Biology Reference
In-Depth Information
FIGURE 8.2
Strand-break termini produced by oxidative DNA
damaging agents including IR. The chemical nature of the 3
0
-termini
depends on the site of attack on the deoxyribose group. (
Please refer to
color plate section
).
continues to be an effective agent in the treatment of
testicular germ-cell tumors (in combination with
cisplatin and etoposide), Hodgkin's disease (in combi-
nation with doxorubicin, vinblastine and dacarbazine),
and brain tumors.
25
e
27
After activation by complexation
with iron and molecular oxygen, bleomycin abstracts the
hydrogen atom from the DNA deoxyribose C-4
0
posi-
tion, leading to the formation of a strand break with
3
0
-phosphoglycolate and 5
0
-phosphate termini, or, alter-
natively, an intact strand with an oxidized abasic site.
24
Following reactivation of the bleomycin, the other
strand can be similarly damaged either directly opposite
the initial break or with a 1-base 5
0
-stagger (
Figure 8.3
).
Approximately 10% of bleomycin-induced lesions are
bistranded, composed of DSBs or an SSB opposite an
abasic site, but the latter lesions readily undergo
amine-catalyzed cleavage to convert them to DSBs.
28
Not surprisingly, the treatment of cells with bleomycin
was observed to produce frequent DNA deletions and
chromosomal aberrations at the
aprt
locus.
29
Enediynes are natural products found in soil and
marine microorganisms that exhibit remarkable antibi-
otic and antitumor activity.
30,31
The unique structural
feature of these compounds is a 9- or 10-membered
ring containing two carbon-carbon triple bonds. These
compounds bind in the minor groove of chromosomal
DNA in a sequence-dependent manner. They then
undergo an activation process that generates a di-radical
intermediate, which abstracts hydrogen atoms from the
DNA deoxyribose groups to generate a high level of
DSBs. Neocarzinostatin, for example, produces single-
strand:double-strand lesions in a ratio of ~ 2:1,
32
while
the even more toxic enediyne, calicheamicin, produces
a single-strand:double-strand lesion ratio of at least
1:20.
33
Figure 8.3
shows the major bistranded products
FIGURE 8.3
Chemically induced bistranded DNA lesions. Exam-
ples of bistranded lesions produced by bleomycin and the enediynes,
neocarzinostatin and calicheamicin, indicating the deoxyribose carbon
atoms from which hydrogen atoms are abstracted. Vertical arrows
indicate the sites of strand cleavage. 3
0
-Phosphoglycolate groups
are indicated by pg, while thymidine and deoxycytidine bearing
5
0
-aldehyde groups are labeled t and c, respectively. X represents an
abasic site.
Adapted from Chaudhry
et al.
, 1999.
289
following DNA reaction with these two enediynes. Neo-
carzinostatin can abstract hydrogen from the C-5
0
of
deoxyribose in one strand, and simultaneously abstract
the hydrogen from C-1
0
or C-4
0
in the opposite strand.
This produces a complex lesion with a strand break
bearing a terminal nucleoside with a 5
0
-aldehyde (C-5
0
abstraction) opposite either an abasic site with the deoxy-
ribose converted to a deoxyribonolactone (C-1
0
abstrac-
tion), or a strand break with a 3
0
-phosphoglycolate
residue (C-4
0
abstraction).
24
In a similar fashion, the
major lesion induced by calicheamicin is generated
by simultaneous hydrogen abstraction from C-5
0
and
C-4
0
.
34,35
However, the two enediynes have distinct
DNA sequence preferences and the stagger between the
lesions on opposite strands is different.
Their potency at inducing DSBs makes these
compounds highly toxic. Unfortunately, this toxicity
extends to normal tissue as well as cancer cells, which
has limited the therapeutic utility of these compounds.
However, several modifications have been introduced
to improve the efficacy of enediynes. Neocarzinostatin
has been coupled to a maleic acid-based polymer, which
