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5. Identification and characterization of three subtypes of radiation response in normal human urothelial cultures exposed to ionizing radiation.

Author

Mothersill, C E, O'Malley, K J, Murphy, D M, Seymour, C B, Lorimore, S A, and Wright, E G

Abstract

In an attempt to assess genetic variation underlying the variation in human responses to radiation exposure, measurements of apoptosis, necrosis and induction of key proteins were made in primary explant cultures of human normal urothelium and correlated with growth post- exposure to a range of doses of (60)Co. These data were validated by similar experiments using CBA/H and C57/BL6 mouse strains, known to exhibit genetically determined differences in response to radiation. The data for human tissues show a wide variation in response with three broad categories being identifiable. The commonest had a hypersensitive response involving considerable apoptosis in the low dose region, followed by 'induction' of a survival response at higher doses involving the persistence of abnormal cells. The pattern of gene expression was consistent with suppression of apoptosis. The second category showed no induction of survival and considerable necrosis was seen in the progeny. The rarest category showed an extremely hypersensitive low dose response and despite induction of a survival response, the sensitivity to higher doses was very severe. Considerable apoptosis and necrosis were seen in these cultures. In the mouse experiments, strain CBA/H (mice known to exhibit genetic instability post-irradiation) had lower levels of delayed cell death and apoptosis than C57/BL6 mice (which exhibit significantly less instability). It is concluded that there is a variation in response to radiation between human patient cultures which is detectable in this system and which is consistent with a pattern of radiation- induced delayed death/apoptosis correlating with long-term genomic stability. The mouse experiments demonstrate the importance of genetic factors in determining these responses.

Published
1999
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6. DOSE CALCULATIONS FOR [131I] META-IODOBENZYLGUANIDINEINDUCED BYSTANDER EFFECTS.

Author

Gow, M. D., Seymour, C. B., Boyd, M., Mairs, R. J., Prestiwch, W. V., and Mothersill, C. E.

Subjects
*CANCER radiotherapy, *RADIOBIOLOGY, *ABSORBED dose, *CELL lines, *CONTROL groups, *RADIOPHARMACEUTICALS, *NORADRENALINE regulation
Abstract

Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier - Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 - 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 - 0.75 Gy/h for UVW/NAT and 0.07 - 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 - 0.23 Gy for UVW and 0.03 - 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander doseresponse profile similar to that generated by external beam gamma irradiation but with significantly greater cell death. [ABSTRACT FROM AUTHOR]

Published
2014
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7. Induction of bystander response in human glioma cells using high-energy electrons: a role for TGF-beta1.

Author

Gow MD, Seymour CB, Ryan LA, and Mothersill CE

Subjects
Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Cell Death radiation effects, Cell Line, Tumor, Cell Survival drug effects, Cell Survival radiation effects, Culture Media, Conditioned metabolism, Dose-Response Relationship, Radiation, Humans, Transforming Growth Factor alpha immunology, Transforming Growth Factor alpha metabolism, Transforming Growth Factor beta1 immunology, Bystander Effect radiation effects, Electrons, Glioma pathology, Transforming Growth Factor beta1 metabolism
Abstract

We examined bystander cell death produced in T98G cells by exposure to irradiated cell conditioned medium (ICCM) produced by high-energy 20 MeV electrons at a dose rate of 10 Gy min(-1) and doses up to 20 Gy. ICCM induced a bystander response in T98G glioma cells, reducing recipient cell survival by more than 25% below controls at 5 and 10 Gy. Higher doses increased survival to near control levels. ICCM was analyzed for the presence of transforming growth factor alpha (TGF-alpha) and transforming growth factor beta1 (TGF-beta1). Monoclonal antibodies for TGF-alpha (mAb TGF-alpha) and TGF-beta1 (mAb TGF-beta1) were added to the ICCM to neutralize any potential effect of the cytokines. The results indicate that TGF-alpha was not present in the ICCM and addition of mAb TGF-alpha to the ICCM had no effect on bystander cell survival. No active TGF-beta1 was present in the ICCM; however, addition of mAb TGF-beta1 completely abolished bystander death of reporter cells at all doses. These results indicate that bystander cell death can be induced in T98G glioma if a large enough radiation stress is applied and that TGF-beta1 plays a downstream role in this response.

Published
2010
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