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Chemical modifiers of cancer treatment
C N Coleman1, E A Bump, R A Kramer
1Harvard Medical School, Joint Center for Radiation Therapy, Boston, MA 02115.
Abstract:
Chemical modification is a concept in cancer therapy in which the state of tumor cells or normal tissues is modified such that a therapeutic gain can be achieved using conventional therapeutic modalities. Hypoxic zones targeted as cells within them may be radiation resistant, poorly perfused by chemotherapeutic agents, and possibly drug resistant due to hypoxia-related gene amplification. Nitroimidazoles have gained particular attention as chemical modifiers because they can increase the radiation sensitivity of hypoxic cells, are cytotoxic to hypoxic cells, can increase sensitivity to chemotherapeutic agents, and are useful for imaging hypoxic cells. While both radiosensitization and chemosensitization require hypoxia, the mechanism of the enhancement of each of the modalities is different. The 2-nitroimidazole hypoxic sensitizers SR 2508 and Ro-03-8799, which are less toxic than the prototype misonidazole (Miso), are in clinical trials, and dual function molecules that include a hypoxic sensitizer and alkylating function are being developed. The presence of both acutely and chronically hypoxic cells in animal tumors has been demonstrated by new imaging techniques. Oxygen delivery to tumors is being altered by the use of perfluorocarbons, and agents that alter hemoglobin affinity for oxygen. Compounds that are selectively toxic to hypoxic cells are being developed. Nonhypoxic modifiers are also being investigated. Thiol modification, particularly the alteration of glutathione concentration, has complex effects on the cell's biochemistry, in addition to affecting the competition between oxygen and thiol groups for the restoration and fixation of radiation-induced radicals. WR-2721 is being studied as a means of reducing the normal tissue toxicity of radiation and chemotherapy. Increased thiol concentration may be a mechanism of cross-resistance between certain chemotherapeutic agents and radiation.
Insights
Chemical modification enhances cancer therapy by targeting hypoxic tumor cells. Nitroimidazoles increase radiation sensitivity and drug efficacy, while other modifiers target thiol concentration to reduce normal tissue toxicity.
Area of Science:
- Oncology
- Radiotherapy
- Pharmacology
Background:
- Hypoxic tumor zones are resistant to radiation and chemotherapy.
- Nitroimidazoles are promising chemical modifiers for cancer therapy.
- Understanding hypoxia mechanisms is crucial for therapeutic gain.
Purpose of the Study:
- To explore chemical modification strategies in cancer therapy.
- To investigate the role of nitroimidazoles in enhancing treatment efficacy.
- To review novel approaches for targeting hypoxic cells and reducing normal tissue toxicity.
Main Methods:
- Review of existing literature on chemical modifiers in cancer therapy.
- Analysis of nitroimidazole mechanisms for radiosensitization and chemosensitization.
- Investigation of imaging techniques for hypoxic cell detection.
- Exploration of agents altering oxygen delivery and thiol concentration.
Main Results:
- Nitroimidazoles increase radiation sensitivity and cytotoxicity of hypoxic cells.
- Dual-function molecules combining hypoxic sensitization and alkylation are under development.
- New imaging techniques reveal acute and chronic hypoxia in tumors.
- Thiol modification affects cellular biochemistry and radiation response.
Conclusions:
- Chemical modification, particularly using nitroimidazoles, offers significant therapeutic potential in cancer treatment.
- Targeting tumor hypoxia and modulating thiol concentration are key strategies for improving treatment outcomes.
- Further research into novel chemical modifiers and delivery systems is warranted.