CBLB502 — a toll-like receptor 5 (TLR5) agonist that induces NF-B activation — inhibits apoptosis to protect hematopoietic and gastrointestinal tract cells from the radiation damage associated with radiotherapy.
Toxic side effects of radiotherapy are largely determined by massive apoptosis in the haematopoietic system and/or gastrointestinal tract, thus limiting the dose a patient can receive. Borrowing from the pathways that are mutated in tumour cells to suppress apoptosis, Gudkov, Feinstein and colleagues have made a promising step forward in the hunt for radioprotective agents that could increase the dose — and hopefully the success rate — of radiotherapy.
Activation of the transcription factor NFB reduces the sensitivity of tumour cells to apoptosis and so Gudkov, Feinstein and colleagues investigated whether activation of NFB could protect normal tissues from radiation damage. They injected flagellin — a toll-like receptor 5 (TLR5) agonist that leads to NFB activation — into mice 30 min before total body irradiation (TBI) at lethal doses and found that survival was significantly increased. The dose-modifying factor (the fold change in irradiation dose that is lethal for 50% of animals) was 1.6, which is higher than radioprotective agents currently in clinical use. The authors produced a less toxic and immunogenic derivative of flagellin of comparable activity and stability, CBLB502, and showed that it also increased the survival of primates that were exposed to a lethal dose of radiation. However, radiotherapy regimens are usually fractionated, so the authors treated TLR5+ tumour-bearing mice with fractionated lethal TBI and found that pre-treatment with CBLB502 completely prevented radiation-induced mortality. Importantly, they showed that the tumours were not protected from radiation damage, probably owing to the frequent deregulation of NFB, TLR5 and/or downstream pathways, providing further evidence that CBLB502 might be a viable radioprotective agent.
So, how is radioprotection conferred? Examination of the lamina propria of the small intestine of CBLB502-treated irradiated mice revealed a reduction in the proportion of apoptotic cells, and stem cells of the small intestine crypts and haematopoietic stem cells and progenitors were also protected. In addition, increased expression of NFB target genes, such as superoxide dismutase 2, was evident in the lamina propria, as was the expression of cytokines known to have radioprotective effects (such as GCSF, IL6 and TNF). This indicates that CBLB502 might protect against radiation damage by maintaining the cellularity and morphology of radiosensitive tissues through numerous mechanisms, including the TLR5-dependent activation of NFB.
An obvious concern is that pharmacologically mimicking an anti-apoptotic pathway might itself be carcinogenic, particularly in the presence of DNA damage induced by radiotherapy. However, the rate and frequency of tumour development in the tumour-prone Trp53-/+ mouse model did not increase after CBLB502 pre-treatment and sublethal TBI. In addition, the mice treated with CBLB502 that survived lethal TBI also showed no signs of tumour development after 6 months. Therefore, by activating a common tumour-associated survival mechanism, CBLB502 might effectively confer radioprotection to normal tissues, which could increase the therapeutic ratio of radiotherapy.
Gemma K. Alderton
References
Burdelya, L. G. et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science320, 226–230 (2008) | Article | PubMed |
B activation — inhibits apoptosis to protect hematopoietic and gastrointestinal tract cells from the radiation damage associated with radiotherapy.
). This indicates that CBLB502 might protect against radiation damage by maintaining the cellularity and morphology of radiosensitive tissues through numerous mechanisms, including the TLR5-dependent activation of NF