Hydroxyurea

Evidence Level: L5

Predicted Indications: 6

Hydroxyurea

Pharmacist Assessment Report

Hydroxyurea: Female breast carcinoma

One-Sentence Summary

Hydroxyurea is a ribonucleotide reductase inhibitor, originally used for melanoma, sickle cell anaemia and ovarian cancer. The TxGNN model predicts it may be effective for female breast carcinoma (score 0.9997), but no clinical trials are registered for this indication and the 20 publications retrieved are almost entirely preclinical, in-silico or off-topic. The prediction is therefore best viewed as a hypothesis.

Note: The ranked predictions also include sickle cell-haemoglobin C disease, which has markedly stronger evidence (a Phase 2 trial and a 2025 clinical publication). It is summarised under “Other Predicted Indications” below.

Quick Overview

Item	Content
Original Indication	Not recorded in the local data
Predicted New Indication	Female breast carcinoma
TxGNN Prediction Score	0.9997
Evidence Level	L5 (preclinical and mechanistic studies only)
Australia Market Status	Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data
Number of PBS Items	1 (valid: 1)
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism of action data was not available in the data compiled for this report. Based on known pharmacology, hydroxyurea inhibits ribonucleotide reductase, which depletes deoxynucleotide (dNTP) pools and induces DNA replication stress. This mechanism underlies its use in cancers such as melanoma and ovarian cancer.

Breast cancer cells are also dependent on DNA replication and repair. Preclinical papers link replication stress, ATR signalling and RPA2-mediated DNA repair to breast cancer cell sensitivity to hydroxyurea. Examples include valproic acid sensitising breast cancer cells to hydroxyurea, and BRCA1-deficient breast cancer cells being susceptible to ribonucleotide reductase inhibition.

The mechanistic rationale is plausible, but it has not been tested in breast cancer patients in the data compiled. The very high TxGNN score is a computational output and should not be read as clinical evidence.

Clinical Trial Evidence

Currently no related clinical trials registered for female breast carcinoma.

Literature Evidence

None of the retrieved publications is a randomised trial of hydroxyurea in breast cancer. The most relevant items are listed below.

PMID	Year	Type	Journal	Key Findings
38211596	2024	In-silico/Preclinical	Drug Research	Design of hydroxyurea–lipid conjugates to improve cellular uptake in breast cancer, targeting the PI3K/AKT/mTOR pathway
28837865	2017	Preclinical	DNA Repair	Valproic acid sensitises breast cancer cells to hydroxyurea by inhibiting RPA2 hyperphosphorylation-mediated DNA repair
32795962	2020	Preclinical	DNA Repair	A valproic acid analogue influences RPA2-mediated DNA repair, potentially sensitising breast carcinoma cells to hydroxyurea
21730979	2011	Preclinical	British Journal of Cancer	Novel ATR inhibitor NU6027 evaluated in breast and ovarian cancer cell lines
1957839	1991	Phase I	American Journal of Clinical Oncology	Allopurinol, 5-FU and leucovorin followed by hydroxyurea in 20 patients with advanced gastrointestinal and breast cancer
1733549	1992	Phase I/II	Cancer Chemotherapy and Pharmacology	5-FU, leucovorin, hydroxyurea and escalating cisplatin with radiotherapy in mixed advanced solid tumours
25814515	2015	Preclinical	Molecular Pharmacology	Novel ribonucleotide reductase inhibitor COH29 inhibits DNA repair in BRCA1-defective breast cancer cells
30159181	2018	Case report	Case Reports in Hematology	Management of coexisting breast cancer and essential thrombocythaemia

The remaining retrieved papers were either not specific to hydroxyurea or off-topic.

Australia Market Information

ARTG Number	Product Name	Dosage Form	Approved Indication
ARTG 4281H	Egoderm Cream	Cream 10 mg per g (1%), 50 g	Not stated in the data compiled

The only registered Australian product is a topical hydroxyurea 1% cream. No oral dosage form appears in the data compiled, so the systemic route used for oncology and sickle cell disease is not represented in the ARTG data reviewed here.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (antimetabolite; ribonucleotide reductase inhibitor)
Emetogenicity Classification	Please refer to the Product Information (PI) warnings and precautions
Monitoring Items	Full blood count (with differential), renal function and liver function
Handling Protection	Follow local cytotoxic drug handling requirements

Safety Considerations

Contraindications (TxGNN model (deep learning) output, not label text; may reflect similarities the model learned between related diseases, not biological evidence): kidney disease, pyoureter, thrombocytopenia, anaemia, macrocytic anaemia, leukopenia and cutaneous vasculitis.
Drug Interactions: 100 interactions were identified. Only the severity of levofloxacin (Minor) is classified; the others (for example doxycycline, amphotericin B, hydrocortisone, famotidine, acetylsalicylic acid, pantoprazole, morphine, metformin, omeprazole, vancomycin, prednisone and simvastatin) have no assigned severity level in the source. Review the full interaction list before use.

Please refer to the TGA-approved Product Information (PI) for formal warnings and contraindications.

Other Predicted Indications

Rank	Indication	Score	Evidence Level	Comment
2	Sickle cell-haemoglobin C disease	0.9967	L5	Phase 2 trial NCT00532883 (n=44, terminated) plus a 2025 NEJM Evidence publication (39647172) and cohort studies. No Phase 3 trial is evident. Research question.
3–5	Sickle cell-HbE, sickle cell-HbD, HPFH-sickle cell	0.9967	L5	Only indirect or irrelevant literature. Hold.
6	Sickle cell-beta-thalassaemia	0.9967	L5	Small 1999 clinical trial (10326220); the listed trials are transplant studies, not hydroxyurea trials. Research question.
7–10	Cervical adenosarcoma; colon, rectum and gallbladder mucinous adenocarcinoma	99.28–0.9940	L5	Model prediction only, with no trials or literature. Hold.

Conclusion and Next Steps

Decision: Hold

Rationale: The breast carcinoma prediction rests on a plausible mechanism and preclinical work only. There are no registered trials and no clinical efficacy data, and the Australian product is a topical cream rather than a systemic formulation. Of the predictions, sickle cell-haemoglobin C disease is the strongest candidate for further investigation.

To proceed, the following is needed:

Mechanism of action data to support the mechanistic-link analysis
TGA Product Information warnings and contraindications (a blocking gap for safety screening)
Clinical evidence in breast cancer, such as a well-designed Phase 2 study or a systematic review of existing combination-chemotherapy data
Confirmation of whether a systemic hydroxyurea formulation is available in Australia
For sickle cell-haemoglobin C disease, a review of the 2025 trial and the terminated Phase 2 trial to decide whether it should be prioritised
Disclaimer

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