Oteracil

證據等級: L5

預測適應症: 10 個

Oteracil: From No Standalone Indication (S-1 Combination Component) to Colonic Neoplasm

One-Sentence Summary

Oteracil has no independent antineoplastic indication — it exists solely as a fixed component of the S-1 fluoropyrimidine combination (tegafur + gimeracil + oteracil), where it protects the gastrointestinal tract from 5-FU toxicity. The TxGNN model predicts it may be effective for Colonic Neoplasm, supported by 8 clinical trials and 20 publications — though this evidence largely confirms the S-1 combination's already-established role in colorectal cancer rather than a novel repurposing signal for oteracil itself.

Quick Overview

Item	Content
Original Indication	No standalone indication — Oteracil is not an independently marketed API; it is used only as a fixed component of the S-1 combination, and no German license/indication text is available in this evidence pack
Predicted New Indication	Colonic Neoplasm
TxGNN Prediction Score	99.99%
Evidence Level	L1
Germany Market Status	未上市 (Not marketed)
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data for oteracil is not available (Data Gap). Based on known information, oteracil is part of the S-1 combination (tegafur + gimeracil + oteracil). Within this combination, oteracil potassium has no independent antitumour activity — its role is to inhibit intestinal orotate phosphoribosyltransferase (OPRT), which reduces premature activation of 5-FU (derived from tegafur) in the gut. This lowers gastrointestinal toxicity and allows higher effective systemic doses of 5-FU to reach tumour tissue.

Colonic neoplasm and gastric cancer (S-1's core indication) are both gastrointestinal malignancies that share the same fluoropyrimidine-sensitive pathway (thymidylate synthase inhibition). S-1 has already been approved in Japan and across Asia for colorectal cancer (adjuvant stage III colon/rectal cancer and metastatic disease), making the mechanistic extrapolation to colonic neoplasm biologically coherent.

Important caveat: the clinical trial and literature evidence assembled here almost entirely evaluates the S-1 combination as a whole, not oteracil in isolation. As explicitly noted in the underlying evidence, this is best understood as confirmation of an already-established combination product's indication, not a novel drug-repurposing discovery. This distinction matters for how the "Go/Hold" decision should be interpreted — the pharmacology is sound, but the regulatory/commercial pathway concerns the S-1 product, not oteracil as a standalone entity.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00660894	Phase 3	Completed	1535	UFT+Leucovorin vs S-1 (TS-1) as adjuvant treatment for stage III colon cancer, with gene-expression-based predictive factor analysis
NCT01918852	Phase 3	Completed	161	SALTO study: S-1 vs capecitabine as first-line treatment for metastatic colorectal cancer
NCT03448549	Phase 3	Unknown	1191	SOX (oxaliplatin+S-1) vs XELOX as adjuvant chemotherapy for stage III colorectal cancer
NCT02618356	Phase 2	Unknown	82	Raltitrexed + S-1 for metastatic colorectal cancer after failure of standard chemotherapy
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 failure of irinotecan/oxaliplatin regimens
NCT06255379	Phase 2	Not yet recruiting	52	Fuquinitinib + tegafur/gimeracil/oteracil as third-line treatment for advanced metastatic CRC
NCT02216149	Phase 2	Terminated	20	S-1/capecitabine + oxaliplatin effects on coronary microvascular blood flow in metastatic GI adenocarcinoma (safety-focused, not efficacy)

Literature Evidence

PMID	Year	Type	Journal	Key Findings
31917122	2020	RCT	Clin Colorectal Cancer	ACTS-CC 02: S-1+oxaliplatin (SOX) vs UFT/LV as adjuvant chemotherapy in high-risk stage III colon cancer
27056996	2016	RCT	Ann Oncol	ACTS-RC (JFMC35-C1): S-1 vs UFT as adjuvant chemotherapy for stage II/III rectal cancer
24942277	2014	RCT	Ann Oncol	ACTS-CC trial: S-1 noninferior to UFT/LV as adjuvant chemotherapy for stage III colon cancer
22415232	2012	RCT sub-study (safety)	Br J Cancer	Planned safety analysis of ACTS-CC phase III trial comparing UFT/LV and S-1
26976971	2016	RCT biomarker sub-study	Anticancer Res	Genome-wide DNA copy-number analysis within the ACTS-CC phase III trial
32189156	2020	Phase II/III efficacy study	Int J Clin Oncol	KSCC1303: 3-year DFS analysis of S-1+oxaliplatin (C-SOX) adjuvant therapy for stage III colon cancer
25209093	2014	Review	Clin Colorectal Cancer	Asian consensus guidelines for management of metastatic colorectal cancer, incorporating S-1-based regimens
17496461	2007	Review	Gan To Kagaku Ryoho	Current state and issues of adjuvant chemotherapy for colorectal cancer in Japan
10897209	2000	Review	Gan To Kagaku Ryoho	Conceptual basis for S-1's biochemical modulation of 5-FU (self-rescuing concept, includes oteracil's role)
20500514	2010	Preclinical	Cancer Sci	Anti-lymph-node-metastasis efficacy of oral S-1 vs UFT/LV in a colon cancer xenograft model

Germany Market Information

Oteracil currently holds no marketing authorization in Germany — taiwan_regulatory.market_status is recorded as "未上市 (Not marketed)" with 0 total licenses. No license records, product names, or approved-indication text are available in this evidence pack. Note that oteracil is not intended to be marketed as a standalone product; it is only clinically relevant as a fixed component within combination products (e.g., S-1-type formulations), for which no separate license data was provided here.

Cytotoxicity

Oteracil is evaluated here as a required cytotoxic-chemotherapy adjunct because it is a fixed, non-separable component of the fluoropyrimidine combination S-1, used exclusively in antineoplastic regimens for gastrointestinal cancers.

Item	Content
Cytotoxicity Classification	Conventional cytotoxic — Fluoropyrimidine combination adjunct (component of S-1; oteracil itself is not independently cytotoxic but modulates 5-FU activation)
Myelosuppression Risk	Moderate — S-1-based regimens are commonly associated with neutropenia and thrombocytopenia in reported case series and trial safety analyses
Emetogenicity Classification	Low to Moderate (consistent with oral fluoropyrimidine class)
Monitoring Items	CBC with differential, liver and renal function, serum triglycerides (hypertriglyceridemia reported, PMID 32936722), skin/mucosal surveillance (severe cutaneous reactions reported, PMID 28414195)
Handling Protection	Must follow cytotoxic drug handling regulations, as oteracil is only used as part of cytotoxic chemotherapy regimens

Safety Considerations

Please refer to the package insert for safety information. No key warnings, contraindications, or drug-drug interaction data were available for oteracil in this evidence pack (DDI query returned no results).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Evidence level L1 is supported by multiple completed Phase 3 RCTs (ACTS-CC, ACTS-RC, SALTO) demonstrating efficacy of the S-1 combination in colorectal cancer. However, this evidence pertains to the S-1 combination as a whole rather than oteracil in isolation, and critical safety/regulatory data specific to oteracil (German label warnings, MOA) remain unresolved (Blocking Data Gap DG001).

To proceed, the following is needed:

German (BfArM) package insert warnings and contraindications for oteracil/S-1-containing products (currently a Blocking data gap)
Independent MOA documentation for oteracil (High-severity data gap, from DrugBank)
Clarification of whether the repurposing target is oteracil as an API or the S-1 combination product, since oteracil has no standalone marketing pathway
Confirmation of drug-drug interaction profile, given DDI query currently returns no data
Disclaimer

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