A variety of approaches have been developed for diminishing the effects of radiation on normal tissues of enhancing tumour cell killing by ionizing radiations. Strategies will provide a therapeutic gain in radiation therapy. Results obtained with model systems do not always apply to more complicated biological systems. Many of these compounds have multiple pharmacological actions, which are sometimes antagonistic.
Most often, agents have been tested clinically at sub optimal doses because of limiting toxicities, the possibility that radioprotectors could protect the tumour makes it difficult to test radioprotectors in the clinic. Unless the rationale for selective radioprotection of normal tissues or radio sensitization of the tumour is foolproof, there is a risk in clinical testing, since the clinical impact is often not known for several years.
Nevertheless, several clinical trials are in progress, mostly with sensitizers, and substantial new information is expected from these trials within the next few years.
Several problems make it particularly difficult to develop clinical strategies for modification of radiation therapy. One problem is selective and effective drug delivery. Many of these compounds are metabolized or chemically altered before they reach the target cells. Electron-affinic hypoxic cells. Radiosensitisers or bioreductive drugs that are excellent in vitro can be metabolically inactivated before they reach the hypoxic tumor cells.
Reducing agents that might be excellent protectors in vitro can be inactivated by oxidation in vivo. Tumor vasculature is chaotic, creating problems in drug delivery. The intermittent vascular occlusion that creates problems in drug delivery is the same phenomenon that creates the hypoxic areas that need to be sensitized.
Selective drug delivery to the tumour is a difficult problem. Boron neutrons capture therapy, for example, depends entirely on selective uptake of the sensitizer in the tumor, and animal studies have suggested that this can be achieved, but the clinical results have not been as impressive. It is not enough to deliver more sensitizer to the tumour - it needs to be delivered to all the target cells in the tumor. The exponential relationship between dose and cell killing means that an equal increment in radiation dose is required for each log of cell kill. It is therefore of little use to sensitize 90% or 99% of the cells - this only decreases the dose necessary to kill the first log or two of cells, but has no impact on the remaining 107 and 108 cells.
The situation in normal tissues is the reverse. It is not enough to protect some of the cells in the normal tissue because tissue damage can occur even if a small subset of these cells are killed, if their function is vital. In the case of early boron neutron capture trials, it appears that accumulation of the sensitizer in the normal tissue vasculature negated the potential therapeutic gain that was expected from lower overall sensitizer concentrations in the normal tissue.
Despite the problems, the outlook for radiation modifiers is good. The radiation dose - response relationships for both tumor cure and normal tissue damage are steep, so that the challenge for modifiers is not too great - even a 20% shift in either response curve should have a large impact of clinical results. The classical view of the mechanism of action of ionizing radiation is that all of the biological effects can be accounted for by cell killing that results from clustered DNA lesions. That particular mechanism does not lend itself easily to differential modification of tumors and normal tissues, since the radiation chemistry is the same in both cases, with the exception that hypoxic tumor cells can be targeted with specific strategies.
However, it is now recognized that ionizing radiation produces subtle change in cell function, in addition to classical reproductive cell death, and that these other effects of radiation may be modified with agents that do not affect classical reproductive cell death.
Cytokine cascades persist for months after radiation, possibly contributing to tissue fibrosis, as a pathogenic mechanism, Dittman et al have suggested that radiation - induced differentiation of progenitor fibroblasts could be related to the development of tissue fibrosis, and they have found that the Bowman-Birk proteinase inhibitor can inhibit radiation - induced premature differentiation of these cells. Delayed mutagenesis and cell death that occurs many cell divisions postirradiation could be due to an induced hypermutability. There are indications that mutagenesis may be inhibitable with strategies that would not affect the formation of clustered DNA lesions that are though to be responsible for classical reproductive cell death. Apoptosis is a regulated mechanism of cell death that occurs in certain cell types more than others, and can be modified with agents that do not affect classical reproductive cell death. Vascular effects of radiation may be mediated in part by bioactive products that can be specifically antagonized.
The implication of these new findings is that new types of modifiers can be developed that target a specific aspect of the mechanism of action of ionizing radiation. If the mechanism is more important to normal tissue than to the tumor, or vice-versa, the modifiers would not have to be delivered differentially and selectivity would be achieved by mechanistic differences. Selective and effective drug delivery is still awaiting.
-- The author is with Noorie College of Pharmacy, Andersonpet, KGF, Karnataka