Radiosensitizer

Conventional chemotherapeutics are currently being used in conjunction with radiation therapy to increase its effectiveness. Examples include the fluoropyrimidines, gemcitabine and platinum analogs; fluoropyrimidines increase sensitivity by dysregulating S-phase cell cycle checkpoints in tumor cells. Gemcitabine progresses through a similar mechanism, causing cells in the S-phase to disrepair DNA damage caused by the radiation. Platinum analogs such as cisplatin inhibit DNA repair by cross linking strands, and so aggravate the effects of DNA damage induced by radiation.^[1] Mechanisms of Action Radiosensitizers enhance the effects of radiation therapy through various mechanisms, broadly classified as:

These agents increase DNA damage caused by radiation or inhibit its repair.^[2]

Halogenated pyrimidines: Incorporate into DNA, making it more susceptible to radiation damage. Platinum analogs: Create DNA crosslinks, preventing repair. PARP inhibitors: Block DNA repair enzymes, increasing damage.

These agents disrupt the cell cycle, increasing radiosensitivity at specific phases.^[3]

Taxanes: Arrest cells in the radiosensitive G2/M phase. Antimetabolites: Interfere with DNA synthesis, leading to cell cycle arrest.

These agents address low oxygen levels (hypoxia) in tumors, which can hinder radiation effectiveness.^[4]

Nitroimidazoles: Mimic oxygen, enhancing free radical formation in hypoxic cells. Oxygen delivery agents: Improve oxygen supply to tumors.

One of the major limitations of radiotherapy is that the cells of solid tumors become deficient in oxygen. Solid tumors can outgrow their blood supply, causing a low-oxygen state known as hypoxia. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment.^[5] Much research has been devoted to overcoming this problem including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitizers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine.

As of September 2016, there are a number of radiosensitizers in clinical trials.