Oxygen Effect

Question 1

How does oxygen affect dose deposition?

Answer 1

For photon beams (indirectly ionizing), each ion pair reacts with water to produce free radicals. The free radicals then go on to interact with DNA. Oxygen reacts with radical-DNA to form peroxides, which are not easily repaired.

Thus, oxygen enhances the effect of photon irradiation

Question 2

What is the time course of radiolysis and indirect ionization?

Answer 2

Ion pairs react with water to create ROS in nanoseconds

ROS interact with DNA in microseconds

Question 3

What is the fate of ROS in DNA?

Answer 3

ROS can be scavenged and removed by GSH or fixed through reacting with oxygen to produce peroxides

Question 4

At what %O2 is the oxygen effect saturating?

Answer 4

2%

Question 5

What is the oxygen tension of hypoxic tumors? venous blood? arterial blood?

Answer 5

Hypoxic tissue = 0.13%
Venous = 2-5%
Arterial = 8-13%

Question 6

What is the OER for MV photons?

Answer 6

2.5 - 3.5

Question 7

What is the interplay of OER and fraction size?

Answer 7

Small fractions: survival is dominated by sensitive cells, which have the lowest OER
Large fractions: survival is dominated by resistant cells which have the highest OER.

Thus, OER is larger at large fraction sizes

Question 8

Per the Thomlinson-Gray hypothesis, what is the extent of oxygenation of a tumor?

Answer 8

The outer 70 um are fully oxygenated
70-100 um are chronically hypoxi
100 um and further in are anoxic/necrotic

Question 9

What does the mixed normoxic/hypoxic survival curve look like?

Answer 9

At low doses, normoxic cells are prevalent and the surviving fraction declines steeply. At higher doses, the normoxic cells have been selectively killed and the resistant hypoxic cells left (akin to beam hardening). The slope then levels out. If you were to take the flatter portion of the survival curve and extrapolate to y-axis, this would give you the fraction of cells that are hypoxic.

Question 10

How do 2-nitroimidazole drugs identify hypoxic cells?

Answer 10

under hypoxic conditions, they form stable macromolecular adducts which can be stained for by IHC

Question 11

What IHC markers are there for hypoxia?

Answer 11

pimonidazole, CA9, HIF1

Question 12

What radiotracers are available for hypoxia?

Answer 12

O-15 PET
F-MISO
Cu-ASTM
F-EF5

Question 13

What is the mechanism of transient hypoxia?

Answer 13

Cells within 70 um of the blood vessels; these vessels are typically leaky and dysfunctional, may temporary clot or close.

Question 14

How can chronically hypoxic cells become normoxic?

Answer 14

1) angiogenesis

2) through tumor shrinkage

Question 15

What genes are induced by hypoxia?

Answer 15

HIF-1, NK-kB, CREB

Question 16

Describe HIF-1

Answer 16

1) consists of two subunits, IF-1a and HIF-1b
2) under normoxic conditions HPH hydroxylates (via O2) HIF-1a and VHL marks it for degradation
3) under hypoxic conditions, HPH is unable to hydroxylate, VHL does not mark it for degradation
4) free HIF-1a dimerizes with HIF-1b and translocates to the nucleus where HIF-1b acts as a transcription factor

Note: loss of VHL activates HIF