The Use of Free Radicals in Cancer Therapy

The use of radiation has a long history in cancer therapy. As a high-energy source, radiation exerts its effect through the formation of free radicals. Unfortunately, in many instances tumors can be resistant to the effects of radiation. This is due to the fact that tumors tend to be poorly vascularized (poorly nourished by blood vessels), which results in their being hypoxic (low in oxygen). As a result, there may not be enough free radicals formed to be effective.

Development of drugs against hypoxic tumor cells

Several groups are exploiting the low oxygen concentrations of tumor cells to develop drug delivery systems. 3 A typical research direction is to prepare an inactive prodrug that consists of "effector" and "trigger" groups. This prodrug is then reduced by enzymes to a free radical. In normal cells with high oxygen concentration, the free radical passes on its extra electron to oxygen, reforming the inactive prodrug. In the hypoxic tumor cells, the free radical breaks down into the "effector" (active drug) and the "trigger" residue.

Another group 1 found that low doses of a drug called tirapazamine are effective in killing cells that are oxygen-starved (tumor cells), while sparing well-oxygenated cells. This drug is especially effective in combination with radiation, or with the chemotherapy drug cisplatin.

Photodynamic therapy

Photodynamic therapy involves the administration of a so-called photosensitizer drug that accumulates preferentially in tumor cells. 3The drug is then activated by laser light, and reacts with oxygen to form highly toxic singlet oxygen radicals that destroy the tumor cells. Wang and co-workers 7found that high levels of glutathionone peroxidase enzyme in the tumor cells could protect against singlet oxygen damage.

Prodrugs based on indole acetic acid

The Gray Cancer Institute 4is developing several approaches to release toxic drugs to tumor cells. All approaches lead to the activation by oxidation of a prodrug based on idole acetic acid. The resultant free radical intermediate can damage cellular DNA, and it undergoes further oxidation to produce other damaging radicals. The procedure starts with the introduction of the prodrug to the tumor cell. The peroxidase enzyme is then delivered by means of a tumor-seeking antibody, which activates the prodrug. Alternatively, the peroxidase gene could be introduced into the tumor cells by gene therapy techniques. A third option involves a variation of photodynamic therapy. When the photosensitizer is activated by red light, it is able to react with and activate the prodrug.

Targeting superoxide

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