Cell Cycle & Growth

Question 1

What is the cyclin/cdk complext for early G1/S transition?

Answer 1

cyclin D

cdk 4/6

Question 2

What is the cyclin/cdk complext for late G1/S transition?

Answer 2

cyclin E

cdk 2

Question 3

What is the cyclin/cdk complext for S progression?

Answer 3

cyclin A

cdk 2

Question 4

What is the cyclin/cdk complext for G2/M transition?

Answer 4

cyclin B

cdk 1

Question 5

Which cell cycle checkpoint is frequently inactivated in tumors?

Answer 5

early G1/S (cyclin D, cdk 4/6)

p21 and p15/p16 inhibit the interaction

Question 6

What is the function of Cyclin D/cdk4/6?

Answer 6

it phosphorylates and activates the Rb gene, which releases E2F
E2F then facilitates transcription of cyclins E and A and genes involved in DNA synthesis

Question 7

What is the function of E/2 and A/2?

Answer 7

they further phosphorylate Rb, driving the progression into S

Question 8

What blocks the progression of G1/S?

Answer 8

p53 induces p21 in response to DNA damage –> prevents interaction of Cyclin D and cdk4/6

Question 9

If p53 is inactivated in a tumor, what happens? What about Rb?

Answer 9

No p53 = no G1/S stop
No Rb = constitutive E2F activation = pushes S phase.

Note E6 and E7 facilitate this in HPV

Question 10

What is the function of Cyclin B/cdk1?

Answer 10

It drives progression through G2/M by phosphorylating Histone H1 –> chromosome condensation

Question 11

What is the mitotic index?

Answer 11

MI = % of cells in mitosis (as measured by light micrsocopy, which can ‘see’ condensed chromatin)

Question 12

What is the labeling index?

Answer 12

tritiated thymidine labels cells in S phase

LI =% of cells in S phase

Question 13

How much of the cell cycle does S phase take up?

Answer 13

Approx 1/3

Question 14

What is BrdU labeling for?

Answer 14

Can identify cells in the S-phase by flow cytometry

Question 15

Approximately how long is S phase?

Answer 15

6-8 h

Question 16

How long is M phase?

Answer 16

1 h

Question 17

How long is G2?

Answer 17

3-4 h

Question 18

How long is G1?

Answer 18

variable!

Question 19

What is the “growth fraction”, what is it for various tumors?

Answer 19

The percentage of cells in a tumor that are actively cycling

1) Lymphoma = 90%
2) Squam = 40%
3) Adeno = 5%

Question 20

What is the “cell loss factor”, what is it in most tumors?

Answer 20

the percentage of newly produced cells that die. Approx 75% in most tumors

Note: low CLF indicates cells may be resistant to death/therapy

Question 21

What is Tpot? Tvol?

Answer 21

Tpot is the potential volume doubling time, not taking into account cell loss
Tvol is the observed volume doubling time

Tpot = Tvol *(1-CLF)
Tpot = Tc/GF

Question 22

What is diameter doubling time?

Answer 22

Tvol * 3

Question 23

What is the average for tumors:

1) Tc
2) Tpot
3) Tvol
4) Tdiam

Answer 23

1) 2 days
2) 5 days
3) Assuming 75% cell loss, = 20 days
4) 60 days

Question 24

What is the theory behind accelerated repopulation?

Answer 24

prolonged cytotoxic treatment stimulates tumor cells to rapidly divide. This has been seen in HNSCC and cervical cancers

Question 25

What is "kickoff time" and "Dprolif"?

Answer 25

kickoff time is the delay between treatment start and accelerated repopulation. Once kickoff time is reached, additional dose must be given to counteract this (Dprolif)

Question 26

What is hydroxyurea used for?

Answer 26

HU selectively kills cells in the S-phase (inactivates ribonucleotide reductase), thus accumulates cells at G1/S checkpoint

Question 27

At what phase of the cell cycle are cells most sensitive to RT?

Answer 27

In G2/M transition, as there is not enough time to repair the DNA before dividing --> mitotic catastrophe

Question 28

When are cells least sensitive to RT?

Answer 28

In S phase -- extensive templates for HRR

Question 29

What does Dq look like in the various cell cycle phases?

Answer 29

In G2/M, there is very little repair going on, so Dq (shoulder) is small In S there is very good repair going on, so Dq (shoulder) is large

Question 30

At what phase of the cell cycle is OER maximally influential?

Answer 30

S phase since so much DNA repair going on

Question 31

What is the influence of LET on cell cycle sensitivity?

Answer 31

Minimal

Question 32

How does cell cycle impact dose rate sensitivity?

Answer 32

In ultra-low dose rate brachy, cells are able to reassort in the cell cycle and accumulate in the G2 phase, where they are maximally sensitive. = inverse dose rate effect