and the Dose-Rate EffectBrian D. Yard and Mohamed E. Abazeed

RADIOSENSITIVITY AND THE DOSE-RATE EFFECT

BRIAN D. YARD AND MOHAMED E. ABAZEED

Question 1

What are the phases of the cell cycle?

Question 2

What phase of the cell cycle has the most variable length of time across various cell lines?

Question 3

What molecules regulate the transitions from one phase of the cell cycle to the next? How would you characterize them?

Question 4

What are the most radiosensitive phases of the cell cycle? What is the most resistant?

Question 1 What are the phases of the cell cycle?

Answer 1

Proliferating mammalian cells have a cycle of DNA synthesis (S phase) followed by a pause or gap (G2), followed by mitosis (M phase), which is followed by another pause or gap (G1). If cells are not actively dividing, they are arrested in G.

Hall EJ, Giaccia AJ. Cell, tissue, and tumor kinetics. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:372–390.

Question 2 What phase of the cell cycle has the most variable length of time across various cell lines?

Answer 2

The most variable phase of the cell cycle is G1, which is typically the rate-determining step of the total cell cycle time across various cell lines. The other three phases (S, G2, and M) have limited variability among different cells.

Hall EJ, Giaccia AJ. Cell, tissue, and tumor kinetics. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:372–390.

Question 3 What molecules regulate the transitions from one phase of the cell cycle to the next? How would you characterize them?

Answer 3

The cell cycle is regulated by several cyclin-dependent kinases (Cdk), whose sequential activation preserves the temporal order of the cell cycle. Cdk enzymes are activated by cyclin and inactivated by Cdk inhibitory proteins. Cyclins and Cdk inhibitors are themselves regulated to ensure sequential and precise activation and deactivation.

Hall EJ, Giaccia AJ. Cell, tissue, and tumor kinetics. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:372–390.

Question 4 What are the most radiosensitive phases of the cell cycle? What is the most resistant?

Answer 4

Generally, the most radiosensitive phases of the cell cycle are M and G2. The most resistant phase is late S, presumably due to the ability to undergo homologous recombination. In slow replicating cells, early G1 is also considered to be radioresistant.

Hall EJ, Giaccia AJ. Cell, tissue, and tumor kinetics. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:372–390.

Question 5

How does the dependence of radiosensitivity on cell cycle phase apply to an asynchronously dividing population?

Question 6

What are the three categories of radiation-induced damage?

Question 7

What is an example of an experimental manipulation that can modify potentially lethal damage (PLD)?

Question 8

What is sublethal damage (SLD) and why is this type of damage important?

Question 5 How does the dependence of radiosensitivity on cell cycle phase apply to an asynchronously dividing population?

Answer 5

Cells replicating in culture are asynchronously dividing, that is, they are comprised of cells that are cycling independently of each other. The aforementioned experiments were conducted by various manipulations to “synchronize” these cells such that the population is cycling largely in sync. Virtually all tumors and normal tissue that is irradiated are comprised of asynchronously dividing populations. Therefore, unless the cells are arrested or timed such that they are in a particular phase of the cell cycle, either by chemical means or by “reassortment” (see the following), the dependence of radiosensitivity on cell cycle phases is not a major determinant of therapeutic radiosensitivity.

Hall EJ, Giaccia AJ. Cell, tissue, and tumor kinetics. In: Hall EJ, Giaccia AJ, eds. Radiobiology for the Radiologist. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:372–390.

Only gold members can continue reading. Log In or Register to continue