Gimeracil

證據等級: L5

預測適應症: 10 個

Gimeracil: From DPD-Inhibiting Component of S-1 to Colonic Neoplasm

One-Sentence Summary

Gimeracil has no standalone approved indication — it is the DPD (dihydropyrimidine dehydrogenase) inhibitor component of the S-1 combination (tegafur/gimeracil/oteracil), where it works by blocking the rapid breakdown of 5-FU rather than exerting direct cytotoxicity itself. The TxGNN model predicts the S-1 regimen containing gimeracil may be effective for Colonic Neoplasm, with 8 clinical trials (including 2 completed Phase 3 RCTs) and 15 publications currently supporting this direction.

Quick Overview

Item	Content
Original Indication	None independently approved — gimeracil is a pharmacokinetic enhancer within the S-1 combination (tegafur/gimeracil/oteracil), not a standalone antineoplastic agent
Predicted New Indication	Colonic Neoplasm
TxGNN Prediction Score	99.88%
Evidence Level	L1 (2 completed Phase 3 RCTs)
Norway Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed DrugBank-sourced mechanism-of-action data for gimeracil is not currently available (Data Gap). Based on known pharmacology, gimeracil is a competitive DPD inhibitor and is not cytotoxic on its own. Within the S-1 combination, it blocks DPD-mediated degradation of 5-FU (generated from tegafur), thereby prolonging and stabilizing systemic 5-FU exposure. This is a pharmacokinetic-enhancing role, not an independent antitumour mechanism.

Because 5-FU-based chemotherapy is a cornerstone of colorectal cancer treatment, and S-1 has already received regulatory approval for colorectal cancer in Japan and other Asian markets, the mechanistic rationale for extending S-1 (and by extension gimeracil as its enabling component) to colonic neoplasm is well established in oncology practice.

Important caveat: This "repurposing" signal actually reflects an existing combination-product use rather than a genuinely novel mechanistic extension. All supporting clinical evidence comes from the S-1 three-drug combination — none isolates gimeracil's independent contribution. Any regulatory or clinical decision should treat this as evidence for the S-1 regimen, not for gimeracil monotherapy.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00660894	Phase 3	Completed	1535	S-1 vs UFT+leucovorin as adjuvant therapy for Stage III colon cancer; largest completed head-to-head trial, also investigated gene-expression predictive factors
NCT01918852	Phase 3	Completed	161	SALTO trial: S-1 vs capecitabine as first-line treatment for metastatic colorectal cancer; safety evaluation of oral fluoropyrimidines
NCT03448549	Phase 3	Unknown	1191	SOX (S-1+oxaliplatin) vs XELOX as adjuvant chemotherapy for Stage III colorectal cancer; large sample but outcome status unreported
NCT02618356	Phase 2	Unknown	82	Raltitrexed + S-1 in metastatic colorectal cancer after standard chemotherapy failure; primary endpoint PFS
NCT00524706	Phase 1/2	Unknown	42	S-1 + oral leucovorin + oxaliplatin (SOL regimen) in untreated metastatic colorectal cancer
NCT00974389	Phase 2	Unknown	40	S-1 + bevacizumab in unresectable/recurrent colorectal cancer after irinotecan/oxaliplatin failure
NCT02216149	Phase 2	Terminated	20	Cardiac safety comparison (coronary artery blood flow) of S-1/capecitabine + oxaliplatin in metastatic GI adenocarcinoma
NCT06255379	Phase 2	Not Yet Recruiting	52	Furquintinib + S-1 as third-line treatment for advanced metastatic colorectal cancer

Literature Evidence

PMID	Year	Type	Journal	Key Findings
41724114	2026	Real-world cohort	Eur J Cancer	Population-based study: S-1 feasible and safe after capecitabine-induced HFS/cardiotoxicity in adjuvant colon cancer treatment
21875473	2011	Cohort	Zhonghua Zhong Liu Za Zhi	Efficacy and side effects of oxaliplatin + S-1 combination in postoperative colorectal cancer
21084813	2010	Cohort	Gan To Kagaku Ryoho	Risk factors for grade 3–4 hematological toxicity with S-1 + irinotecan in advanced/recurrent colonic cancer (16.1% incidence)
20811661	2010	Preclinical/xenograft	Oncology Reports	Irinotecan overcomes 5-FU resistance via thymidylate synthase downregulation in S-1-treated colon cancer xenografts
18630468	2008	Case report	Anticancer Research	Complete response obtained and maintained with S-1 + CPT-11 in colon cancer hepatic metastases
29394831	2017	Case report	Gan To Kagaku Ryoho	SOX (S-1+oxaliplatin) + panitumumab downstaging enabling two-stage hepatectomy for irresectable colorectal liver metastases
29483452	2018	Case report	Gan To Kagaku Ryoho	Chemotherapy management of transverse colon cancer with liver metastasis and portal vein tumor thrombosis
20841935	2010	PK study	Gan To Kagaku Ryoho	S-1 pharmacokinetics in a mouse peritoneal metastasis model derived from colon cancer
35444144	2022	Case report	Gan To Kagaku Ryoho	Laparoscopic resection of peritoneal recurrence after colorectal cancer resection with S-1-containing adjuvant therapy
32936722	2021	Case report (toxicity)	J Oncol Pharm Pract	Hypertriglyceridemia induced by S-1 during colorectal cancer treatment — novel toxicity signal

Norway Market Information

Gimeracil (as part of the S-1 combination) is currently not marketed in Norway; no authorization records are available (0 licenses on file).

Cytotoxicity

Gimeracil itself is non-cytotoxic (a DPD inhibitor), but it is always administered as an integral component of the S-1 fluoropyrimidine chemotherapy regimen. It should therefore be managed under conventional cytotoxic chemotherapy protocols.

Item	Content
Cytotoxicity Classification	Non-cytotoxic PK-enhancer within a conventional cytotoxic regimen (fluoropyrimidine class, S-1)
Myelosuppression Risk	Moderate — grade 3–4 hematological toxicity reported in ~16.1% of patients receiving S-1 + irinotecan for colonic cancer (PMID 21084813)
Emetogenicity Classification	Low to moderate (consistent with oral fluoropyrimidine regimens)
Monitoring Items	CBC with differential, liver and renal function, serum triglycerides (hypertriglyceridemia reported, PMID 32936722), skin/mucosal toxicity monitoring
Handling Protection	Standard cytotoxic drug handling precautions apply, as gimeracil is co-administered as part of the S-1 cytotoxic regimen

Safety Considerations

Please refer to the package insert for safety information. Drug-specific warnings, contraindications, and drug-interaction data for gimeracil are not currently available (flagged as a Blocking data gap pending TFDA label acquisition).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Two completed Phase 3 RCTs (NCT00660894, n=1535; NCT01918852, n=161) support S-1 — the combination containing gimeracil — in colorectal/colon cancer, giving L1 evidence strength. However, all evidence pertains to the S-1 combination product, not gimeracil alone, and product-level safety labeling (warnings/contraindications) is still missing.

To proceed, the following is needed:

TFDA/manufacturer product label with warnings and contraindications (Blocking gap, DG001)
Confirmed mechanism-of-action documentation from DrugBank (High priority gap, DG002)
Explicit clarification in any regulatory submission that efficacy evidence applies to the S-1 combination, not gimeracil monotherapy
Norway market entry/authorization pathway assessment, since the product is not currently marketed there

Note: Nine additional predicted indications (ranks 2–10) were reviewed but are not detailed here — all but "cardia cancer" (L4, Research Question) carry only TxGNN prediction scores with no supporting trials or literature (L5, Hold), including several biologically implausible candidates (e.g., benign lesions such as lipoma of colon, colonic lymphangioma) that should not be pursued.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.