Fluorouracil

證據等級: L5

預測適應症: 10 個

Fluorouracil: From Antineoplastic Chemotherapy to Liver Sarcoma

One-Sentence Summary

Fluorouracil (5-FU, DB00544) is a fluoropyrimidine antimetabolite used as a chemotherapy backbone (e.g. FOLFOX, FOLFIRINOX) in gastrointestinal malignancies. TxGNN generated 10 candidate indications for this drug, but 9 of the 10 have zero supporting clinical trials or literature and several are flagged in the model rationale itself as likely embedding-similarity artefacts (confusion with hydroxyurea). This report therefore focuses on the one candidate that reached an actual evidence-backed decision stage — Liver Sarcoma — supported by 5 clinical trials (indirect) and 20 publications, including a directly relevant cohort study.

Quick Overview

Item	Content
Original Indication	Not available in the regulatory record supplied (fluorouracil is not currently ARTG-registered under this candidate). Known clinically as a fluoropyrimidine chemotherapy agent for GI malignancies.
Predicted New Indication	Liver Sarcoma
TxGNN Prediction Score	99.68% (rank 4316 of model output)
Evidence Level	L3
Australia Market Status	Not Marketed
Number of ARTG Entries	0
Recommended Decision	Hold

Note on candidate selection: TxGNN’s numerically top-ranked predictions for fluorouracil (botryoid-type embryonal rhabdomyosarcoma of the vagina, rhabdomyosarcoma variants, sickle-cell/haemoglobinopathy syndromes) all returned zero clinical trials and zero-to-minimal literature, and the model rationale explicitly flags the haemoglobinopathy predictions (ranks 8–10) as probable false positives from embedding proximity to hydroxyurea. Liver Sarcoma (TxGNN rank 4316) is the only candidate that reached Decision Stage S1 with real evidentiary support, so it is used as the reportable indication here.

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (DrugBank MOA query returned a data gap). Based on the evidence assembled, fluorouracil is a pyrimidine antimetabolite that inhibits thymidylate synthase (TS), and is an established chemotherapy backbone for gastrointestinal and hepatobiliary malignancies (e.g. FOLFOX, FOLFIRINOX regimens for metastatic colorectal cancer).

Liver sarcoma is mechanistically a “neighbouring indication” extrapolation rather than a direct match: the existing evidence base is drawn largely from colorectal cancer with liver metastasis or general solid-tumour trials, not from primary hepatic sarcoma populations specifically. One directly relevant cohort study (Zhou et al., 2019) examined surgical treatment and chemotherapy of adult primary liver sarcoma in China, providing the strongest single piece of evidence for this candidate.

Overall, the mechanistic plausibility is moderate-to-low: 5-FU’s antimetabolite activity is broadly cytotoxic to rapidly dividing tumour cells, which provides a generic rationale for activity in sarcoma, but there is no sarcoma-specific mechanistic data confirming meaningful efficacy over other cytotoxic options.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT01228734	Phase 3	Completed	553	Cetuximab + FOLFOX-4 vs FOLFOX-4 alone in RAS wild-type metastatic colorectal cancer. Relevance grade C — not liver sarcoma, but shows 5-FU-containing regimen safety data.
NCT03914170	N/A (retrospective)	Completed	70	FOLFIRINOX (incl. 5-FU) + cetuximab in RAS wild-type mCRC; population included liver-metastatic patients. Relevance grade B — indirect.
NCT01374425	Phase 2	Completed	376	Bevacizumab + mFOLFOX6 vs bevacizumab + FOLFIRI in untreated mCRC. Relevance grade C.
NCT04999761	Phase 1	Recruiting	917	Platform study of AB122-based treatments in advanced solid tumours. Relevance grade C — not sarcoma-specific.
NCT07059494	Phase 4	Recruiting	40	Atezolizumab + bevacizumab + Y-90 radioembolization for hepatocellular carcinoma bridging/downstaging to transplant. Relevance grade C — no 5-FU arm identified.

None of the above trials directly enrol a primary liver sarcoma population; all evidence is indirectly extrapolated from colorectal cancer or general solid-tumour settings.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
29346784	2019	Cohort (Tier 2)	Digestive Surgery	Surgical treatment and chemotherapy outcomes in adult primary liver sarcoma, single-centre China experience — the most directly relevant evidence for this indication.
9873095	1999	Review	Liver Transplantation and Surgery	Review of management of hepatic metastases, including gastrointestinal sarcoma as one of several origins.
11294295	2001	Case Report	J Hepatobiliary Pancreat Surg	Two paediatric cases of ruptured undifferentiated (embryonal) liver sarcoma; chemotherapy regimen used did not include 5-FU.
37112602	2023	Preclinical	Toxics	5-FU combined with chamomile flower extract in a Sarcoma 180 mouse model — antitumour and toxicological profiling.
1406088	1992	Preclinical (pharmacology)	Magnetic Resonance Imaging	19F-MRS study of 5-FU metabolism in liver and RIF-1 tumour-bearing mice.
4032755	1985	Early-phase pharmacology	Gan no Rinsho	Phase I dose-finding of a 5-FU derivative (590-S/tegafur-related), general anticancer activity.
3630210	1987	Preclinical (metabolism)	Xenobiotica	Hepatic metabolism of a 5-FU prodrug and enzyme induction studies in rats.
28239866	2017	Preclinical (pharmacokinetics)	Biopharm Drug Dispos	Effect of vasomodulators on hepatic disposition of 5-FU applied to the liver surface in rats.
52569	1975	Preclinical	Gan	Antitumour agent comparison (including 5-FU) in Sarcoma-180 cells transplanted to liver, kidney, lung.
37018833	2023	Preclinical	An Acad Bras Cienc	Histological evaluation of 5-FU-treated liver in Sarcoma-180-bearing mice.

10 additional lower-relevance publications (mostly preclinical pharmacology/metabolism studies, plus colorectal-cancer-focused reviews) are available in the underlying evidence pack but are omitted here for brevity.

Australia Market Information

Fluorouracil is not currently registered on the ARTG (Australian Register of Therapeutic Goods) under this drug candidate — 0 licences were found in the evidence pack.

Cytotoxicity

(Fluorouracil is a fluoropyrimidine antimetabolite chemotherapy agent, meeting the antineoplastic classification criteria.)

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (fluoropyrimidine antimetabolite; inhibits thymidylate synthase)
Myelosuppression Risk	Please refer to the Product Information (PI) warnings and precautions
Emetogenicity Classification	Please refer to the Product Information (PI) warnings and precautions
Monitoring Items	Please refer to the Product Information (PI) warnings and precautions
Handling Protection	Please refer to the Product Information (PI) warnings and precautions

Safety Considerations

Please refer to the TGA-approved Product Information (PI) for safety information. TFDA/TGA label warnings, contraindications, and drug-drug interaction data were not available in this evidence pack (flagged as a Blocking data gap — DG001 — preventing the S1 safety pre-assessment stage).

Conclusion and Next Steps

Decision: Hold

Rationale:

A Blocking data gap (DG001) means TFDA/TGA-level safety warnings and contraindications could not be assessed, which by itself precludes progression past initial safety screening.
Evidence for Liver Sarcoma is indirect (extrapolated from colorectal/hepatobiliary trials, not a primary liver-sarcoma population), reaching only L3/Research-Question status, and fluorouracil is not currently marketed in Australia under this candidate.
The remaining 9 of 10 TxGNN-predicted indications for this drug have no clinical trial or literature support and should not be progressed at all.

To proceed, the following is needed:

Retrieve TGA/TFDA Product Information (label warnings, contraindications, DDI) to close DG001
Obtain formal DrugBank/pharmacology MOA data to close DG002
Seek liver-sarcoma-specific clinical evidence (case series or trial), rather than relying on colorectal-cancer extrapolation
Clarify Australian registration pathway/status for fluorouracil under this specific candidate
Disclaimer

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