Table 4.

Summary of novel radiosensitizing agents

Reference	Study design	Findings
COX‐2 inhibitors	Cox‐2 is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in epithelial malignancy tumours101. It is involved in the regulation of apoptosis, angiogenesis and tumour cell invasiveness. Preclinical studies suggest the potential of COX‐2 inhibitors as selective radiosensitizers102
Debucquoy et al.103	Double‐blind randomized phase II; in addition to 5‐FU; 35patients	Improved downstaging No increased toxicity
Nanoparticles	Aim to improve the therapeutic index of chemoradiotherapy and overcome potential systemic excess toxicity. Focus on particle size sub‐50 nm
Caster et al.104	Particles 50, 100 and 150 nm in size loaded with 2 DNA repair inhibitor model drugs in colorectal cancer cell lines	All sizes potent radiosensitizers Good toxicity tolerance
Tian et al.105	CRLX101 in combination with oxaliplatin and 5‐FU	Increased efficacy of chemoradiotherapy Early stage; needs expansion
Histone deacetylase inhibitors	Emerging therapeutic concept attempting to target epigenetic regulatory mechanisms and act as a radiosensitizer in combination therapy. SAHA approved as a single agent for refractory cutaneous T‐cell lymphoma
Folkvord et al.106	Preclinical study of SAHA using 2 xenograft models	In vitro: improved radiosensitivity (P ≤ 0·050) across cell lines at all radiation doses less than 6 h after exposure In vivo: pCR achieved in 1 model
Saelen et al.107	Vorinostat assessed under hypoxic conditions in vitro	Enhanced radiosensitivity across cell lines Warrants further research
Small molecular inhibitors	Low molecular weight; able to target both extracellular and intracellular proteins
Kleiman et al 108	Preclinical Focus on radiosensitizers for KRAS mutant tumours 28 known radiosensitizers assessed	6 effective; AZD7762 most highly potent Suggested investigation into role of CHK2 inhibitors
Nelfinavir	HIV protease inhibitor; inhibits Akt at standard clinical doses and results in radiosensitivity
Hill et al.109	Non‐randomized SONATINA clinical trial focusing on safety in 10 patients with T3–4 N0–2 M1 rectal cancers recruited over 2 years 14 days total oral treatment (7 days preoperative)	2 discontinued owing to toxicity 5 grade 3 toxicity Warrants further research
Buijsen et al.110	Phase I trial including 12 patients Escalating doses with capecitabine Primary endpoint: dose‐limiting toxicity	4 of 6 experienced toxicity, precluding further dose escalation pCR 27% Further toxicity concerns
Zerumbone	Cyclic sesquiterpene from rhizomes of edible ginger plant; emerging evidence of potential for inhibition of proliferation of human colonic adenocarcinoma cells, with minimal toxicity111
Deorukhkar et al.112	3 colorectal cancer cell lines Inhibition of proliferation identified in dose‐dependentmanner	Marked radiosensitizer in clonogenic survival curves Little effect on normal fibroblasts Warrants further research
Bortezomib	Modified dipeptidyl boronic acid derived from leucine and phenylalanine that acts as a 26S proteasome inhibitor. The ubiquitin–proteasome pathway is involved in intracellular protein degradation in eukaryotic cells
O'Neil et al.113	10 patients with stage II or III rectal cancer received 5‐FU‐based chemoradiotherapy plus bortezomib twiceper week	pCR 10% High toxicity – diarrhoea Study not progressed

COX, cyclo‐oxygenase; 5‐FU, 5‐fluorouracil; SAHA, suberoylanilide hydroxamic acid; pCR, pathological complete response; CHK2, serine–threonine kinase 2; HIV, human immunodeficiency virus.