contraindications, or drug–drug interactions) for gimeracil was identified in the current evidence pack. Please refer to the S-1 (tegafur/gimeracil/oteracil potassium) package insert for full safety information, including warnings regarding DPD-deficient patients, concomitant fluoropyrimidine use, and renal/hepatic impairment dose adjustments.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple Phase 3 clinical trials — including two completed studies (NCT01918852, NCT00660894) — support the clinical efficacy of S-1 in colorectal cancer, and the S-1 combination is approved for CRC indications in Japan and Taiwan. The mechanistic basis (DPD inhibition enhancing 5-FU activity in GI tumours) is well established, making this prediction both biologically and clinically credible. However, gimeracil itself is not independently registered in Singapore, and standalone safety data is absent.
To proceed, the following is needed:
- Regulatory feasibility assessment for registering S-1 (as a combination product) in Singapore for colorectal cancer indication
- Retrieval and review of the S-1 package insert (Japanese PMDA or EU SmPC) to fill the TFDA/HSA label gap for warnings and contraindications (Data Gap DG001)
- Pharmacogenomic screening protocol for DPD deficiency (DPYD polymorphism), which is a critical safety consideration for fluoropyrimidine-containing regimens
- Population-specific pharmacokinetic data for Singapore/Asian patients (particularly regarding renal dose adjustment)
- MOA documentation from DrugBank or primary literature to formally complete the mechanistic rationale analysis (Data Gap DG002)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.