178
Cancer Chemotherapy, Theoretical Foundations of
Growth-factor
sensitivity
Cdk4/6
Cyclin D1, 2, 3
Cdk2
Cyclin E
Cdk2
Cyclin A
Cdc2
Cyclin A
Cdc2
Cyclin B
S
G2
M
Restriction
point
E2F
pRb
pRb
p
p
E2F
G1
Cell cycle
progression
Fig. 3
Regulation of the cell cycle. The four phases of the cell cycle is indicated, together with
the nature and the timing of the cyclin-Cdk complexes involved in cell cycle progression. The
Restriction point, positioned in G1(R), is the point at which cells become committed to cell
cycle progression and no longer require growth factors. The regulation of E2F activity, which
controls the early cell cycle, is indicated underneath. In normal cells, the pRb binds to E2F to
inactivate E2F activity. As pRb becomes phosphorylated (indicated by p) by Cdk complexes, E2F
is released leading to the activation of target genes required for cell cycle progression. Normal
control of pRb activity is frequently lost in human tumor cells, either through mutation in pRb
or altered levels of its upstream regulators, including Cdk complexes.
polymerase II to influence the expression
of a diverse set of genes.
Compounds that act on multiple Cdk
enzymes, together with those that are more
selective, have been taken into clinical
development. UCN-01 is an example of a
nonspeciFc kinase inhibitor active against
a variety of kinases including Cdks, pro-
tein kinase C, and checkpoint 1 kinase.
In contrast, flavopiridol and R-roscovitine
exhibit greater speciFcity for Cdk targets.
±lavopiridol inhibits Cdk1, 2, 4, and 7
(including Cdk2 at nM concentrations)
by competing with the ATP binding site,
and has reached Phase II clinical trials
as a monotherapy for cancer. Roscovitine
possesses moderate speciFcity for Cdk2,
but also inhibits other kinases like Cdk7
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