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The radiation abscopal anti-tumor effect is mediated through p53
226
I. J. Radiation Oncology
2025
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
The Radiation Abscopal Anti-Tumor Effect is Mediated Through p53
K. Camphausen1, M. O’Reilly2, C. Menard1, M. Sproull1, W. Beecken3, J. Folkman3, M. Moses3 1 Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, 2Department of Radiation Oncology, MD Anderson, Houston, TX, 3Department of Surgery, Children, Boston, MA
Purpose/Objective: The abscopal effect, a term coined by Mole, is an anti-tumor effect observed at a site distant to that irradiated within the same organism. We hypothesized that this effect could be demonstrated in mice, and may be mediated by p53. To investigate this further, we irradiated the normal leg of C57Bl/6 and p53 null mice that were distally implanted with xenografts of Lewis lung carcinoma (LLC) and T241 cells. Materials/Methods: LCC and T241 cells were subcutaneously implanted in the dorsum of C57Bl/6 and p53 null mice. The animals were placed in a 3.5cm block of lead, shielding the body to receive 0.3% of the dose delivered to the normal irradiated leg (verified by TLD). Animals received a range of dose schedules of radiotherapy to the leg or were sham irradiated in the control group. Every third day, dorsal tumors were measured with calipers and animal weights were obtained. Results: In the first experiment C57BL/6 mice (n⫽5/group) were implanted with LLC and irradiated with 10Gy*5 fractions to the right leg or sham irradiated. Tumors in irradiated mice grew more slowly than those in the sham irradiated group, 2200mm3 versus 6000mm3 at day 18 post-implantation, respectively. This abscopal effect was radiation dose dependent, as a smaller effect was observed when the experiment was repeated with a third group using a lower dose schedule (2Gy ⫻ 12 fractions). The tumor volumes at day 15 were 400 mm3 versus 2060mm3 (10Gy*5 versus 2Gy*12), and the weights in each group were comparable if tumor weight/ body weight were combined. The abscopal effect was reproduced with T241, a second murine tumor cell line (1750mm3 versus 5000mm3). The abscopal effect was not observed with low dose whole animal radiation to simulate the scatter whole body dose received during our experiments. The abscopal effect was also not seen when p53 null mice (day 20, 5800mm3 versus 6500mm3) or mice treated with pifthrin-alpha, a p53 blocker, (day 16, 3500mm3 versus 4700mm3) were irradiated. Conclusions: We have demonstrated that there is a radiation abscopal anti-tumor effect in C57BL/6 mice implanted with either LLC or T241 tumors that is dose dependent, and independent of weight loss or scatter radiation. The effect is not seen in p53 null animals and may be mediated, at least in part, through an up-regulation of p53.
2026
The Relative Biological Effectiveness of High Dose Rate Cf-252 Neutrons: A Parameter-Based Radiobiological Model
L.J. Stapleford, M.J. Rivard, A. Mahajan, D.E. Wazer Department of Radiation Oncology, Tufts-New England Medical Center, Boston, MA Purpose/Objective: Knowledge of the relative biological effectiveness (RBE) of high dose rate (HDR) californium-252 (Cf-252) neutrons is necessary preceding clinical implementation of this new modality. Though high-linear energy transfer (high-LET) radiation has been demonstrated to offer increased survival rates for some types of cancers, high-LET radiation is not readily available due to the cost and sophisticated maintenance required for clinical devices such as cyclotrons and particle accelerators. Availability of a HDR Cf-252 brachytherapy remote afterloading device would improve availability of this type of radiation, and we hypothesize that a HDR Cf-252 treatment delivery system will have many significant advantages over currently available radiation treatment delivery systems such ad HDR Ir-192 and LDR Cf-252: 1. 2. 3. 4. 5. 6.
accessibility to previously inaccessible anatomic sites within the patient, decreased dose delivery to both the patient and hospital staff, decreased treatment times, decreased treatment costs, lower toxicities, and increased survival.
Materials/Methods: The linear-quadratic model, ln(S)⫽-(␣D⫹D2), characterizing cell survival following irradiation was used as the basis for the studies performed herein. Total equivalent dose, DT-EQ, was related to the sum of gamma and neutron dose components modified with the appropriate RBE factor: DT-EQ⫽ RBEG DG ⫹ RBEN DN. While the proportion of gamma:neutron dose varies as a function of distance from the source and as a function of the material, we start off with DG ⫽ 1/2 DN for clinical applications. Since RBE is the ratio of doses needed to achieve a given biologic effect, we define the effect as identical cell survival: ln(SG) ⫽ ln(SN), -(␣GDG⫹GDG2) ⫽ -(␣NDN⫹NDN2). One can readily rearrange the terms to glean: GDG2 ⫹ ␣GDG–(␣NDN ⫹ NDN2) ⫽ 0. Applying the quadratic equation, DT-EQ is solved which permits direct derivation of RBEN. Results: Using radiobiological parameter values of ␣G⫽0.21Gy-1, G⫽0.035Gy-2, ␣N⫽0.71Gy-1, and N⫽0.078Gy-2 with a clinically appropriate DT-EQ of 6 Gy, we found RBEN ⬃3. This RBE value did not significantly vary with large changes in all 4 parameters and DN. Furthermore, RBEN for high dose rate Cf-252 neutrons did not significantly differ from that typically used for teletherapy neutron sources. Conclusions: A parameter-based radiobiological model was developed that determined RBEN as required for clinical implementation of HDR Cf-252 brachytherapy. Agreement of RBEN with that used for clinical teletherapy neutron sources supports our model.
I. J. Radiation Oncology
2025
● Biology ● Physics
Volume 54, Number 2, Supplement, 2002
The Radiation Abscopal Anti-Tumor Effect is Mediated Through p53
K. Camphausen1, M. O’Reilly2, C. Menard1, M. Sproull1, W. Beecken3, J. Folkman3, M. Moses3 1 Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, 2Department of Radiation Oncology, MD Anderson, Houston, TX, 3Department of Surgery, Children, Boston, MA
Purpose/Objective: The abscopal effect, a term coined by Mole, is an anti-tumor effect observed at a site distant to that irradiated within the same organism. We hypothesized that this effect could be demonstrated in mice, and may be mediated by p53. To investigate this further, we irradiated the normal leg of C57Bl/6 and p53 null mice that were distally implanted with xenografts of Lewis lung carcinoma (LLC) and T241 cells. Materials/Methods: LCC and T241 cells were subcutaneously implanted in the dorsum of C57Bl/6 and p53 null mice. The animals were placed in a 3.5cm block of lead, shielding the body to receive 0.3% of the dose delivered to the normal irradiated leg (verified by TLD). Animals received a range of dose schedules of radiotherapy to the leg or were sham irradiated in the control group. Every third day, dorsal tumors were measured with calipers and animal weights were obtained. Results: In the first experiment C57BL/6 mice (n⫽5/group) were implanted with LLC and irradiated with 10Gy*5 fractions to the right leg or sham irradiated. Tumors in irradiated mice grew more slowly than those in the sham irradiated group, 2200mm3 versus 6000mm3 at day 18 post-implantation, respectively. This abscopal effect was radiation dose dependent, as a smaller effect was observed when the experiment was repeated with a third group using a lower dose schedule (2Gy ⫻ 12 fractions). The tumor volumes at day 15 were 400 mm3 versus 2060mm3 (10Gy*5 versus 2Gy*12), and the weights in each group were comparable if tumor weight/ body weight were combined. The abscopal effect was reproduced with T241, a second murine tumor cell line (1750mm3 versus 5000mm3). The abscopal effect was not observed with low dose whole animal radiation to simulate the scatter whole body dose received during our experiments. The abscopal effect was also not seen when p53 null mice (day 20, 5800mm3 versus 6500mm3) or mice treated with pifthrin-alpha, a p53 blocker, (day 16, 3500mm3 versus 4700mm3) were irradiated. Conclusions: We have demonstrated that there is a radiation abscopal anti-tumor effect in C57BL/6 mice implanted with either LLC or T241 tumors that is dose dependent, and independent of weight loss or scatter radiation. The effect is not seen in p53 null animals and may be mediated, at least in part, through an up-regulation of p53.
2026
The Relative Biological Effectiveness of High Dose Rate Cf-252 Neutrons: A Parameter-Based Radiobiological Model
L.J. Stapleford, M.J. Rivard, A. Mahajan, D.E. Wazer Department of Radiation Oncology, Tufts-New England Medical Center, Boston, MA Purpose/Objective: Knowledge of the relative biological effectiveness (RBE) of high dose rate (HDR) californium-252 (Cf-252) neutrons is necessary preceding clinical implementation of this new modality. Though high-linear energy transfer (high-LET) radiation has been demonstrated to offer increased survival rates for some types of cancers, high-LET radiation is not readily available due to the cost and sophisticated maintenance required for clinical devices such as cyclotrons and particle accelerators. Availability of a HDR Cf-252 brachytherapy remote afterloading device would improve availability of this type of radiation, and we hypothesize that a HDR Cf-252 treatment delivery system will have many significant advantages over currently available radiation treatment delivery systems such ad HDR Ir-192 and LDR Cf-252: 1. 2. 3. 4. 5. 6.
accessibility to previously inaccessible anatomic sites within the patient, decreased dose delivery to both the patient and hospital staff, decreased treatment times, decreased treatment costs, lower toxicities, and increased survival.
Materials/Methods: The linear-quadratic model, ln(S)⫽-(␣D⫹D2), characterizing cell survival following irradiation was used as the basis for the studies performed herein. Total equivalent dose, DT-EQ, was related to the sum of gamma and neutron dose components modified with the appropriate RBE factor: DT-EQ⫽ RBEG DG ⫹ RBEN DN. While the proportion of gamma:neutron dose varies as a function of distance from the source and as a function of the material, we start off with DG ⫽ 1/2 DN for clinical applications. Since RBE is the ratio of doses needed to achieve a given biologic effect, we define the effect as identical cell survival: ln(SG) ⫽ ln(SN), -(␣GDG⫹GDG2) ⫽ -(␣NDN⫹NDN2). One can readily rearrange the terms to glean: GDG2 ⫹ ␣GDG–(␣NDN ⫹ NDN2) ⫽ 0. Applying the quadratic equation, DT-EQ is solved which permits direct derivation of RBEN. Results: Using radiobiological parameter values of ␣G⫽0.21Gy-1, G⫽0.035Gy-2, ␣N⫽0.71Gy-1, and N⫽0.078Gy-2 with a clinically appropriate DT-EQ of 6 Gy, we found RBEN ⬃3. This RBE value did not significantly vary with large changes in all 4 parameters and DN. Furthermore, RBEN for high dose rate Cf-252 neutrons did not significantly differ from that typically used for teletherapy neutron sources. Conclusions: A parameter-based radiobiological model was developed that determined RBEN as required for clinical implementation of HDR Cf-252 brachytherapy. Agreement of RBEN with that used for clinical teletherapy neutron sources supports our model.