Hall Book Ch 22 (Cell, Tissue, and Tumor Kinetics)

Question 1

The division of the cell cycle into its constituent phases, ( `), was accomplished in the 1950s.

Answer 1

M, G1, S, and G2

Question 2

The arrest of cells at various positions in the cycle by the action of ( ) is an important response to DNA damage.

The two principal checkpoints are the ( ) boundary, but there is also a checkpoint in ( ).

Answer 2

“checkpoint genes”, G1/S and the G2/M, S

Question 3

Which checkpoint is the most important following radiation damage? G2/M is the most important checkpoint following radiation damage; cells pause at G2/M to repair radiation-induced damage before attempting the complex process of mitosis.

Progression through the cell cycle is governed by protein kinases, activated by
cyclins. Each cyclin protein is synthesized at a discrete phase of the cycle:
cyclin D and E in G1, cyclin A in S and G2, and cyclin B in G2 and M.
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Transitions in the cycle occur only if a given kinase activates the proteins
required for progression.
Most of the difference in cell cycle between fast- and slow-growing cells is a
result of differences in G1, which varies from less than 1 hour to more than a
week.
The mitotic index (MI) is the fraction of cells in mitosis:
MI = λTM / TC
The labeling index (LI) is the fraction of cells that take up tritiated thymidine
(i.e., the fraction of cells in S):
LI = λTS / TC
The percent-labeled mitoses technique allows an estimate to be made of the
lengths of the constituent phases of the cell cycle. The basis of the technique
is to label cells with tritiated thymidine or bromodeoxyuridine in S phase and
time their arrival in mitosis.
Flow cytometry allows a rapid analysis of the distribution of cells in the cycle.
Cells are stained with a DNA-specific dye and sorted based on DNA content.
The bromodeoxyuridine–DNA assay in flow cytometry allows cells to be
stained simultaneously with two dyes that fluoresce at different wavelengths:
One binds in proportion to DNA content to indicate the phase of the cell
cycle, and the other binds in proportion to bromodeoxyuridine incorporation
to show if cells are synthesizing DNA.
The growth fraction is the fraction of cells in active cell cycle (i.e., the fraction
of proliferative cells).
In animal tumors, the growth fraction frequently ranges from 30% to 50%.
The cell-loss factor (ϕ) is the fraction of cells produced by cell division lost
from the tumor.
In animal tumors, ϕ varies from 0% to more than 90%, tending to be small in
small tumors and to increase with tumor size.
The cell-loss factor ϕ tends to be large for carcinomas and small for sarcomas.
The shape of a tumor growth-curve is best fitted by a Gompertz function.
Growth may be exponential when the tumor is small but slows as the tumor
gets larger and outgrows the supply of oxygen and nutrients.
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The observed volume doubling time of a tumor is the gross time for it to
double overall in size as measured, for example, in serial radiographs.
Tumors grow much more slowly than would be predicted from the cycle time
of individual cells. One reason is the growth fraction, but the principal reason
is the cell-loss factor.
The overall pattern of tumor growth may be summarized as follows: A
minority of cells (the growth fraction) are proliferating rapidly; most are
quiescent. Most new cells produced by mitosis are lost from the tumor.
In general, the cell cycle time of malignant cells is appreciably shorter than
that of their normal tissue counterparts.
In general, irradiation causes an elongation of the cell cycle time in tumor cells
and a shortening of the cell cycle in normal tissues.
In 90% of human tumors, the cell cycle time has a modal value of 48 hours (a
range of 15 to 125 hours).
In human tumors, TS has a modal value of about 16 hours (a range of 9.5 to 24
hours).
As a first approximation, the mean duration of the cell cycle in human tumors
is about 3 times the duration of the S phase.
Growth fraction is more variable in human tumors than in rodent tumors and
correlates better with gross volume doubling time.
Cell-loss factor for human tumors has been estimated by Tubiana and Malaise
to have an average value for a range of tumors in excess of 50%. Steel’s
estimate for a median value for all human tumors studied is 77%.