ESTRO 37 Abstract book

S1275

ESTRO 37

Purpose or Objective The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) have demonstrated antitumor activity in various models. However, their radiomodulatory effect under hypoxic condition is largely unknown. This study therefore examines whether PHEN and METF as mitochondrial complex I blockades could overcome hypoxia radioresistance through inhibition of oxygen consumption Material and Methods The radiosensitizing effect of PHEN and METF in a panel of colorectal cancer cells was examined in vitro by clonogenic assay. The inhibition of complex I and oxygen consumption were measured by Seahorse. Reactive oxygen species (ROS) production was measured by FACS. The radiosensitizing effect was further validated in vivo. Results PHEN significantly inhibited complex I activity and subsequently disrupted cellular respiration at dose ≥ 30µM, with cell line dependent modest upregulation of reactive oxygen species. Consistently, PHEN pronounced radiosensitized hypoxic tumor cells with enhancement ratio more than 2, while leaving the intrinsic radiosensitivity unchanged. Similar effects were demonstrated by METF at 100-fold higher concentrations. In tumor-bearing mice, PHEN significantly improved tumor radioresponse while METF failed to reveal any effect at a clinical achievable dose Conclusion Our results suggest that inhibition of mitochondrial respiration by PHEN is associated with increased hypoxic radioresponse, and providing a rationale for exploring the efficacy of combination of PHEN with radiotherapy. EP-2311 Biological effects of radiation dose-rate and intra-fraction breaks in stereotactic radiotherapy K. Thippu Jayaprakash 1,2 , M. Hussein 3 , A. Nisbet 3,4 , R. Shaffer 2 , M. Ajaz 1,2 1 University of Surrey, Department of Clinical and Experimental Medicine, Guildford, United Kingdom 2 St Luke's Cancer Centre- Royal Surrey County Hospital, Department of Oncology, Guildford, United Kingdom 3 St Luke's Cancer Centre- Royal Surrey County Hospital, Department of Medical Physics, Guildford, United Kingdom 4 University of Surrey, Department of Physics, Guildford, United Kingdom Purpose or Objective Stereotactic radiotherapy (SRT) delivers a high radiation dose per fraction. Different technical platforms mean that there is variability in practice, for example in dose- rate (and therefore overall treatment time), and also in the need for intra-fraction treatment breaks. We wished to evaluate whether these differences have significant radiobiological effects, using an in-vitro experimental platform. Material and Methods Melanoma (A375) and glioma (LN18) cells in 96-well plates were irradiated to 15, 18 and 24 Gy using 10 MV X- rays with two dose-rate settings (400 monitor units (MU) /min and 2400 MU/min) in a linear accelerator using a custom made perspex phantom. Cell viability (tetrazolium colorimetric cell viability (MTS) assay, Electronic Poster: Radiobiology track: Radiobiology of cancer (others)

Conclusion Irinotecan has radiosensitization effects on HT29 and SW620 cells and the SER increases with the increase of concentration. It attributes to the activation of DNA damage and repair system, leading to significant G2/M phase arrest followed by enhanced apoptosis. And the process is probably through ATM/Chk/Cdc25c pathway in p53-mutant colon cancer cells. EP-2310 Phenformin radiosensitizes hypoxic tumor cells through inhibition of mitochondrial complex S. De Mey 1 , H. Wang 1 , J. Heng 1 , I. Dufait 2 , K. Law 1 , C. Corbet 3 , V. Verovski 1 , T. Gevaert 1 , O. Feron 3 , M. De Ridder 1 1 University Hospital Brussels, Radiotherapy, Jette, Belgium 2 Vrije Universiteit Brussel, Laboratory of Molecular and cellular technology, Jette, Belgium 3 Université Catholique de Louvain, Pole of Pharmacology and Therapeutics FATH- Institut de Recherche Expérimentale et Clinique IREC, Brussel, Belgium