One of the most challenging aspects in realising the full potential of ionising radiation for the treatment of cancer has been its side effects - damage to healthy cells. In April this year, a team of scientists led by L G Burdelya of the Roswell Park Cancer Institute, New York, announced an experimental drug, which promises to protect healthy cells without interfering with the action of radiation on the tumour. A single dose of the drug named CBLB502 protected both mice and monkeys from what could have been lethal doses of radiation. This is of particular interest to oncologists here, since most of the cancer cases reported are in advanced stages, requiring aggressive therapeutic approaches.

Gastrointestinal tract, bone marrow, liver, spleen are some of the highly radiosensitive organs in the body. The seriousness of the problem may be seen from the fact that a total body irradiation (TBI) of four to six gray (gray is a unit of radiation dose) can be lethal to 50 per cent of the population. However, in cancer therapy, tumours are irradiated to doses as high as 30 to 50 gray or even more, thus exposing the nearby healthy tissues to high levels of radiation. This has been a major hurdle in the success of the radiotherapy of cancer.

Radiation acts through the production of free radicals. Free radicals are chemical species with an unpaired electron and hence highly reactive. They attack vital molecules like the DNA in the cell. Cells have a capacity to repair damage to DNA. However, if the damage is too severe, then a biochemical pathway called apoptosis is triggered, which makes the cells commit suicide. This is body's way to prevent defective cells from proliferating. The researchers found that healthy cells over-react to radiation damage and take to apoptosis.

Several approaches have been tried in the past to overcome this problem. Antioxidants to scavenge free radicals before they attack the DNA, cytokines that stimulate tissue regeneration, inhibitors of energy metabolism, etc. have been tried as adjutants to radiotherapy to protect healthy cells. However, there has not been much success. The only drug that has been found to be of some application is Amifostine. 

Now researchers at Roswell Park have mimicked one of cancer cells’ own tricks to increase the radiation tolerance of healthy cells.

What is CBLB502?

Cancer cells block apoptosis, despite carrying mutated DNA, enabling them to proliferate indefinitely. They do this by activating a family of transcription factors known as nuclear factor - kappa B (NF-kB). NF-kB not only inhibits apoptosis, but also activates free radical scavengers and cytokines. Earlier, many scientists tried to inhibit this activation in tumour cells so that they commit suicide, but without success. The Roswell Park researchers tried the other way - help normal cells survive the radiation damage by triggering in them the NF-kB.

In earlier experiments, they had observed that micro flora could activate NF-kB in gut cells in response to infectious agents. This plays a protective role in the GI tract. In this activation, a protein called flagellin, present on the whip-like tail of the bacteria, binds to another protein TLR 5 present on the surface of gut cells to trigger the activation of NF-kB. However, in vitro experiments they found that flagellin was toxic to cells. Hence, they prepared a derivative of the protein using recombinant DNA technique in bacteria E.coli. This derivative, dubbed as CBLB502, could not only bind to TLR5 to activate NF-kB but was half as toxic as flagellin.

To test the effectiveness of CBLB502 in protecting healthy tissues against radiation damage the researchers administered the drug at various periods to mice and exposed them to total body irradiation of 10 and 13 gray. At these doses, all the animals would die within 30 days due to lethal damage in hematopoietic and gastrointestinal systems. The drug injected as a single dose of less than one per cent of the maximum tolerated dose at 30 minutes before irradiation, provided excellent survival benefits. The 30-day post irradiation survivals were as high as 85 and 70 per cent respectively. At lower radiation doses, the drug provided protection even when administered as early as 24 hours before or one hour after TBI.

Similarly, non-toxic levels of the drug injected 30 minutes before TBI protected monkeys which otherwise would have died of radiation sickness.

Further experiments with tumour bearing mice demonstrated that the drug would not interfere with the actual treatment of cancer with radiation. There were no obvious side effects of the drug. Suppression of apoptosis itself carries the risk of cancer. However, there were no more second cancers in the animals that survived lethal radiation, than in those animals that did not receive the drug. Hence, many oncologists feel that the drug has scope for use as an adjuvant in the radiotherapy of cancers to protect healthy tissues.

The drug is now ready for human trials. If found successful, oncologists will be able to prescribe higher radiation doses for more effective cancer cure, than has been possible until now.

The drug also fulfils another long-standing requirement - an antidote during nuclear emergencies. Until now, there has been no effective biological protection for rescue workers who enter high radiation areas as in a nuclear reactor accident, explosion of nuclear weapons or dirty bombs, etc. It may be recalled that 31 persons died of radiation injuries while fighting fire during the Chernobyl nuclear reactor accident. A drug of this type could have saved their lives.