ESTRO 2024 - Abstract Book

S5208

Radiobiology - Microenvironment

ESTRO 2024

A dose-dependent reduction in oxygen consumption rate (OCR) was observed for both cell lines following exposure to H 2 O 2 /KORTUC, correlating with the inhibition of mitochondrial complexes I and II activity. Correspondingly, mitochondrial superoxide levels increased. After a 24-hour interval, cellular metabolism, as indicated by ATP levels, recovered for both cell lines, validating the transient nature of the OCR reduction. Injection of KORTUC resulted in a significant and instant elevation of O 2 levels in both cell lines under hypoxic conditions. After treatment with H 2 O 2 /KORTUC, we detected elevations in superoxide, DNA-damage, apoptosis and ferroptosis. However, no additive or synergistic effects could be observed when combining H 2 O 2 /KORTUC with radiation. Notwithstanding, an accumulative increase in the levels of apoptosis and ferroptosis could be detected when combining KORTUC with radiation.

KORTUC radiosensitized CT26 tumors, resulting in a growth delay of 14 days and a reduction in poorly oxygenated regions within the tumor.

Conclusion:

The primary radiosensitizing effects of KORTUC can be attributed to the reoxygenation of hypoxic cells and the inhibition of cellular respiration through the blockade of mitochondrial complexes I and II. Beyond the well established apoptosis-inducing properties of H 2 O 2 , our findings reveal that KORTUC, a combination of H 2 O 2 and SH, has the capacity to enhance both apoptosis and ferroptosis. Ferroptosis has recently been recognized as the predominant mode of action in other potent radiosensitizers (2). Our in vivo results indicate that KORTUC enables the use of higher concentrations of H 2 O 2 without inducing toxic effects. Gaining a deeper understanding of the underlying pathways of KORTUC is essential for the development of combination therapies for cancer patients.

Keywords: hypoxia, radiosensitization, hydrogen peroxide

References:

(1) Tokuhiro S, Ogawa Y, Tsuzuki H, Akima R, Ue H, Kariya H and Nishioka A. Development of a novel enzyme targeting radiosensitizer (KORTUC) containing hydrogen peroxide for intratumoral injection for patients with low linear energy transfer-radioresistant neoplasms. Oncology Letters 2010.

(2) Kerkhove L, Geirnaert F, Rifi AL, Law KL, Gutiérrez A, Oudaert I, Corbet C, Gevaert T, Dufait I, De Ridder M. Repurposing Sulfasalazine as a Radiosensitizer in Hypoxic Human Colorectal Cancer. Cancers (Basel) 2023.

1240

Proffered Paper

Fusobacterium associates with a better prognosis and radiosensitizes head and neck cancers

Anjali Rani Chander 1,2 , Jacopo Iacovacci 3 , Aize Pellon Rodriguez 1 , Victoria Butterworth 4 , Radhika Kataria 5 , Anita Grigoriadis 5 , Ester Orlandi 6,7 , Nicola Alessandro Iacovelli 6 , Loris De Cecco 8 , Mara Serena Serafini 8,9 , Teresa Guerrero Urbano 2 , Anthony Kong 2,10 , Mary Lei 2 , Imran Petkar 2 , Tony Ng 10 , Gilad Bachrach 11 , Cynthia Sears 12 , David Moyes 1 , Tiziana Rancati 3 , Miguel Reis Ferreira 2,1,10