Hydroxyurea

證據等級: L5

預測適應症: 10 個

Hydroxyurea: From Hematologic Malignancies / Sickle Cell Disease to Female Breast Carcinoma

One-Sentence Summary

Hydroxyurea is a ribonucleotide reductase (RNR) inhibitor historically used as an antineoplastic and antisickling agent for conditions such as leukemia, sickle cell disease, and thrombocythemia. The TxGNN model predicts it may be effective for Female Breast Carcinoma, but this specific indication is currently supported only by 0 breast-cancer-specific clinical trials and 20 publications, most of which are preclinical, mechanistic, or decades-old combination-regimen studies.

Quick Overview

Item	Content
Original Indication	Not documented in this evidence pack (no Canadian licenses on file); internationally recognized uses include chronic myeloid leukemia, sickle cell disease, and essential thrombocythemia
Predicted New Indication	Female Breast Carcinoma
TxGNN Prediction Score	99.97%
Evidence Level	L3
Canada Market Status	Not Marketed
Number of DINs	0
Recommended Decision	Hold (Research Question stage)

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (flagged as a High-severity data gap, DG002). Based on the literature retrieved in this evidence pack (PMID 26844848), hydroxyurea is described as an antineoplastic drug historically used for leukemia, sickle-cell disease, HIV, psoriasis, thrombocythemia, and various neoplastic diseases — its core pharmacology is inhibition of ribonucleotide reductase (RNR), which blocks DNA synthesis.

Because RNR inhibition blocks DNA synthesis broadly, the mechanistic rationale extends in theory to rapidly dividing breast carcinoma cells, and hydroxyurea has historically been explored as a radiosensitizer within combination chemoradiotherapy regimens for solid tumors. However, the direct clinical evidence for breast cancer specifically is thin: it is limited to early-1990s Phase I combination trials (HALF regimen, high-dose consolidation with autologous stem cell rescue) in which hydroxyurea was a secondary agent rather than the primary therapeutic driver.

More recent literature is predominantly preclinical or computational — in-silico lipid-conjugate design, radiolabeling/imaging studies, and mechanistic work on replication stress and DNA repair (e.g., valproic acid sensitization, ATR inhibition) — rather than modern controlled trials. This pattern is consistent with a plausible but so far unproven mechanistic hypothesis rather than a clinically validated repurposing signal.

Clinical Trial Evidence

Currently no related clinical trials registered for hydroxyurea in female breast carcinoma.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
1957839	1991	Phase I Trial	American Journal of Clinical Oncology	HALF regimen (5-FU/leucovorin + allopurinol, followed by hydroxyurea) tested in 20 patients with advanced GI and breast cancer
7914447	1994	Phase I/II Trial	Bone Marrow Transplantation	High-dose cyclophosphamide + thiotepa + hydroxyurea with autologous stem cell rescue as consolidation for metastatic breast cancer (n=26)
38211596	2024	Preclinical/In-silico	Drug Research	In-silico design of hydroxyurea–lipid conjugates targeting PI3K/AKT/mTOR to improve HU lipophilicity and efficacy in breast cancer
26844848	2016	Preclinical (In Vitro/In Vivo)	Cancer Biotherapy & Radiopharmaceuticals	Radiolabeling of hydroxyurea ([99mTc(CO)3]-HU) for imaging; confirms HU’s use across leukemia, sickle-cell disease, and neoplastic disease
28837865	2017	Preclinical	DNA Repair	Valproic acid sensitizes breast cancer cells to hydroxyurea by inhibiting RPA2-mediated DNA repair
32795962	2020	Preclinical	DNA Repair	2-hexyl-4-pentynoic acid influences RPA2 hyperphosphorylation as a potential alternative to valproic acid for HU-sensitization in breast carcinoma
33631478	2021	Review	Pathology, Research and Practice	Review of long non-coding RNAs in breast cancer pathogenesis and prognosis
31338966	2019	Preclinical	Journal of Cellular and Molecular Medicine	Berberine attenuates XRCC1-mediated base excision repair, sensitizing breast cancer cells to chemotherapeutic drugs
21730979	2011	Preclinical	British Journal of Cancer	ATR inhibitor NU6027 evaluated in breast and ovarian cancer cell lines (replication-stress pathway relevant to HU mechanism)
28585003	2017	Case Report	Breast Cancer (Tokyo, Japan)	Secondary breast carcinoma reported in a patient previously treated with hydroxyurea and imatinib for CML

Canada Market Information

Hydroxyurea is currently not marketed in Canada under this evidence pack — no Drug Identification Numbers (DINs) or license records are on file.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (Ribonucleotide reductase inhibitor / antimetabolite class)
Myelosuppression Risk	Please refer to the package insert warnings and precautions
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Please refer to the package insert warnings and precautions
Handling Protection	Please refer to the package insert warnings and precautions

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold (Research Question stage)

Rationale:

There is a Blocking-severity data gap (DG001) on TFDA/Health Canada product monograph warnings and contraindications, which prevents even an initial safety screen (S1). Combined with the absence of any breast-cancer-specific clinical trials and evidence limited to preclinical/in-silico work plus non-specific 1990s Phase I combination regimens, this indication remains at a hypothesis-generation stage rather than one ready for development decisions.

To proceed, the following is needed:

TFDA/Health Canada product monograph — warnings, contraindications, and drug interaction data (resolves Blocking gap DG001)
Detailed mechanism of action (MOA) data from DrugBank (resolves High-severity gap DG002)
Modern controlled clinical trials evaluating hydroxyurea specifically (not as a secondary combination agent) in breast carcinoma
Confirmation of hydroxyurea’s original approved indications and Canadian regulatory status, since no licenses are currently on file

Note: This evidence pack contains 9 additional TxGNN-predicted indications for hydroxyurea. Notably, Sickle Cell–Hemoglobin C Disease Syndrome (rank 6) carries a much stronger evidence base — Evidence Level L1, supported by multiple Cochrane systematic reviews and a completed Phase 3 RCT (NOHARM, n=187) — and a recommendation of “Proceed with Guardrails.” That candidate likely warrants its own dedicated evaluation report separate from this breast carcinoma assessment.

Disclaimer

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