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[Present status of hypoxic cell sensitizers and PLDR inhibitors]
1Dept. of Radiology, Faculty of Med., Kyoto Univ.
Abstract:
Clinical and basic studies in hypoxic cell radiosensitizers and potentially lethal damage (PLD) repair inhibitors were reviewed. Most clinical trails on misonidazole (MISO) show that the toxicity of MISO is a major reason for failure in the trials and an adequate selection of tumors is needed for the success. Phase III studies on SR-2508 and RO 03-8799, less toxic and more effective sensitizers, are in progress. AK-2123 and RK-28 developed in Japan are drugs with similar clinical applicability of MISO. Thiol depletion of tumors is one of the way to increase the radiosensitization. The measurement of intercapillary distance on histopathological microslide is a valuable method to select the tumors containing much hypoxic cell fractions. Stable and effective chemicals as MISO in hypoxic cell sensitization must be developed to investigate the clinical applicability of PLD repair inhibitors.
Insights
Clinical trials of radiosensitizers like misonidazole (MISO) show toxicity issues. Newer, less toxic drugs and better tumor selection are needed for effective cancer treatment using hypoxic cell radiosensitizers and PLD repair inhibitors.
Area of Science:
- Oncology
- Radiation Oncology
- Cancer Biology
Context:
- Hypoxic cells in tumors are resistant to radiation therapy.
- Radiosensitizers aim to enhance radiation's effectiveness against these resistant cells.
- Potentially lethal damage (PLD) repair inhibitors offer another strategy to increase cell death post-irradiation.
Purpose:
- To review clinical and basic studies on hypoxic cell radiosensitizers and PLD repair inhibitors.
- To evaluate the efficacy and toxicity of existing and developing sensitizing agents.
- To identify optimal strategies for patient and tumor selection in clinical trials.
Summary:
- Misonidazole (MISO) trials were hampered by toxicity, necessitating careful tumor selection.
- Newer agents like SR-2508 and RO 03-8799 show promise with reduced toxicity.
- Japanese agents AK-2123 and RK-28 have similar clinical potential to MISO.
- Thiol depletion and measuring intercapillary distance are methods to enhance radiosensitization and select tumors with high hypoxic fractions.
- Development of stable, effective radiosensitizers is crucial for investigating PLD repair inhibitors.
Impact:
- Highlights the limitations of early radiosensitizers like MISO due to toxicity.
- Identifies promising next-generation radiosensitizers for further clinical investigation.
- Suggests histopathological methods for improved patient selection in radiosensitizer trials.
- Emphasizes the need for novel chemical agents to advance the clinical application of PLD repair inhibitors in cancer therapy.