Biology Reference
In-Depth Information
that is a powerful chemotherapeutic regimen. Indeed, it is
now common practice for modern chemotherapeutic
regimens to combine several of the aforementioned
chemotherapeutic agents in order to strike multiple
cellular pathways andmaximize the cell killing potential.
One example is the CHOP regimen (cyclophosphamide,
hydroxydaunorubicin, Oncovin (vincristine), and pre-
gnisone) that is widely used in the treatment of non-
Hodgkin's lymphoma.
24
There are a large number of
other regimens used in the treatment of other hematolog-
ical disorders as well as various solid tumors. The details
of their clinical and biochemical effects are reviewed else-
where.
25,26
In this chapter, discussions will focus on
understanding the role of DNA polymerases in cancer,
how their activity is influenced by DNA damaging
agents, and how they participate in various DNA repair
pathways. Particular emphasis is placed on describing
the biochemical and clinical aspects of anti-metabolites
andDNAdamaging agents usedas antineoplastic agents.
linking of one nucleotide at a time to the end of a preex-
isting DNA chain serving as a primer. Since the
sequence of the template varies, DNA polymerases are
faced with the difficult task of remaining flexible enough
to recognize four distinct pairing combinations (A:T,
C:G, T:A, and G:C) while being stringent enough to
maintain faithful duplication of the template so that A
is always incorporated opposite T and never opposite
C, G, or A. This polymerization process results in the
synthesis of a DNA chain that is complementary to the
template strand of DNA and is sequenced according to
the proper Watson
e
Crick nucleotide base pairing rules
(
Figure 5.2
).
DNA polymerases use the deoxynucleoside triphos-
phate forms of the deoxynucleotides to build the DNA
polymer. During the reaction, the monophosphate form
of the deoxynucleotide is incorporated into the growing
DNA chain while the pyrophosphate moiety is released.
Occasionally, DNA polymerase incorrectly incorporates
a nucleotide onto the growing DNA chain. In some cases,
removal of this misincorporated nucleotide is performed
by a exonuclease “proofreading” activity that excises the
mispaired nucleotide from the 3
0
end of the DNA. In
general, the combined actions of key steps associated
with polymerization and exonuclease proofreading
DNA POLYMERASES
All DNA polymerases share a common mechanism
for DNA chain synthesis that involves the covalent
A
dNTPs, Mg
2+
B
M-Phase
Staurosporine
(kinase inhibitor)
Vincristine
(anti-mitotic)
G
2
G
1
S-Phase
F-Ara-ATP
(DNA polymerase inhibitor)
Cisplatin
(DNA damaging agent)
FIGURE 5.1
(A) DNA polymerases share a common mechanism for DNA synthesis. During polymerization, a nucleotide is covalently
attached to the 3'-OH group of a preexisting DNA chain serving as a primer. With most DNA polymerases, DNA or RNA is used as the template
to guide each incorporation event. Correct polymerization results in the synthesis of a DNA chain that is complementary to the template strand
of DNA. (B) Chemotherapeutic strategies to inhibit DNA synthesis. These include (
i
) the use of kinase inhibitors to block cell-cycle progression,
(
ii
) anti-mitotic agents that block microtubule assembly and formation, (
iii
) compounds that induce the formation of DNA lesions, and (
iv
) anti-
metabolites that directly or indirectly inhibit DNA polymerase activity.
