Pyrimethamine reduced tumour growth in pre-clinical cancer models: a systematic review to identify potential pre-clinical studies for subsequent human clinical trials

Sivananthan Manoharan; Lee Ying Ying

doi:10.1093/biomethods/bpae021

Pyrimethamine reduced tumour growth in pre-clinical cancer models: a systematic review to identify potential pre-clinical studies for subsequent human clinical trials

Biol Methods Protoc. 2024 Mar 29;9(1):bpae021. doi: 10.1093/biomethods/bpae021. eCollection 2024.

Authors

Sivananthan Manoharan¹, Lee Ying Ying²

Affiliations

¹ Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Shah Alam 40170, Selangor, Malaysia.
² Department of Biomedical Sciences, Asia Metropolitan University, Johor Bahru 81750, Johor, Malaysia.

Abstract

Pyrimethamine (PYR), a STAT3 inhibitor, has been shown to reduce tumour burden in mouse cancer models. It is unclear how much of a reduction occurred or whether the PYR dosages and route of administration used in mice were consistent with the FDA's recommendations for drug repurposing. Search engines such as ScienceDirect, PubMed/MEDLINE, and other databases, including Google Scholar, were thoroughly searched, as was the reference list. The systematic review includes fourteen (14) articles. The risk of bias (RoB) was assessed using SYRCLE's guidelines. Due to the heterogeneity of the data, no meta-analysis was performed. According to the RoB assessment, 13/14 studies fall into the moderate RoB category, with one study classified as high RoB. None adhered to the ARRIVE guideline for transparent research reporting. Oral (FDA-recommended) and non-oral routes of PYR administration were used in mice, with several studies reporting very high PYR dosages that could lead to myelosuppression, while oral PYR dosages of 30 mg/kg or less are considered safe. Direct human equivalent dose translation is probably not the best strategy for comparing whether the used PYR dosages in mice are in line with FDA-approved strength because pharmacokinetic profiles, particularly PYR's half-life (t_1/2), between humans (t_1/2 = 96 h) and mice (t_1/2 = 6 h), must also be considered. Based on the presence of appropriate control and treatment groups, as well as the presence of appropriate clinically proven chemotherapy drug(s) for comparison purposes, only one study (1/14) involving liver cancer can be directed into a clinical trial. Furthermore, oesophageal cancer too can be directed into clinical trials, where the indirect effect of PYR on the NRF2 gene may suppress oesophageal cancer in patients, but this must be done with caution because PYR is an investigational drug for oesophageal cancer, and combining it with proven chemotherapy drug(s) is recommended.

Keywords: STAT3; animal models; cancer; clinical trial; pyrimethamine; systematic review.

Publication types

Review