Oteracil

證據等級: L5

預測適應症: 10 個

Oteracil: From Chemotherapy Toxicity Modulator to Colonic Neoplasm

One-Sentence Summary

Oteracil (potassium oxonate) is a fixed component of the oral combination product S-1 (tegafur/gimeracil/oteracil), where it works by inhibiting intestinal OPRT to reduce gastrointestinal toxicity from tegafur-derived 5-FU rather than acting as an independent anticancer agent. The TxGNN model predicts potential efficacy for Colonic Neoplasm, supported by 8 clinical trials (including 3 completed Phase 3 RCTs) and 20 publications. Importantly, this evidence applies to the S-1 combination as a whole — oteracil itself has no standalone antitumor activity.

Quick Overview

Item	Content
Original Indication	Not available — no Norway marketing authorization on record for oteracil monotherapy; per literature, it is used exclusively as a fixed component of the S-1 combination for gastrointestinal cancers
Predicted New Indication	Colonic Neoplasm
TxGNN Prediction Score	99.99%
Evidence Level	L1
Norway Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed standalone mechanism-of-action data for oteracil is not available (original_moa: [Data Gap]), but the evidence pack's repurposing rationale provides substantial mechanistic context. Oteracil (potassium oxonate) has no independent antitumor activity. Its pharmacological role is to inhibit orotate phosphoribosyltransferase (OPRT) in the intestinal mucosa, which reduces local activation of 5-FU and thereby lowers the gastrointestinal toxicity caused by tegafur (a 5-FU prodrug). It is one of three fixed components of S-1 (tegafur/gimeracil/oteracil, brand name TS-1).

S-1 has already been approved and widely used in Japan and other Asian countries for colorectal cancer, both as adjuvant therapy for resected Stage III colon/rectal cancer and as first-line/later-line treatment for metastatic colorectal cancer. Since gastric and colorectal cancers are both fluoropyrimidine-sensitive gastrointestinal malignancies, and S-1 is a validated fluoropyrimidine-based regimen across this tumor family, the TxGNN prediction of colonic neoplasm is mechanistically plausible.

Key caveat: because oteracil is never administered as monotherapy, all clinical and mechanistic support for this indication is evidence for the S-1 combination product, not for oteracil in isolation. Any repurposing decision needs to be made at the combination-product level, and this distinction should be treated as a structural limitation of the evidence rather than a gap that can be closed with more oteracil-specific data.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00660894	Phase 3	Completed	1,535	UFT+LV vs TS-1 as adjuvant therapy for Stage III colon cancer; direct head-to-head Phase 3 RCT for this indication (Grade A)
NCT01918852	Phase 3	Completed	161	SALTO trial — S-1 vs capecitabine first-line for metastatic colorectal cancer, comparable efficacy (Grade A)
NCT03448549	Phase 3	Unknown	1,191	SOX vs XELOX as adjuvant chemotherapy for Stage III colorectal cancer; well-designed RCT, results status unclear (Grade B)
NCT02618356	Phase 2	Unknown	82	Raltitrexed + S-1 in metastatic CRC after failure of standard chemotherapy (Grade B)
NCT00524706	Phase 1/2	Unknown	42	S-1 + oral leucovorin + oxaliplatin (SOL) in untreated metastatic colorectal cancer (Grade B)
NCT00974389	Phase 2	Unknown	40	S-1 + bevacizumab in unresectable/recurrent CRC after irinotecan/oxaliplatin failure (Grade B)
NCT02216149	Phase 2	Terminated	20	S-1/capecitabine + oxaliplatin, coronary blood-flow safety endpoint (cardiotoxicity focus, not efficacy) (Grade C)
NCT06255379	Phase 2	Not yet recruiting	52	Fuquinitinib + S-1 (tegafur/gimeracil/oteracil) as third-line therapy in advanced metastatic CRC (Grade C)

Literature Evidence

PMID	Year	Type	Journal	Key Findings
31917122	2020	RCT	Clin Colorectal Cancer	ACTS-CC 02: SOX (S-1+oxaliplatin) vs UFT/LV as adjuvant therapy in high-risk Stage III colon cancer
27056996	2016	RCT	Annals of Oncology	JFMC35-C1 (ACTS-RC): S-1 vs UFT as adjuvant chemotherapy for Stage II/III rectal cancer
24942277	2014	RCT	Annals of Oncology	ACTS-CC trial: S-1 non-inferior to UFT/LV as adjuvant therapy for Stage III colon cancer
25209093	2014	Review/Guideline	Clin Colorectal Cancer	Asian consensus guidelines for metastatic colorectal cancer management
17496461	2007	Review	Gan To Kagaku Ryoho	Overview of adjuvant chemotherapy for colorectal cancer in Japan
22415232	2012	Clinical study (safety analysis)	Br J Cancer	ACTS-CC trial planned safety analysis of UFT/LV vs S-1 as Stage III colon cancer adjuvant therapy
32189156	2020	Clinical study	Int J Clin Oncol	KSCC1303: C-SOX (S-1+oxaliplatin) adjuvant therapy for Stage III colon cancer, 3-year DFS final analysis
26036466	2015	RCT (Phase 2)	BMC Cancer	Randomized study of S-1 dosing schedule for resected colorectal cancer
21875473	2011	Clinical study	Chin J Oncology	Efficacy and side effects of oxaliplatin + S-1 in colorectal cancer
20500514	2010	Preclinical	Cancer Science	Anti-lymph-node-metastasis efficacy comparison of S-1 vs UFT/LV in a colonic cancer xenograft model

Norway Market Information

Oteracil currently has no marketing authorization in Norway (total_licenses: 0), and no S-1 combination product license records are present in this evidence pack. No authorization table can be generated at this time.

Cytotoxicity

This section applies because oteracil is a fixed component of the cytotoxic S-1 fluoropyrimidine combination, though oteracil itself is not independently cytotoxic.

Item	Content
Cytotoxicity Classification	Not independently cytotoxic — functions as a biochemical modulator (intestinal OPRT inhibitor) within the S-1 fluoropyrimidine combination (tegafur/gimeracil/oteracil); the cytotoxic activity of S-1 derives from tegafur (5-FU prodrug)
Myelosuppression Risk	Moderate — attributable to the tegafur/5-FU component of S-1; oteracil itself does not cause myelosuppression and is included specifically to reduce GI toxicity of the combination
Emetogenicity Classification	Low to moderate (typical of oral fluoropyrimidine regimens)
Monitoring Items	CBC with differential, liver and renal function, electrolytes — per standard S-1 combination monitoring protocols
Handling Protection	If pursued via the S-1 combination product, standard cytotoxic drug handling precautions apply; oteracil alone has not been evaluated as a standalone hazardous handling concern

Safety Considerations

Please refer to the package insert for safety information. No key warnings, contraindications, or drug-drug interaction data are currently available for oteracil in this evidence pack (DG001, marked as a blocking data gap for safety pre-screening).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple completed Phase 3 RCTs (ACTS-CC, ACTS-RC, SALTO) demonstrate that the S-1 combination — of which oteracil is a fixed component — is effective in both adjuvant and metastatic colorectal/colon cancer settings, and S-1 already holds regulatory approval for this indication in Japan and other Asian markets. However, since oteracil has no independent antitumor activity and is never used as monotherapy, this recommendation should be understood as applying to the S-1 combination product, not to oteracil as a standalone repurposing candidate.

To proceed, the following is needed:

TFDA/Norway package insert safety data for oteracil and/or the S-1 combination (DG001, blocking)
Confirmed mechanism-of-action documentation from DrugBank or equivalent source (DG002)
Clarification of regulatory pathway: repurposing should target the S-1 combination product (tegafur/gimeracil/oteracil) rather than oteracil alone, given its non-independent pharmacological role
Verification of Norway/EU marketing authorization status for the S-1 combination product, since oteracil itself currently has zero registered licenses
Disclaimer

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