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Experimental Therapeutics, Preclinical Pharmacology |
Cancer Research Unit, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH United Kingdom [C. A. D., L-Z. W., S. K., A. H. C., N. J. C., B. W. D., D. R. N.]; Department of Chemistry, University of Newcastle, Newcastle upon Tyne, NE1 7RU United Kingdom [A. W. W.]; and Agouron Pharmaceuticals, Inc., San Diego, California 92121 [Z. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PARP activation after DNA damage has pleiotropic functions, including mediation of DNA repair (e.g., Refs. 6 and 7 ), modulation of p53 stability and function (8 , 9) , and regulation of apoptosis (reviewed in Ref. 10 ). Although precise molecular mechanisms for these functions have not been elucidated, the role of PARP in DNA BER has been well documented, using both PARP inhibitors and molecular genetic approaches. Recent evidence indicates that PARP is a member of a BER multiprotein complex, comprising PARP, DNA ligase III, XRCC, and DNA polymerase ß, which is involved in the DNA synthesis step of BER (see Ref. 11 and references therein). PARP may also cooperate with DNA-dependent protein kinase in the regulation of DNA double strand break repair and in the maintenance of genomic stability by the prevention of unwanted recombination events (12, 13, 14) . After DNA damage by alkylating agents, biochemical inhibition of PARP in cells mimics the altered responses in PARP knockout cells, namely, inhibition of DNA strand break repair and enhanced cytotoxicity (6 , 7) .
On the basis of its functional involvement in cell survival after DNA damage, PARP has been identified as a promising target for developing inhibitors for use in chemo- and radiopotentiation strategies, particularly because PARP function in the absence of extensive DNA damage is not essential for cell survival. This is exemplified by the survival and normal phenotype of knock out mice (15 , 16) . The potential of PARP inhibitors as resistance-modifying agents in cancer therapy has been comprehensively reviewed in Ref. (17) . With rational drug design approaches, two structural classes of compounds have been identified as potent PARP inhibitors, namely, the benzimidazole-4-carboxamides and quinazolin-4-[3H]-ones (18, 19, 20) . We have previously reported the ability of representatives of each of these classes, NU1025 (Ki = 48 nM) and NU1064 (Ki = 99 nM), to potentiate the cytotoxicity and inhibit the repair of DNA damage induced by DNA-methylating agents, ionizing radiation, and bleomycin in murine leukemia L1210 cells (6 , 21) .
The aim of the present study was to evaluate the growth-inhibitory and
cytotoxic effects of novel PARP inhibitors used alone or in combination
with clinically relevant anticancer drugs in a panel of human tumor
cell lines. The 12 cell lines used represented 4 of the most common
malignancies, namely, lung, breast, colon, and ovarian. They were
selected on the basis of their reported p53 status to investigate
whether or not cell lines harboring wild-type or mutant p53 showed
differential susceptibility to PARP inhibitor-mediated potentiation.
NU1025 and the 8-fold more potent benzamidazole NU1085
(Ki = 6 nM (19)
), were
selected as PARP inhibitors for this study (see Fig. 1
for structures). TM, a methylating
agent showing promise in the treatment of melanomas and gliomas
(22)
, was selected because the base methylation it induces
promotes BER and because our previous studies have shown useful
potentiation of cytotoxicity by NU1025 in L1210 cells (6)
.
The selection of the topoisomerase I inhibitor TP, a camptothecin
analogue, was based on observations that PARP inhibitors can potentiate
camptothecin cytotoxicity (23, 24, 25)
. TP has shown a wide
range of antitumor activity against adult and pediatric malignancies
(26
, 27)
.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Lines and Culture.
A panel of human tumor cell lines representative of four common cancers
were used: colon, HT29, LoVo, LS174T, breast: MCF-7, T47D, MDA-231;
ovarian, SKOV-3, A2780, OAW-42; and lung A549, COR-L23, H522. The p53
status of the following cell lines has been characterized by DNA
sequencing: A549 and MCF7, wild-type (28)
; LoVo, LST174T,
and A2780, wild-type (29, 30, 31)
; H522, SKOV-3, HT29, MDA,
and T47D, mutant (28)
; COR-L23, mutant (Dr. Xiaohong Lu,
Cancer Research Unit, University of Newcastle upon Tyne, unpublished
results). The p53 status of the OAW-42 cell line has not been reported
to our knowledge. Cells were maintained as exponentially growing
monolayers in RPMI 1640 supplemented with 10% (v/v) FCS (Sigma, Poole,
United Kingdom), 1000 units/ml penicillin, and 100 µg/ml streptomycin
(Life Technologies, Inc., Paisley, United Kingdom). In the case of the
OAW-42 cell line, insulin (10 units/liter) was also added. Cells were
tested every 4–8 weeks to exclude Mycoplasma contamination
(32)
. The cell lines were obtained from either the
European Collection of Animal Cell Cultures or the American Type
Culture Collection, except for the COR-L23 cell line, a gift from Dr.
P. Twentyman (United Kingdom Co-ordinating Committee for Cancer
Research, London, United Kingdom).
Growth Inhibition Assays.
Cells were plated at between 2.5 x
104 and 4 x 104/ml,
dependent on cell line-doubling time, to ensure exponential growth
during the course of the experiment, in 96-well plates (Nunc-Life A/S,
Roskilde, Denmark), and incubated for 24 h. The medium was then
replaced with medium containing TM or TP ± NU1025 or NU1085 (six
replicates for each drug treatment). Controls containing either no
drugs or NU1025 or NU1085 alone were also included. Replicate wells
were fixed at this time to estimate cell number at the start of the
drug incubation. After a 72-h exposure period cells were fixed, washed,
and stained with sulforhodamine B as described previously
(33)
. The absorbance of the wells relative to blank wells
that contained no cells was measured on a computer-interfaced Dynatech
MR7000 96-well microtiter plate reader (Dynatech, Billinghurst, United
Kingdom) using a 570-nm filter. In single drug treatment experiments,
drug-free controls containing 1% DMSO were included. In drug
combination experiments, where a fixed concentration of PARP inhibitor
was used in combination with increasing concentrations of TM or TP, the
PARP inhibitor alone samples (e.g., 50
µM NU1025) were used as controls. Similarly,
when growth inhibition experiments were carried out with a fixed
concentration of TM or TP in combination with increasing concentrations
of PARP inhibitor, the controls for these experiments were the TM or TP
alone samples. All control values were normalized to 100%. The values
obtained for each of the six replicates were averaged, and
IC50 values were defined as the concentrations of
drug(s) that inhibited growth by 50% relative to controls. The
IC50 values were calculated from the growth
inhibition curves generated by fitting sigmoidal curves to the data
using unweighted nonlinear least square regression analysis (GraphPad
Software, Inc., San Diego, CA). The PF50 was
expressed as the ratio IC50
(control):IC50 (sample).
Clonogenic Survival Assays.
Cell survival was determined by means of colony-forming assays. Cells
were plated at a density of 2 x 104
cells/ml for 24–48 h before treatment. All cell lines were treated
with TM or TP ± NU1025 or NU1085 for 24 h. After the
exposure period, the cells were trypsinized, resuspended in medium, and
counted with a Coulter Counter (model Z1, Coulter Electronics,
Bedfordshire, United Kingdom). A known number of cells were seeded onto
10-cm plastic Petri dishes to allow colony formation. After 2 weeks,
colonies were fixed and stained with crystal violet
(N-hexamethylpararosaniline). Survival was calculated as a
percentage of control for each drug concentration (see definition of
"control" in previous section).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20%); this was accounted for in the analyses of the
results (see "Materials and Methods"). The effects of these fixed
concentrations of NU1025 and NU1085 on growth inhibition produced by
continuous exposure to increasing concentrations of TM or TP during a
72-h incubation were investigated in all 12 cell lines. Representative
growth inhibition curves for the A549 cell line are shown in Fig. 2
, where it can be seen that 10
µM NU1085 potentiated both TM and TP growth
inhibition at least 2-fold, and to about the same extent as 50
µM NU1025, with 200 µM
NU1025 producing greater potentiation.
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ranged from
IC50 447 µM in the A2780 cell line
to IC50 >1500 µM for eight of the
other cell lines. (IC50 values >1500
µM could not be accurately determined due to the limited
solubility of TM in DMSO). For the cell lines where
PF50 values could be calculated for TM + NU1025
or NU1085, these values ranged from >5 to little greater than 1
(i.e., almost no potentiation by the inhibitors). A 200
µM concentration of NU1025 consistently gave
higher PF50 values than 50
µM NU1025, suggesting that complete cellular
inhibition of PARP had not been achieved at the lower concentration of
the inhibitor. No obvious tissue specificity for high versus
low PF50 values was observed.
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. The range of sensitivities to TP alone
in the cell lines was much broader than with TM, with
IC50 values ranging from >300 nM in
three of the cell lines (MCF7, MDA-231, and H522) to 10 nM
(LS147T). With the exception of the latter cell line, the three ovarian
cell lines were notably more sensitive to TP than all of the other
tumor types. The majority of the PF50 values were
between 2 and 4, although the cell line most sensitive to TP alone
(LS147T) displayed little or no potentiation of growth inhibition by
the PARP inhibitors (values from 0.9 to 1.3). For four of the cell
lines (A549, SKOV, LoVo, and MCF7), 200 µM NU1025 gave
higher PF50 values than 50 µM. For
the remaining cell lines, there was no persuasive increase in the
PF50 values at 200 µM compared with
50 µM, and indeed, in some cases, the
PF50 values at 50 µM were higher
than at 200 µM. However, because of the high number of
cell lines involved, the majority of the data represent two independent
experiments only and were not amenable to statistical analyses.
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2
).
Potentiation of TM and TP Clonogenic Cytotoxicity by NU1025 and
NU1085.
Growth inhibition does not necessarily result in cytotoxicity; some
drugs exert reversible cytostatic effects with minimal effects on cell
survival. Clonogenic survival assays were therefore performed to
ascertain whether the enhanced growth-inhibitory effects produced by
NU1025 and NU1085 correlated with increased cell killing.
Three of the twelve cell lines, LoVo, A549, and OAW-42, were selected
for all subsequent studies, and survival curves for A549 and LoVo are
shown in Fig. 3
. TM proved to be
considerably more cytotoxic than cytostatic. (The half-life of TM is
<2 h; thus, the shorter exposure time in this experiment, 24 h
compared with 72 h, is not relevant (34)
). For
example, 
200 µM TM reduced clonogenic survival by 50%
in the LoVo cell line, whereas the IC50 value for
growth inhibition was >1500 µM (compare Fig. 3
and Table 1
), and the same trend was observed with the A549 cells. NU1025 and
NU1085 (at 200 and 10 µM, respectively) potentiated the
cytotoxicity of TM in both cell lines, in general agreement with the
results obtained for growth inhibition in Table 1
. TP cytotoxicity was
also potentiated to similar extents by coincubation with NU1025 and
NU1085, and again these results were consistent with the potentiation
of growth inhibition observed.
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20%) growth inhibition. The
concentration-dependent effects of NU1025 and NU1085 on growth and
survival in the absence of TM and TP were assessed in more detail. Fig. 4
shows representative growth inhibition
and survival experiments for LoVo cells exposed either continuously (72
h) to increasing concentrations of NU1025 or NU1085 for growth
inhibition analysis (Fig. 4A
) or for 24 h before
plating for survival in the absence of inhibitor (Fig. 4B
).
NU1085 was considerably more growth inhibitory and cytotoxic than
NU1025.
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for three of the cell lines. Notably,
whereas NU1025 was about 3-fold more cytostatic than cytotoxic in the
OAW-42 and LoVo cell lines, the cytostatic and cytotoxic potencies of
NU1085 were nearly equivalent. The IC50 values
for NU1085 clustered between 80 and 100 µM, and were in
close agreement with the LC50 values. In
comparison, the IC50 values for NU1025 were 330
µM for two of three cell lines, whereas the
LC50 values were 
920 µM for all
three.
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, 2
, and 3
). An experiment was designed to compare
quantitatively the concentration-dependent effects of NU1025 on these
two biological end points. LoVo cells were exposed to increasing
concentrations of NU1025 in the presence or absence of a single fixed
concentration of TM (1 mM), which itself caused
20% growth inhibition, and growth inhibition and clonogenic
survival determined respectively. A comparison of the data for growth
inhibition (Fig. 5A
) and
clonogenic survival (Fig. 5B
) confirms that potentiation of
TM could be achieved at concentrations of NU1025 that exerted no
growth-inhibitory or cytotoxic effects when used by itself.
Furthermore, a concentration-dependent increase in the extent of
potentiation of TM-induced growth inhibition and cytotoxicity by NU1025
was obtained. Maximal potentiation was achieved by 300
µM NU1025 in the growth inhibition experiments
and 500 µM NU1025 in the clonogenic survival
experiments. This concentration-dependent increase in the extent of the
potentiation of TM was found in all of the cell lines tested, by both
NU1025 and NU1085, and is consistent with the results in Table 1
for
potentiation of TM-induced growth inhibition, where the
PF50 values for 200 µM
NU1025 were consistently higher than the 50 µM
values. However, in contrast to NU1025, NU1085 alone became cytotoxic
at concentrations at which its potentiating effects were still
increasing (results not shown).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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An evaluation of 12 human tumor cell lines was conducted with the intention of establishing whether there were marked differential sensitivities or selectivities to the PARP inhibitors, either in their ability to potentiate TM or TP, or in their inherent toxicities per se. The comparison of growth inhibition by the sulforhodamine B assay with clonogenic survival demonstrated that the far more rapid sulforhodamine B screen produced results consistent with the survival data and validated the former technique as a sufficient single method for studies with multiple cell lines. Although the PF50 values for the two inhibitors varied between cell lines, there was no single tissue type that displayed unusually marked or limited potentiation with either TM or TP. Furthermore, although both p53 mutant and WT cells were represented in the panel of cell lines (see "Materials and Methods" for details), no differential sensitivity to potentiation by the PARP inhibitors was noted. These observations suggest that PARP inhibitors as chemotherapeutic tools will not be limited by either cancer type or p53 status.
Although the Ki values for
NU1025 and NU1085 were 48 and 6 nM, respectively,
micromolar concentrations were required in cell culture to produce
significant potentiation. In general, 10 µM
NU1085 was about as effective as 50 µM NU1025
in the growth inhibition assays, with 200 µM
NU1025 showing greater potentiation in the majority of experiments,
indicating that PARP inhibition was not maximal at the lower
concentrations. This was confirmed by assessing the
concentration-dependent effects of NU1025 on TM-induced growth
inhibition, where maximal potentiation was not achieved until 300
µM NU1025 (see below). The extent of PARP
inhibition achieved in cell culture will depend on factors such as
inhibitor stability, membrane diffusion, and/or transport,
intracellular distribution, and metabolic inactivation, as well as PARP
and NAD+ levels in the cell lines.
A method for quantitatively assessing the relative potency of the inhibitors as potentiators of cytotoxicity was devised by inverting the conventional protocol of assessing the growth-inhibitory or cytotoxic effects of increasing concentrations of an anticancer agent in the presence or absence of a fixed concentration of resistance modifier (in this case, a PARP inhibitor). Thus, cells were treated with increasing concentrations of NU1025 in the presence or absence of a fixed concentration of TM, which itself caused only limited toxicity. This methodology proved useful for determining the optimum concentration of PARP inhibitor for maximal potentiation in cell culture, and also the ratio of the PARP inhibitor concentration required for potentiation to that which produced growth inhibition/cytotoxicity in its own right. Resistance modifiers, such as PARP inhibitors, should ideally be active at doses or concentrations that are nontoxic, and in this study NU1025 clearly fulfilled this criterion.
The data presented herein provide a comprehensive preclinical in vitro evaluation of the potential therapeutic efficacy and potency of chemotherapeutic agent-PARP inhibitor combinations. The development of this screen has facilitated the selection of the most suitable PARP inhibitors for studies with human tumor xenografts in nude mice and, ultimately, for clinical trials.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Cancer Research Campaign and by
Agouron Pharmaceuticals, Inc., San Diego, CA. 
2 To whom requests for reprints should be
addressed, at Cancer Research Unit, University of Newcastle upon Tyne
Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom Phone:
44(0)191 222 7133; Fax: 44(0)191 222 7556; E-mail: b.w.durkacz{at}newcastle.ac.uk
3 The abbreviations used are: PARP,
poly(ADP-ribose) polymerase; LC50, concentration of drug
causing 50% cytotoxicity; PF50, potentiation factor at
50% growth inhibition; TM, temozolomide; TP, topotecan; NU1025,
8-hydroxy-2-methylquinazolin-4-[3H]one; NU1085,
2-(4-hydroxyphenyl)benzamidazole-4-carboxamide; BER, base excision
repair.
Received 12/17/99; revised 3/21/00; accepted 3/22/00.
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, + NU1025 (50 µM); 
, + NU1025 (200
µM); 
, + NU1085 (10 µM).
, NU1085.
; B,
effect on survival of a 24-h exposure to NU1025 