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Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC), a combination of hydrogen peroxide and sodium hyaluronate, effectively overcomes tumor hypoxia-induced radioresistance. This novel therapy inhibits oxygen consumption, leading to tumor reoxygenation and enhanced radiosensitivity.

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Area of Science:

  • Oncology
  • Radiation Oncology
  • Cancer Biology

Background:

  • Tumor hypoxia is a primary driver of radioresistance in cancer treatment.
  • Hydrogen peroxide (H2O2) acts as a radiosensitizer but faces clinical challenges due to stability and toxicity.
  • Sodium hyaluronate (SH) is utilized to improve H2O2 delivery and stability for intratumoral administration.

Purpose of the Study:

  • To investigate the radiomodulatory effects and underlying mechanisms of Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC) in hypoxic tumor models.
  • To evaluate the efficacy of KORTUC in overcoming hypoxia-induced radioresistance.
  • To assess the safety and therapeutic potential of KORTUC as a combination therapy.

Main Methods:

  • In vitro studies exposed CT26 and 4T1 cells to H2O2, SH, and KORTUC under hypoxic conditions.
  • Toxicity was assessed via MTT assays and live-cell analysis; radiosensitizing properties were evaluated using colony formation assays and spheroid models.
  • Mechanisms investigated included reactive oxygen species (ROS) levels, DNA damage, apoptosis, ferroptosis, oxygen consumption rate (OCR), mitochondrial complex activity, and intratumoral oxygen levels.
  • In vivo validation was performed in CT26-bearing mice.

Main Results:

  • KORTUC exhibited reduced cytotoxicity compared to H2O2 alone.
  • KORTUC demonstrated dose-dependent radiosensitization of hypoxic tumor cells, with enhancement ratios of 3.1 for CT26 and 2.7 for 4T1.
  • KORTUC treatment led to decreased OCR, inhibition of mitochondrial complexes I and II, and elevated mitochondrial ROS.
  • Intratumoral injection of KORTUC increased oxygen levels in a 2D hypoxic model and delayed CT26 tumor growth by 14 days in mice.

Conclusions:

  • Sodium hyaluronate (SH) in KORTUC effectively mitigates the cytotoxicity of hydrogen peroxide (H2O2).
  • KORTUC overcomes hypoxia-induced radioresistance by inhibiting oxygen consumption via mitochondrial complex I and II blockade, promoting tumor reoxygenation.
  • Understanding these mechanisms is crucial for developing advanced cancer combination therapies involving KORTUC.