Pharmacological Enhancement of Radiosurgery Response: Studies on an in Vitro Model System

Newton, C. J.; Schlatterer, Kathrin; Stalla, GK; Angerer, E. von; Kreiner, H.J.; Wowra, Berndt

doi:10.1023/b:jora.0000010877.65003.31

Cited by 9 publications

(10 citation statements)

References 20 publications

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“…As we have suggested earlier, our observations might provide the explanation for our recent findings that ZM 182780 increased the sensitivity of breast tumour cells to gamma radiation exposure (Newton et al 1998). The current work also raises the question as to whether pure antioestrogens enhance the effect of ROS generating agents in other ER containing tumour cell types, such as the breast.…”

Section: Figuresupporting

confidence: 78%

“…A major premise on which these studies were conducted was that ROS have been shown to have a role in several human diseases, amongst which notable examples are Alzheimer's (Coyle & Puttfarcken 1993) and atherosclerosis (Diaz et al 1997). This was reinforced by our recent demonstration that ZM 182780 enhances sensitivity to gamma irradiation (Newton et al 1998), a treatment modality known to induce ROS (Datta et al 1992). ROS are formed within cells as a fundamental consequence of an aerobic environment.…”

Section: Discussionmentioning

confidence: 99%

“…Given the potential importance of these findings with regard to the treatment of oestrogen dependent tumours, such as those of the pituitary and indeed those of the breast, we have sought to determine the mechanism for this effect. Most recently we have provided evidence that ZM 182780 enhances sensitivity to gamma irradiation of breast tumour cells (Newton et al 1998). As it is well established that reactive oxygen species (ROS) are mediators of radiation-induced cell death (Datta et al 1992), we have sought to determine the role that these agents play in the death of cells due to functional ER ablation by ZM 182780.…”

Section: Introductionmentioning

confidence: 99%

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Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species

Newton

Drummond

Burgoyne

et al. 1999

Journal of Endocrinology

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Reactive oxygen species (ROS) play a fundamental role in both apoptotic and necrotic cell death. Their importance is highlighted by studies showing that they mediate cell death in response to radiotherapy and to some forms of chemotherapy. Here we provide the first evidence for a role of ROS in response to an antiendocrine agent currently undergoing clinical trials. Using the oestrogen receptor (ER) containing rat pituitary GH 3 cell line, we show that cell death is induced by the pure steroidal antioestrogen, ZM 182780, and that this is blocked by the antioxidant, N-acetyl cysteine (NAC). By flow cytometry, we show that, prior to the onset of DNA breakdown measured by ELISA, ZM 182780 exposure has no significant effect on intracellular oxidant concentrations. In contrast, ZM 182780 exposure greatly increases sensitivity to oxidants generated by blocking cellular antioxidant pathways and from exogenous administration of hydrogen peroxide (H 2 O 2 ). As both necrosis and apoptosis are controlled by mitochondrial function, further experiments conducted to determine mitochondrial membrane potential ( m ) have indicated that the ZM 182780-induced loss of ER function increases the ease with which oxidants collapse mitochondrial activity and, as a consequence, cell death.

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Section: Figuresupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species

Newton

Drummond

Burgoyne

et al. 1999

Journal of Endocrinology

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“…Newton et al (1998) (1996) MCF-7 Villalobos et al (1995) MCF-7 BUS + 3* Estradiol + Villalobos et al (1996) MCF-7 BUS + 3* Estradiol Paulsen et al (1996) MCF-7 Sarkaria et al (1994) MCF-7 + 5* 4OH-TAM No interaction Newton et al (1998) MCF-7 + 1 Tamoxifen + ZM 182780 + Interaction: + , increased sensitivity to ionizing irradiation; − , decreased sensitivity to ionizing irradiation. *Phenol red-free medium and charcoal-stripped bovine serum.…”

Section: In Vitro Experiments On the Interaction Of Estrogens Anti-ementioning

confidence: 99%

“…It should be kept in mind that in vitro conditions such as the presence of phenol red or fetal bovine serum might mimic estrogenic activity on the cells. Some studies have been performed in the presence of one or both of these factors (Wazer et al 1989, Böhning et al 1996, Paulsen et al 1996, Newton et al 1998, others have used charcoal-stripped calf serum and phenol-free media (Sarkaria et al 1994, Villalobos et al 1995. The in vitro action of tamoxifen is dependent on the presence of estradiol in the medium.…”

mentioning

confidence: 99%

Interactions between radiation and endocrine therapy in breast cancer.

Schmidberger¹,

Hermann²,

Hess³

et al. 2003

Endocrine-Related Cancer

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Adjuvant radiotherapy and adjuvant endocrine therapy are commonly given to patients with invasive breast cancer or with ductal carcinoma in situ (DCIS). Although both therapies have been well established through a number of randomized studies, little is known about a possible interaction of both treatment modalities if they are given simultaneously. A number of in vitro studies have indicated that tamoxifen treatment might reduce the intrinsic radiosensitivity of MCF-7 breast cancer cells. Conversely, estradiol treatment increases the intrinsic radiosensitivity of MCF-7 cells. In one available animal study, an antagonistic effect of tamoxifen and ionizing radiation (XRT) could not be observed. Retrospective analyses of randomized clinical studies have not indicated an antagonistic effect of tamoxifen on the effectiveness of XRT, since local control has been consistently higher when XRT was combined with tamoxifen, compared with treatment with XRT alone, regardless of whether tamoxifen was started simultaneously with radiotherapy or after completion of radiotherapy. Currently there are no clinical data available that would suggest an adverse effect of adjuvant tamoxifen treatment started prior to or simultaneously with radiotherapy in breast cancer or DCIS. However, since an antagonistic effect of tamoxifen and simultaneous chemotherapy has been reported recently, the issue of simultaneous versus sequential radiation and tamoxifen treatment in breast cancer should be addressed in further studies.

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