Some Modifiers of Dose-Response Relationships

Abstract

1. DNA is the main target for the radiation-induced cell death. Of all the DNA molecular lesions, double strand break (DSB) is the one most likely to evolve into a lethal lesion. DSBs are either repaired or interact with each other to form a composite lesion leading to a lethal event. The a-type of the linear-quadratic equation requires a concentrated deposition of energy. It is the type of damage that dominates the effect of high LET radiations and small doses or low dose-rate low-LET radiation. 2. The intrinsic sensitivity can be described in terms of the surviving fraction after 2 Gy, the most commonly used fraction size in clinical practice. Reduction in the surviving fraction in tumours after such a dose is mainly due to the a-component. Its dominant role is further amplified after multifraction irradiation leaving to the 0-type of damage a trivial role. 3. A large number of agents capable of inhibiting the recovery of radiation-induced damage has been experimentally tested and some were also tested in man. A modest reduction in the surviving fraction after a single dose may be amplified during fractionated irradiation. This may be of therapeutic value if there is no parallel enhancement of normal tissue damage. 4. Phase-specific fluctuations in radiosensitivity are known to occur with a tendency for increased sensitivity at the G1/S and G2/M boundaries probably associated with changes in the degree of chromatin compactness. 5. Oxygen owes its radiation enhancement effect to its electron affinity and to the competition with H-donors for reacting with damaged sites. Oxygen enhances the s-type of damage more than the a-type. At low doses and with low dose-rate irradiation where the a-damage dominates, the oxygen enhancement ratio (0ER) has a low limiting value of about 2.0 and it increases to about 3.0 in the high dose region. Owing to the overwhelming predominance of a-dage with high LET radiations, a low OER is found (e.g. 1.7 in the case of fast neutrons). 6. Glutathione (GSH) competes with oxygen for interacting with damaged sites. Depletion of cellular thiols en- hances the radiosensitivity of hypoxic cells. They can also sensitize aerobic cells presumably due to detoxification of the organoperoxides formed through the combination of oxygen with damaged sites. GSH also detoxicates some alkylating and antibiotic chemotherapeutic agents and thus interferes with their cytotoxicity. A high cellular GSH may contribute to chemoresistance. 7. The clinical use of aminothiols (e.g. WR-2721) as normal tissue protector is limited by its cumulative toxicity and the possibility of a reduced protection of normal tissues and the exertion of some degree of tumour protection when small doses are used. 8. High-LET radiation enhances a-more than s-damage and eliminates the shoulder on the low-LET radiation dose-survival curve in addition to increasing its steepness. For low-LET radiations late reacting tissues have a broad-shouldered dose-survival curve and would then show a greater degree of damage sparing in multifractionation compared with early reacting tissues. This sparing is lost when high-LET radiations are used. High-LET radiations reduce the differences in radiosensitivity in the different phases of the cell cycle. Slowly growing tumours having a large proportion of their cells in the radioresistant G1-phase are, therefore, expected to respond better to high-LET radiations. This could be confirmed in salivary gland tumours and cancer of the prostate. 9. The cell killing effect of hyperthermia is complemen- tary to radiotherapy since it can kill S-phase and hypoxic cells. Normal tissues may lose heat faster than the more poorly vascularized tumours and this may produce a differential effect. In addition, heat may enhance radiation damage through inhibition of sublethal and potentially lethal damage repair. The clinical use of heat and radiotherapy in combination is limited by the problem of thermotolerance and enhancement of damage to normal tissues. When heat is, however, given 3–4 hours after irradiation the normal tissue enhancement would fade with some extra response in tumours.