L 9: Radioprotectors

Question 1

Radio protectors

Answer 1

• THey protect from radiation damage.
• Anything with a “SH” group is a radioprotector

Question 2

Dose reduction factor

Board question

Answer 2

DRF

Question 3

Radio sensitizers

Answer 3

Opp of radioprotectors
Makes radiation work better
So we want tumor cells to be radio sensitized

Question 4

Two main radioprotectors

Answer 4

• Cystaphos
• Amifostine

Question 5

Amifostine

Board question

Answer 5

• It is a prodrug and becomes active in the body (liver) it becomes active metabolite WR1065.
• Given mins before the exposure
• good protection: hematopoietic system, gut lining, salivary glandsno protection: CNS (doesn’t cross blood-brain barrier)
• Hydrophilic nature gives ↑ uptake in normal tissues
• Dose-limiting toxicity: hypotension
• Also call ethyol
• Is FDA approved for use as a radioprotector for H&N cancer to prevent Xerostomia with no difference in LRC of tumor
• its concentration is the lowest in the tumor and brain, does not cross BBB due to blood flow of tumor, acidosis of tumor, lower expression of alk phos in tumor

Question 6

MnSOD
SOD2

Answer 6

• Superoxide dismutase – mitochondrial superoxide dismutase – Mn – containing free radical scavenging enzyme.
• SOD 1/2/3
• Used for gene therapy – protection from late effects
• SOD-Mn mimetic drug: AEOL 10113 – Mn(III) (N-ethylpyridinium-2-yl) porphyrin or MnTE-2-PyP(st) [and others]
• Anti-oxidant
• Not SOD1= CuZnSODNot SOD3= extracellular SOD
• Low SOD2: accumulation of ROS in mitochondria ROS usually accumulate in mitochondria as toxic products of oxidative phosphorylation

Question 7

Pentoxyfylline

Answer 7

• Used most often for problems with blood flow; improves circulation
• Prevents late tissue toxicity (remember Dr. Craig uses breast pts at the VA), especially fibrosis
• Interferes with cytokine cascades
• Inhibits TNF-alpha and other cytokines involved in the development of fibrosis

Question 8

Zinc DTPA

Answer 8

Decorporation agent

Question 9

Summary

Answer 9

• Amifostine is the predominant radioprotector used clinically today.
• Dose-reduction factors are used to determine how effective a particular radioprotector can be in protecting normal tissue.
• New radioprotectors exploiting superoxide dismutase and other pathways are being explored.

Question 10

Mechanism of action

Answer 10

1. Amifostine: Binds to highly reactive nucleophiles to stabilize DNA.
2. Cysteamine: Donation of a H atom to allow direct chemical repair at the site of DNA damage.
3. G-CSF: Radiation mitigator: REgulates production of neutrophils in the bone marrow

1 and 2 are free radical scavengers too

Question 11

Walter Reed Series

Answer 11

• Radioprotective effects of various compounds could be improved by covering the SH group with Ph.
• It reduces systemic toxicity
• Once drug enters the cell, Ph was removed to allow SH to scavenge for free radicals

Question 12

Radio protectors

Answer 12

Given prior to radiation exposure

Question 13

Radiation mitigators

Answer 13

Given shortly after irradiation

Question 14

Radiation therapheutics

Answer 14

Given After overt symptoms appear

Question 15

Disadvantages of Amifostine
WR-2721

Answer 15

1. Has to be given prior to event
2. Has to be given only IV
3. Nausea and vbomiting toxicity.
4. Extremely short time window for radioprotective