Hall Book Ch 9 (Medical Countermeasures to Radiation Exposure)

Question 1

( ) are agents administered prior to radiation exposure to reduce the level of radiation damage.

Radiation ( ) are drugs administered shortly after irradiation but prior to the manifestation of normal tissue toxicity.

Answer 1

Radioprotectors, mitigators

Question 2

Radiation ( ) are agents given ( ) overt symptoms appear in order to reduce the severity of the radiation response.

Answer 2

therapeutics, after

Question 3

The radioprotectors, ( ), were discovered early but are toxic. If the SH group is covered by a ( ) group, toxicity is reduced.

The mechanism of action is the ( ) and restitution of free radical damage, although this is not the whole story.

Answer 3

cysteine and cysteamine, phosphate, scavenging of free radicals

Question 4

The DRF (Dose Reduction Factor) is the ratio of radiation doses required to produce the same biologic effect in the absence and presence of the radioprotector.

For example, animals injected with cysteamine to concentrations of about 150 mg/kg require doses of x-rays 1.8 times larger than control animals to produce the same mortality rate.

In this case the DRF is ( ).

Answer 4

1.8

Question 5

The best available radioprotectors can attain DRF values of ( ) for bone marrow death in mice irradiated with x-rays, but the effectiveness of radioprotectors decreases with ( ) linear energy transfer.

Answer 5

2.5 to 3.0

increasing

Question 6

During the Cold War, it is said that Soviet infantry in Europe carried the
radioprotector cystaphos for use in a possible nuclear war. The radioprotector
amifostine was carried to the moon by US astronauts to be used in the event
of a solar flare.

More than 4,000 compounds were synthesized by the U.S. Army in studies
conducted at the Walter Reed Institute of Research. Amifostine (WR-2721)
appears to be the best for use in conjunction with radiotherapy.
Amifostine, sold under the trade name Ethyol, is the only radioprotective drug
approved by the FDA for use in the prevention of xerostomia in patients
treated for head and neck cancer.
An RTOG phase III trial demonstrated the efficacy of amifostine in reducing
xerostomia in patients with head and neck cancer receiving radiation therapy
without affecting locoregional control. The radioprotector was administered
30 minutes before radiation.
Amifostine is a “prodrug” that is unreactive and that penetrates poorly into
cells until it is dephosphorylated by the enzyme alkaline phosphatase to the
active metabolite WR-1065.
The rationale for the use of phosphorothioate radioprotectors in radiotherapy is
that they flood normal tissues rapidly after administration but penetrate
250
tumors much more slowly. The strategy is to begin irradiation soon after
administration of the drug to exploit a differential effect.
A dose of 400 mg/kg is required for optimal cytoprotection, which is toxic
with many side effects, but its antimutagenic effect persists at a low nontoxic
dose of 25 mg/kg. Furthermore, its antimutagenic effect still occurs if the
drug is added 3 hours following irradiation.
A new family of aminothiol radioprotectors has been generated, of which PrC210 is the prototype. This drug can be administered orally, protects against
lethality from whole body irradiation in rodents, and appears to be free of the
side effects of nausea and hypotension that are characteristic of amifostine.
Dietary supplements, including various antioxidants, have been suggested as
countermeasures to the long-term biologic effects of radiation exposure.
Radiation mitigators are drugs added after radiation exposure, but before the
symptoms of normal tissue toxicity appear, in an attempt to reduce the
severity of the radiation response. Several colony-stimulating factors, such as
filgrastim (Neupogen), are FDA approved to reduce chemotherapy-induced
neutropenia, but filgrastim (Neupogen) is the only one so far approved by the
FDA for use in humans exposed to radiation. A wide range of experimental
compounds are under investigation to mitigate against the hematopoietic
syndrome that follows total-body exposure to a large dose of radiation.
Radionuclide eliminators are drugs that discorporate or block absorption of
internalized radionuclides released in a nuclear accident or radiologic terrorist
event. Potassium iodide blocks the thyroid from taking up internalized
radioactive iodine. Radiogardase traps cesium in the intestine so that it is
eliminated in the stools. DTPA is used if transuranic elements, such as
plutonium, americium, or curium, are ingested. The DTPA binds to the heavy
radionuclide which is then passed from the body in the urine.
Following the destruction of the World Trade Center on September 11, 2001,
and the rise of a nuclear terrorism threat, there has been a revived interest in
the development of novel, effective, and nontoxic radioprotectors and
radiation mitigators for potential use in homeland defense. In addition,
NASA is interested in countermeasures to the radiation exposure that
astronauts experience on long-term space missions.