Analysis of enhancement at small and large radiation doses for effectiveness of inactivation in cultured cells by combining two agents with radiation

Abstract

Purpose: To evaluate the enhancement effect of two combined radiation-sensitizing agents in mammalian cells at small doses as compared to large doses using the linear-quadratic (LQ) mathematical model. Methods and materials: Data on clonogenic assays concerning the radio-enhancement effects of combined halogenated pyrimidines and hyperthermia or combined cisplatin and hyperthermia, as published in earlier reports, were analyzed according to the LQ-formula:). Effects of sensitizing agents on the linear parameter a and the quadratic parameter b are compared in order to evaluate differences depending on the applied dose, the possible relations to mechanisms of radiation sensitization and to derive suggestions for applications. Results: The values of the linear parameter a, which determines the effectiveness at low doses, are for all cell lines and all conditions more increased than the values of the parameter b which has a higher contribution at larger radiation doses. The combination of hyperthermia with halogenated pyrimidines to radiation as well as the combination of hyperthermia and cisplatin to radiation significantly increases the value of the linear parameter a, as compared to radiation alone or radiation combined with a single agent. Conclusions:The radiation enhancement factors of the values of linear and quadratic parameters demonstrate that the sensitizing agents have a larger effect on the linear parameter which is dominant at low radiation doses as is used in fractionated-radiation treatment in the clinic. Moreover, the effect is even further increased when two radiation sensitizers are used. ARTICLE HISTORY

Enhancement of Radiation Effectiveness in Cervical Cancer Cells by Combining Ionizing Radiation with Hyperthermia and Molecular Targeting Agents

“…HT alone had a significant sensitizing effect on the linear parameter, α, in both SiHa and HeLa cells, which has also been shown previously in other cell lines [29,31,33]. In SiHa cells, both PARP1- i and DNA-PKcs- i appeared to be sensitizing agents for low dosages of RT, since the value of the linear parameter was significantly increased (Figure 2).…”

“…Doses up to 3 Gy are commonly used in the clinic in fractionated applications, implying that the effects of these tri-modality treatments studied here, might be effective in the clinic to improve tumor control [31]. It is of interest to assess whether the changes in the values of the LQ parameters can be interpreted in terms of DNA DSBs and in relation to DSB repair.…”

“…In vitro experiments for radiation combined with hyperthermia and another agent have been published in earlier works [14,27,31,42]. Enhancement of radiation by hyperthermia and targeting drugs is expressed by increases in either the value of α and/or the value of β of the LQ formula.…”

“…The radiation dose survival curves can be analyzed using the linear-quadratic (LQ) model: S(D)/S(0) = exp − (αD + βD 2 ) [28,29,30]. The LQ model is a mathematical model defining the relationship between linear (α) and quadratic (β) contributions to cell kill and indicates at which RT dose (Gy) cells or tissues will die [31]. The α determines the initial slope of cell survival curves and the effectiveness at low doses of ionizing radiation, while β represents the increasing contribution from cumulative damage, presumably due to the interaction of two or more lesions induced by separate energy depositions [32].…”