Use of a SAS analogue tas a radiosensitizer in cancer treatment (copy)
Resistance to radiotherapy is a major challenge in cancer treatment. One way to make this more effective is to block the transmembrane antiport XcT, further reducing the production of the antioxidant glutathione. This protects against reactive oxygen species induced by radiotherapy. Sulfasalazine has been shown efficacy to block glutathione production and acts as a radiosensitiser that prolonged survival when combined with radiotherapy. However, due to enzymatic degradation, limited biodistribution and adverse effects it is not an optimal radiosensitiser for brain tumour patients undergoing radiotherapy. Hence, we aim to develop synthetic analogues of Sulfasalazine that will be more potent, stable and optimised for use as a radiosensitiser in patient treatment. So far, we have synthesized 17 novel Sulfasalazine-analogues and screened them for their ability to sensitize radiotherapy in vitro. One of these Sulfasalazine-analogues (DC10) is highly potent which has shown promising radiosensitizing effects in vitro experiments. This analogue is chemically modified to reduce the adverse effects of Sulfasalazine. Thus, we predict DC10 to be more tolerable than Sulfasalazine which has already been approved for clinical use. The purpose of the study is to validate the anti-tumour efficacy of DC10 as radiosensitizer and determine side effects and toxicity in vivo. We planned to use 82 NOD/SCID mice for the study. The tumour will be implanted subcutaneously in the flanks and the treatment protocol composed of oral gavage and radiation which is pain free, yet will be performed under light sedation so the degree of suffering to the animals in the study will be little/modest.
The study is designed with the compliance of 3R- The number of animals was reduced by doing an extensive in-vitro experiment that gave a solid ground to do further testing. Despite extensive in vitro testing, the need for animal testing cannot be replaced. Cell culture cannot recapitulate the complex environment in a living animal. It is impossible to get information about side effects, pharmacokinetics, and therapeutic efficacy by in vitro assay. The study designed is refined to reduce the discomfort by adequate anaesthesia, analgesics and mild sedation where applicable. The animals will be monitored by clinical inspection and by assessment of weight, heart rate, side effects. (please check details of 3R in the specific section).
We have planned to utilize our already established state-of-the-art animal models and treat the animals with radiation and DC10 in combination. We hope that this animal study will provide valuable information to find an effective radiation treatment for cancer.
The study is designed with the compliance of 3R- The number of animals was reduced by doing an extensive in-vitro experiment that gave a solid ground to do further testing. Despite extensive in vitro testing, the need for animal testing cannot be replaced. Cell culture cannot recapitulate the complex environment in a living animal. It is impossible to get information about side effects, pharmacokinetics, and therapeutic efficacy by in vitro assay. The study designed is refined to reduce the discomfort by adequate anaesthesia, analgesics and mild sedation where applicable. The animals will be monitored by clinical inspection and by assessment of weight, heart rate, side effects. (please check details of 3R in the specific section).
We have planned to utilize our already established state-of-the-art animal models and treat the animals with radiation and DC10 in combination. We hope that this animal study will provide valuable information to find an effective radiation treatment for cancer.