cis-Amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: in vivo activity, toxicology, and pharmacokinetics in mice. F I Raynaud, F E Boxall, P M Goddard, et al. Clin Cancer Res 1997;3:2063-2074. Published online November 1, 1997.
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Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
Vol.
3, 2063-2074,
Noi’e,nber
/997
Clinical
cis-Amminedichloro(2-methylpyridine) Novel
Sterically
Toxicology,
Florence
Hindered
and
I. Raynaud,2
Phyllis
Jones,
Michael
Abrams,
Cancer
Research
Institute Kingdom Matthey Kingdom
A.
and
Campaign
7 days
Centre
for Cancer
Therapeutics.
The
sterically
hindered
platinum
complex,
[cis-amminedichboro(2-methylpyridine) primarily
thiobs,
has
to
be
in vitro
shown
AMD473
platinum(II)J,
less
susceptible activity
several
due
enhanced
to reduced
DNA
adducts AMD473,
drug
repair/increased
(CH1/CHlcisR). at its maximum
administration,
activity in cisplatin
leukemia)
and
human
including
several
ovarian
possessing
[ADJ/PC6cisR, peutic
(ADJIPC6
In the
index
was
administration.
noted In
CHlcisR xenografts comparative growth
models,
model,
following
a
oral
as
opposed
also
noted
against
this
with
model).
a growth
delay
model,
of 34 days
oral
using
at 400
activity
was
mg/kg
When
every
4/10/97; revised 7/I 1/97: accepted
of publication
of this article
defrayed
in part
by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign and the Medical Research Council. 2
To whom
requests
search
Campaign
Cancer
Research,
Kingdom. Phone:
[email protected].
for reprints Centre
for
15 Cotswold 44-181-643-8901;
should Cancer
be addressed, Therapeutics,
Road, Sutton, Fax:
Surrey,
at Cancer The
Re-
Institute
of
SM2 5NG, United
44-181-770-7885:
E-mail:
area
40%
was
noted
p.o.,
13%
of the
results
were
observed
of 20 mg/kg,
i.p.
after following
oral
(over 50% of the administered istration of 400 mgfkg, showing limiting
factor
by
limiting
toxicity
for AMD473
and
no renal
mor
activity
pices
this
route
toxicity
and AMD473
is entering
was
after
repreSimilar
i.v. administration in the feces
following absorption
oral adminmight be a The
dose-
myebosuppression,
was
The
promising its lack
antituof nephro-
profile,
for clinical
I clinical
trials
Cancer
Research
Kingdom
ad24 h,
3 days.
excreted
with
candidate
Phase
Followof the
of administration.
together
In
plasma
recovery
after
pharmacokinetic
is a good
of the United
urine
observed.
was
favorable
in the
dose) that
plasma
of cisplatin. 33%
in mice
of AMD473,
and
of AMD473.
in oil,
and
more
ab-
to different
dose
but significantly
for
platinum
plasma,
72 h. Fecal
administered
of 8.6
bioavailability in area under
doses
of that
eliminated
was
the
and the increase
of binding half
ratios
heart, 5.2 concentration
was similar to that with a bioavailability
oral
mg/kg
a rapid
elimination organs with
the curve
in tissue,
the rate
eliminated
sented
with
by a slow in various
given
increasing
platinum
sched-
a biexpo-
plasma
under
was
of 45
and
(ADJIPC6), the
i.p. administration i.v. administration,
AMD473,
activity
(4 mg/kg)
5.7 for spleen, 3.7 for The plasma and tissue
was
to
xenografts,
comparable
dose
in
was approximately
AMD473
7/1 1/97.
were
Cmax
with
showed that following i.v. AMD473 in saline to Balb/c
observed
following
administration
and
that Received
and
with
toxicity
The costs
or at least
AMD473
growth
retreatment
carcinoma
sorption was rapid (K01 of 30 mm) was 40%. A less than proportional
ministered
to i.p.
ovarian
to plasma
time curve following observed following
ing
doses (q7d x4 schedule), as follows: AMD473, 34
In this
tissue
regrown
of cisplatin-sensitive
plasmacytoma
was
for liver and kidney, lung, and 5 for tumor.
proteins
days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days
platinum
vitro,
thera-
comparison
murine
ultrafiltrate
(carbopla-
an increased
panel
showed
had
(additional for
distribution tl/2a of 24 mm followed ti,213 of 44 h. Platinum accumulated
the curve
to cisplatin
HX11O
head-to-head
and equitoxic delays were
activity
xenograft
and
whole
pharmacokinetics of 20 mg/kg
decay
of 89%. that i.p.
L1210
resistance
CHlcisR,
ADJIPC6
show mg/kg
plasmacytoma,
carcinoma acquired
Ll2lOcisR,
or
of platinum-DNA
study, we dose of 35-40
in vivo antitumor
marked
of murine
(41M/4lMcisR)
tolerance In this tolerated
produced
a variety
tin-resistant)].
transport
by ovarian
carcinoma cell lines. Notably, AMD473 has shown vitro in human carcinoma cells that have acquired resistance
de-
to inactivation
against
the
improved
that
cisplatin
observed
for an equitoxic
bearing
nential
signed
against
showed
Platinum administration mice
with
human
to that observed ule of cisplatin.
ABSTRACT A novel
a
AMD473
xenografts
that
cisplatin-resistant
[M. A.]
In addition, CH1
over
Across
AMD473
doses).
treatment
of 30 days
cisplatin).
of Cancer Research, Sutton, Surrey SM2 5NG, United [F. I. R., F. E. B., P. M. G., M. V.. M. J., L. R. K.]; Johnson Technology Centre, Sonning Common. Reading, United [B. A. Ml; and AnorMED Inc.. Langley, British Columbia,
Canada
2063
Activity,
Vivo
against
initial
delay Kelland
of four
activity
following
Murrer, R.
(AMD473),
In
(total
promising
Valenti,
Lloyd
Complex:
Research
in Mice’
E. Boxall,
Melanie
Barry
Platinum
Pharmacokinetics
Frances
M. Goddard,
Mervyn
Platinum(II)
Cancer
suggests
development. under
the
aus-
Campaign
in
1997. INTRODUCTION
The
platinum
coordination
minedichloroplatinum(II) therapeutic years. being
treatment
However, markedly
complex
has played of a variety the toxic
drug
of neoplasms
possesses
to many
cisplatin,
a major
normal
significant tissues
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
cis-diam-
robe in the chemoover
the past
limitations (especially
25 in
neph-
2064 AMD473,
A Novel
Platinum
Complex
rotoxicities,
neurotoxicities,
and
and
many
are
in that
acquire
tumors
resistance
limitations new
to the
have
intensive drugs
those
Consequently, entered clinical Our
since trial
introduction
carboplatin
ported
the
Ref.
of the
(3),
bioavailable
platinum
which
the
in
and
antitumor
vivo
human
may life
resistant
One complexes
of the early, possessing
mors
is those
against
resistance,
have
(10-1
complexes
human
trials
tin,
1 ,2-diaminocyclohexane
16),
(especially
thus
shown has
cisplatin-resistant
the
cisplatin
of tetraplatin
considerably
xc-
cisplatin
not
in
resistance
platinum-DNA In this
Ref.
has
underlying 17).
predominate:
One
universal
(EloxaRefs.
13
toxicities
oxaliplatin),
but
of activity been
tumor or
more
reduced
man
to
been
platinum
designed
and
platinum
susceptible
to
studies
with
mechanism studies have
shown
lines
are
reported
s.c.
model
profile
murine
Ll210
cisplatin
oral
(in tumors
leukemia;
Ref.
-unresponsive
hu-
tumors
(20).
The
administration
pos-
antitumor
is also
and the disposition
following different routes to mice are also evaluated.
(4lM/ of/to
19). of AMD473
both
and
vitro
cis-
transport tolerance
(1 1), including
to
following
in
acquired
Ref. effects and
have
in
have
in
xenografts
resistance
AMD473
activity
that
of cisplatin-responsive
immunoin head
to detoxification
to reduced drug DNA repair/increased
cisplatin)
toxicity
(using
mech-
platinum-based
cisplatin
has
cell
carcinoma
The
to respond than
AMD473
plasmacytoma
ovarian
synthe-
center
a dissociative
adducts (CH1/CHlcisR; the in vivo antitumor
a range
AMD473 and p.o.)
in
pre-
and excretion
of administration
of
(i.p.,
iv.,
four
platinum
to mech-
trans-
METHODS JM335, and the Johnson
nology
agents
Center;
In Vivo Tumor
structures
Activity
of these
resistant
are shown
were Tech-
in Fig.
1.
Studies
murine
tumor
variants
macytoma
have
and
models been
Ll2lOcisR.
The
female
Balb/c A series
mice
as described nude
Ll2lO
ovarian
previously
(nu/nu)
ascitic
of these
platinum tumors
and
mice,
in DBA, tumor
et al. , submitted
for
publication.
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
i.p.
These
cisplatin-
ADJ/PC6 L1210 and
plasleukemia
their
cali-
has been described grown in syngeneic mice.
xenografts
selected
MTD, alkaline mass by
Holford
respective
models
drugs were
( 1 1). were
their
the s.c. solid
and
derivation
of human
plus
used;
ADJ/PC6cisR
bration with “standard” previously (10). ADJIPC6
4
AMD473 Matthey
Lines Two
female
used are: DACH. 1.2-diaminocyclohexane; dose; ALT, alkaline transaminase: ALP, dose in mg/kg required to reduce tumor every 7 days for a total of 4 weeks.
AND
Drugs
Cisplatin, carboplatin, JM216, synthesized by and obtained from
and
elucidated resistance
of
MATERIALS
used
I The abbreviations maximum tolerated phosphatase; ED,), 90%; q7dX4, once
hindered
at the
previous
carcinoma
study,
with
features of dicar-
[cis-amminedichloro(2-
favoring
failure
to
interaction
positive correlation between for glutathione S-transferase
platin resistance due 4lMcisR) or enhanced
Platinum
Lobaplatin ([1,2lactate; Refs. 15
evidence more
tolerance
of acquired
oxaliplatin
and
for
and
ovarian
sented.
dose-limiting
no compelling
mechanisms
(reviewed
of
with
years,
glutathione,
shown to murine
DACH-platinum
as
predicts
Our
it to be less
acquired
platinum(II)]; such
via
sterically has
bulk
and
of AMD473
(including
of
repair
of resistance
structural ammine/amine
AMD473
of steric
(18).
(ADJ/PC6
disease.
In recent concerning
12) and
a range
been
the
cancer
comparison
[tetrachloro-1,2-diamino-
Ref.
neurotoxicity
far there
neck
activity
carcinoma
is
with
related complexes, cyclobutane-platinum(II)
have
and
sessing
of acquired
(Ormaplatin,
platinum(IV)};
and
ovarian
complexes
clinical
cyclohexane [oxabato-
studies
class
platinum(II)]
Of
(9).
cellular
inactivation
glu-
DNA
mechanisms
the promising asymmetric
upon
described a significant histochemical staining
by
of
increased these
elevated
increased
anism of substitution rather than the associative that predominates with cisplatin. Recent clinical
of
activity against
ligand
models
circumvention
DACH-platinum
and 14) and diaminomethyl
other
preclinical
a new
Introduction
human
the quality chemotherapy,
carrier
However,
that
tetraplatin
sized.
shown
(6- 8). made (or
complexes were cisplatin-resistant
including
Recent
(3),
methylpyridine)
at
[trans-ammine
platinum(IV)] JM216) have
DACH3
additional
shown
by
1).
the
tumors.
nografts, resistance
a range
drug
centered
10) and
upon
in many
especially
chemotherapy
possessing
JM335
(and
DACH-platinum against acquired
cisplatin
anisms
complex
in
described
and thus far few, leads to platinum activity against cisplatin-resistant tu-
based
leukemia own)
p.o.
tumors.
particular note, retain activity Ll2lO
redi-
is now
an overwhelming need to broaden the drugs so as to induce responses
currently
our
which we have
make) a substantial impact in improving for patients undergoing platinum-based
there remains of platinum-based
we
and With
thiols, and building upon the previously described
2-methylpyridine)
ana-
of the first
recently,
models,
(cyclohexylaminedichlorodihydroxo) However, although carboplatin
toxic
[bis-acetato-ammine-
activity
tumor
in
in the
platinum(IV)
of a trans-platinum
some
murine
(4, 5). More
(and
In addition
platinum(IV)], trial
identification
least
less
led to the introduction
dichboro-cyclohexylamine II clinical
the
JM216
mind,
via
levels,
adducts, adducts.
complex
in collab-
Center
ammine/amine
complex,
have
in
detoxification
metallothionein
platinum-DNA
and
resulted
cytoplasmic
and/or
boxylates
far
2).
increased
tathione
of platinum-DNA
disease.
analogues
thus of
(Paraplatin;
discovery
carboxylates
Phase
profiles
resistant
Technology
world-wide
These
to discover
program
has
port, or
drug.
toxicity
against
Matthey Squibb)
logue,
efforts
discovery
Bristol-Myers
successful
of the
1971, over 20 cisplatin (reviewed in Ref. 1)
the Johnson
with
with
effects reduced
drug
toxicities) resistant
synthetic
activity
platinum-based
oration
part
with
possessing
tract
intrinsically
antitumor
driven
platinum-based
especially
gastrointestinal either
lines,
has also grown
to encompass
been s.c.
a broad
in
Clinical
H3N\
/Cl
Pt\ci
H3N/
/
H3N
was
Cl
J/
termed
stated,
Nil
\/
QN112
JM335
JM216
(n
Drugs
lethal
administered
volume.
tumors
Pharmacokinetics
Unless
days
were
difference
to double
at
0,
MTDs
tumor
data
otherwise
7,
14,
and
21.
using calipers, and volumes the tumors had at least doubled
Responses
the
dose).
on
of random-
ADJIPC6
LD,0
2065
Research
administered
and/or
measured weekly (4, 6, 1 1) until
delays:
10); the day
=
were
determinations
were
starting
treated
Cl
0.
MTD/lO%
drugs
their
3
groups
day
on previous
growth
Cl OCOCH
6) or control
=
Tumors were were determined
OH
OCOCH Cl3
2I
(n
ization
(approximately CARBOPLATIN
3\
groups based
CISPLATIN
Nil
//\
/oc\
H3N\
Cancer
compared
in time
taken
in terms for
of
control
and
in volume.
Studies
Nil
/Cl
3\
Animals
Pt /
to the
Cl
Female Babb/c mice laboratory conditions
They ad
1
Structures
JM216,
of
JM335,
the
platinum
allowed food The animals
(SDS expanded weighed 20
complexes
cisplatin,
carboplatin,
and AMD473. Experiment
1
The animals were implanted mm3 ADJIPC6 fragments. The in responsiveness
spectrum
ranged
from
(formerly
relatively
also
(HX/l
10)
models included
to
termed
of
and
HX/62).
cisplatin/carboplatin previously (20);
lOP
line
and
also
(derived
days. excluded
also from
of Antitumor
Platinum the stated
drugs
with
mia
schedules
as sonicated ADJ/PC6 activity
was
following
and
administered
Three
animals weights
previously,
used.
used Ten
and
antitumor
administered
i.p.
efficacy
with
(4,
has
10) group
1 X
on days
die in these survival onset of moribundity.
treated
of antitumor
(4, 6, 10). Briefly, tumor as single dose
l0
level,
and
and
groups
were
compared.
As
been
defined
in terms
Platinum
point
assays,
drugs were
but were
were
span. were then
not permitted sacrificed
ically
Ovarian
Carcinoma
Nude
mice
bearing
to at the
6-8
mm
diameter)
Xenografts
comparably were
sized
randomized
s.c. xenografts into either
then
or small
were
injected
g) AMD473
vasodilation.
vessels.
iv.
Blood
Group
was
were
transient
following
cervical
with
hyperther-
were
given
20
3: the animals
with halothane, and blood following severing of the for
10 mm
at 1000
X g.
and frozen at -70#{176}Cuntil analywas ultrafibtered upon collection
MW
10,000
in liquid
exclusion
membranes
dislocation
by centrif-
(liver, kidney, spleen, collected as quickly as of the animals
and
snap
nitrogen.
and
tissues
were
collected
1 h, 2 h, 4 h, 6 h, 24 h, 48 h, and 4 animals
into
tumors
2: the animals
centrifuged
was decanted of the plasma
Amicon
possible
randomized
in the tail vein
following
ugation at 1500 x g for 45 mm. Tissues heart, lung, brain, skin, and tumors) were
per
Experiment
time
5 mm,
15 mm,
30 mm,
72 h postadministration
(n
=
point).
2
Balb/c
mice
(typtreatment
were
given
25, 50,
100,
200,
and
AMD473 lung were
p.o. in saline. Blood, liver, kidney, spleen, collected 1, 2, 4, 6, 24, 46, and 72 h (n
per
point)
time
postadministration
and
treated
400 heart,
mg/kg and
=
3 animals
as
described
above.
Experiment Human
were large
with I for 20
of a
to the ED). assessed as in life controls
sizes
mI/lO g) AMD473 i.p in saline. Group 20 mg/kg AMD473 p.o. by gavage.
Blood
removed,
mI/lO
and the plasma sis. An abiquot
10 control
were
in the right flank was left to grow
with
The animals were anesthetized collected in heparinized syringes
frozen
tumors
1, 5, and 9. Animals end
drugs
i.p. or p.o. doses.
using an increase and 10 untreated cells.
20 days
fragments,
the ratio of the MTD in mg/kg Antitumor activity was
previously 5 mice/treated
implanted
later,
or
(0.1
through
1-mm3
at each
to
and carboplatin)
Assessment
doses)
days
of control
“therapeutic index”: L1210/Ll2lOcisR. described Briefly,
of
according
oil.
previously
(at halving were
were
(cisplatin
ADJIPC6cisR.
implantation
were
the
in saline in arachis
as described s.c.
animals
either
suspensions
i.p. or p.o.
s.c. tumor
the experiment.
to induce
axillic
administered
tumor Animals
1: the animals
mg/kg (0.1 were given
10 tumors).
Activity
were
from
20 mg/kg
was Assessment
of equal groups.
Group
PXN/l09/
treatment
Animals
the different
xenograft
termed
repeated
CH1
sensitivity Two
formerly
HX/l
and
and
resistance were CHlcisR (derived
through
bearing
animals
carboplatin
[PXN/65
to intermediate
(SKOV-3
cell
HX/l
carboplatin
and
to cisplatin
PXN/lO9T/C)]
refractory
the corresponding and
to cisplatin sensitive
of acquired as described
T/CC)
rodent diet) and water 1 .2 g at the time of
±
treatment.
AMD473
Fig.
were libitum.
(6 weeks of age) were acclimatized 2 weeks prior to the experiment.
3
Animals treated with collected
daily
were placed in metabolic AMD473 on day 1 . The and
frozen
at -70#{176}Cuntil
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
cages urine
for and
analysis.
3 days and feces were
2066 AMD473,
A Novel
Table
Platinum
Complex
In vivo antitumor
I
efficacy
of AMD473
versus
cisplatin
against
murine
tumors,
ADJIPC6
and the corresponding
cisR s.c.
plasmacytomas AMD473
MID ADJ/PC6
i.p.
ADJ/PC6
p.o.
ADJ/PC6cisR ADJIPC6cisR TI. therapeutic
I,
87%
inhibition.
2
Maximum
Table
(mg/kg) 43 560 35 560
i.p. p.o.
“
index:
MTD/ED1.
increase
Cisplatin
ED)
TI”
3
14.3
6.2
90.3
-25” 200
ND.
not
L12l0 Ll2lOcisR
11
2.8
ND
in life span (%) in L1210
and cisR
i.p.
heparinized
(dose)
Cisplatin
54(32mg/kg) 29
BindingfPlasma human
cisplatin
mm,
2
total
absorption
Analytical
tubes;
Disaccharidase
79(4mg/kg) 0
incubated
mm,
S
with
mm,
15
ultrafiltered
platinum
5 iM
AMD473
mm,
1 h, 2 h, 6 h,
30
as described
was
(model
measured
or
previously.
in the samples
were
introduced
of platinum
quantified
in the samples
was
into
using
platinum.
Quality
beginning
and
ng/ml
and
100
feces
was
added
United
ng/ml
Kingdom),
and plasma
by
were run
for
tissue
0.5
ml
of
and
the mixture
ultrafiltrates
the
furnace
Platinum
standard
a 5-cm gently
scraped
ALP,
ALT,
(days
studies
were checked of moribundity.
oil (n
as described
analyzed.
were
The
content
was
previously
To
was
mg
eval-
disaccharide measured
with
(21).
absorption
control
At 2 h, 2 days,
axillary
incision
6 days,
under
a single
group
and
halothane
Urea,
creatinine,
Marsden
Hospital
and
dose
10 days,
in the
they
and plasma ALT,
of drug
6 animals
were
decanted
and
ALP
bled
by
following
were
by conventional
i.p. in treated
analyzed
methods.
Histopathology
Examination
Using
the
same
group
for the hematology lung were removed and
of
study, and
stained
for
mice
liver, fixed
and
the
same
time
point
as
kidney, spleen, gut, heart, and in metharcan until they were
microscopic
examination.
Inulin
Clearance Glomerular
at 50
control
or
i.p in oil)
Co.,
filtration
animals
and
after
rate
10 animals
treatment
with
was
determined
treated
with
‘4C-inulin
in
mice
45 mg/kg
(10
AMD473
as described
previously
(22).
at 50#{176}C over-
the
diluted
Neurotoxicity
samples
spectrophotometry.
diluted
per
Urea received
for and
tissue
Chemical
incubated and
ng/ml tissue
of 20 and
200
mice
3 animals
=
and
Balb/c
group).
as required
Assessment
The
prior
to
effect
AMD473
were several
performed times
under
per day
strict
and
control.
sacrificed
in
of
chronic
(8 or 12 mg/kg i.p.
in saline)
the
on
previously
the
Rat
treatment
over
i.p. in oil twice nerve
conduction
described
method
6
weeks
with
weekly)
or cisplatin
velocity
was
(2
evaluated
(23).
Statistics at
Results between samples,
Toxicity
Female mg/kg
hemoglobin
Studies
Hematological (45
until
trehalose)
Creatinine,
Female
mg/kg
All toxicities
group).
and
of mice as for the hematology study, was removed, and gut mucosa was
frozen and
assays
using
Animals the onset
and
maltose,
sliced
in duplicate
(Sigma
added,
were
for
level
samples. hyamine
was
calibration 100
included
at the
for
terntissue.
at 60#{176}C.The
nm.
between 0 and 0 and 400 mg/kg
of each
used
analysis.
Toxicology
ND
spectro-
was
A 5-7-stage to the type of
an external
night. HC1 (0. 1 M; S ml) was then were analyzed by furnace atomic Plasma
700)
at 265.9
controls
end
absorption
(model
recorded
with platinum standards ultrafiltrates and between
plasma
atomic
furnace
spectrophotometry. used according
absorption
method plasma
1 100)
a graphite
samples
ND
Activity
at the Royal
atomic absorption program was
Fifty-p.l
platelets,
the same group section of jejunum
centrifugation.
A Perkin-Elmer furnace perature
WBC,
Using
spectrophotometry.
with
5.8
(dose)
Conditions
photometer
the
was
subsequently
and the free and atomic
24
Incubation
plasma
at 37#{176}Cfor
and 24 h and
TI 7.1
1.6
uated.
Bio-Rad Fresh
ED)
140
1.4
(sucrose,
Protein
(mg/kg) 11.3
determined.
leukemias
AMD473
MTD
Balb/c’ i.p.
Mice
1, 2, 4, 7,
a single
or control
bled 14,
expressed
Pharmacokinetic received
in oil)
were
were
arachis
as described 22,
and
dose
28).
oil
of either (n
previously The
blood
=
S animals
over was
NONLIN
AMD473 per
28 days placed
in
software
ysis.
Functions
were
fitted
data
as means
± SD.
groups were assessed with Student’s ANOVA, and the Mann-Whitney
was
parameters (Lexington,
consisting
to the data analyzed
with
of
by the
were KY)
The
calculated with
differences
test for unpaired test, as appropriate. t
with
1 , 2, or 3 exponential
least
squares
1 , 2, or 3 compartments
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
the
PC-
compartmental
anal-
components
method. and
Each the
set of best
fit
Clinical
Table
In vivo
3
antitumor
ef ficacy
ye rsus
of AMD473
cisplatin
against
Growth AMD473
(30-40
mg/kg
PXN/65
24 >139 34 6.8 0.1
I, “
“ (.
adopted.
plasma
For example,
iv.
whereas
data
the
model
best
4 (one
to plasma lated
was fit for
ratios
following
ratio
were
i.p.
of total
platinum
oral
shown
that
with
calculated with
and
using
36
25.5
14 43 6.4 2 ND
ND 43 3.5 6 ND
ND 17.5 5.4 6.8 ND
was
was
AUC
the
versus
iv.
JM216,
p.o. administration.
AUC
a
calcu-
Bioavailabil-
calculated
A
7),
Tissue
method.
i.p. administration:
i.p.)
fit for the
absorption).
administration
(4 mg/kg
47
(model
the relative
p.o.)
T 34 10.4 0 -2.9
at 20 mg/kg
the trapezoidal
oral
platinum
level
JM335’
mg/kg:
(90
4V
the best
first-order
JM216” i.p.)
ND
model
plasma
compartment
to the last point
ity
it was
a two-compartment
xenografts”
ND
All drugs were given on a q7d X 4 schedule. AMD473, cisplatin. and JM335, Data taken from Refs. 4. 6. and 20 except for CHlcisR data. Data taken from Ref. 7. ND, not determined. AMD473 and cisplatin were not compared in head-to-head experiments.
“
carcinoma
ND”
64
HX/llOP CHI CHlcisR SKOV-3 HX/62
ovarian
2067
Research
(days)
Carboplatin” (80 mg/kg
i.p.)
209
>215
HXJ11O
was
Cisplatin (4 mg/kg
i.p.)
delay
human
Cancer
500
j I
400
300
as the
administration
200
total
AUC. l0
RESULTS
In Vivo antitumor sible
Antitumor
efficacy
to
data
cisplatin)
models. to that some
for
made
by
oral administration resulting in an
therapeutic
previously
ment
of 90.
in therapeutic
observed AMD473, against
index
following antitumor L1210
and
oral activity
the acquired
ascitic
As shown a loss
murine
leukemia,
to
cisplatin
PXN/65 xenograft
when human
used
the
PXN/65
tumors
eventually
AMD473
was
growth AMD473 mg/kg imately
xenograft, delays
at 40 mg/kg q7dX4
also
CH1
the line
(Fig.
I-
300
. .
200
101
4 mg/kg xenograft.
q7dX4)
was curative;
compared
typically AMD473
growth
14)
0
comparing
50
75
100
125
150
75
DAY
Fig. 2 In vito antitumor activity of AMD473 i.p. schedule) against PXN/65 human ovarian
versus cisplatin (q7dX4 carcinoma xenograft (A) or CH1 human ovarian carcinoma xenograft (B). fl. controls; S. 4 mg/kg cisplatin: V. 30 mg/kg AMD473: A. 40 mg/kg AMD473. Data points, means: bars. SD.
or the
delay
cisplatin
platin,
Against
nograft
induces
cell
In contrast, used
at 30
(approx-
carboplatin, line
mg/kg)
this
AMD473
with
cis-
from
(Fig.
3). Results an
acquired
of 29-34 carboplatin
and
derived shows
cisplatin experiment
25
2B). Whereas
(Fig.
4 and this study).
a substantial
sirn-
80 days). A head-to-head
400
i.p.
the cisplatin-
activity
following this
the
cisplatin-sensitive
xenograft cell against
(Ref.
q7dX4 induced
I-
was
efficacy
against
antitumor either
(4 mg/kg
days
Against
showed
activity
regrew curative
cisplatin
of 25-35
500
a
but with increased
activity
subline.
carcinoma
from
q7dX4,
the CH1
against
ovarian
derived
a
ADJ/PC6
(4) no improve-
in antitumor
AMD473
ilar to cisplatin and retained some resistant variant. AMD473 exhibited improved
12)
B
administration of cisplatin. With by the oral route was also observed
cisplatin-resistant
LOU
Notably,
antiturnor activity was retained with a substantial reduction in toxicity, index
I 11
similar
selection.
in vivo
I)U
600
exhibited
of the
IZ
11,11)
tumor
efficacy
a variant
I)
DAY
AMD473
AMD473
)U
pos-
human
antitumor
ZD
the
wherever
plasmacytorna,
against
to cisplatin
summarize
and
Moreover,
of activity resistant
murine
showed
cisplatin.
1-3
(compared
of
ADJ/PC6
i.p. administration
retention
model
a variety
the murine
observed
Tables
for AMD473
for
Against
by single
Activity.
JM2I6
the
show
encouraging
(10.4 (6.4
about days) days),
that
much
JM216
using
AMD473 of
tumor,
3-fold and
performed cisplatin-resistant
level
cisplatin-resistant days,
was
acquired
greater
in
activity
at 40 against
inducing
a growth
delay
observed
with
days),
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
(especially vito
xc-
than
greater (3.5
the
CH lcisR
that
than
that
or JM335
observed (5.4
for days).
2068 AMD473.
A Novel
Platinum
Complex
(5
E
Fig. 3 In rho antitumor activity of AMD473 versus cisplatin and carboplatin (q7dX4 i.p. schedule) and JM216 (q7dX4 P.O. schedule) against CHlcisR
I-.
human
E 0
> 0
(5 >
ovarian
carcinoma
xc-
nograft. E, controls; #{149}, 4 mg/kg cisplatin; X, 80 mg/kg carboplatin; 0. 90 mg/kg JM2I6: V, 35 mg/kg AMD473: A. 40 mg/kg AMD473. Data points, means; bars, SD.
15
(5
DAY
Fig. 4 In 100 antitumor activity of AMD473 lersus cisplatin (each given on days 42. 49. and 56 following initial treatments) against CH1 human ovarian carcinoma xenografts at regrowth after treatment with cisplatin (3-4 mg/kg on days 0. 7. 14. and 21). fl. controls: 4 mg/kg cisplatin: A. 35 mg/kg AMD473. Data points. means: l)arS. SD. Arrows, days of drug administration.
I
.,
DAY
Across
nografts that
the
used
was
whole
in this
improved
comparable
over
to (e.g.,
cisplatin. Evidence model of acquired vito-derived
4).
mately Retreatment
to
CHI
twice
the
CHlcisR)
SKOV-3)
that
their
were
volume cisplatin
(20)]
ovarian
initial
time
of
carcinoma
was
comparably
at the induced
and a gain of about 20 days growth of the tumors. In contrast, AMD473
observed
also
with (42
of
to that xenografts
cisplatin being
treatment
a plateau delay before administered
in tumor
tumor
(Fig.
after
first
before
(day
route
in
0).
growth
rapid regrowth at 35 mg/kg
the
AMD473 i.p.
and
56 induced
and a gain
a marked
of approximately
reduction 50 days
reemergence of the tumors. Following the observation of antitumor ADJIPC6
were
also
Comparable route
model,
oral
performed activity
of administration
using
activity
antitumor the
was obtained
delay
by the oral studies
CHI/cisR
with
xenograft
to that observed
, maximum
(e.g.
in relative growth
of 34.5
by the
days
with
400 mg/kg p.o. q7dX4). In addition, and with JM216 (24), no schedule dependency
in contrast to results was noted; similar
growth
a daily
schedule
growth
delay
week;
approxi-
42, 49, volume
tumor.
apparent.
days
on days
for
compared
large,
start
or at least
carcinoma
treatment
activity
against another [HX/l lOP with in
was
retreatment
xc-
showed
and
of AMD473 human
tumors
with
CH1
carboplatin
following at
dose),
ovarian
3), AMD473
and
activity
had regrown
cisplatin
HX/62
against
Importantly,
human
of activity for AMD473 platinum drug resistance
antitumor
of cisplatin
of
(Table (e.g.,
resistance
The that
range
study
versus 25.9
delays
were
60 mg/kg/day a weekly days;
Fig.
and
with
for 4 weeks;
schedule
(300
mg/kg
q7dX4;
The
time
course
(5 days of 22.4
growth
per days)
delay
of
5).
Pharmacokinetics. plasma
observed
plasma
ultrafiltrates
Downloaded from clincancerres.aacrjournals.org on July 12, 2011 Copyright © 1997 American Association for Cancer Research
following
of iv.,
platinum i.p.,
and
in oral
Clinical
Fig. 5 Schedule dependency of mor activity of AMD473 following administration to mice bearing
CHlcisR nograft.
Cancer
Research
2069
antituoral the
human ovarian carcinoma xcE. controls: A, 300 mg/kg
AMD473 mg/kg/day
p.o. schedule): #{149}. 60 (p.o. for 5 days per for 4 weeks). Data points, means:
week
(q7dX4
AMD473
bars, SD.
DAY
administration shown
of AMD473
levels
fitted
and
maximum
plasma
levels decay
administration
with
time
versus
model
4). Following
platinum
the
course
two-compartment
tumor-bearing
iv. administration,
a two-compartment
44 h (Table
and
to ADJ/PC6
in Fig. 6. Following
with
in the plasma very
of 89%.
of
platinum
ultrafiltrable
model
given
p.o.,
within
1 h postadministration
with
AMD473
of 24 mm
was
a terminal rapidly
reached
following
a bioavailability
10000
1000
of AMD473,
were
similar
is
platinum
half-lives
i.p. administration
was
mice
the total
by 0.5 h, i.v.
The
and
i.p.
half-life
.
C
concentration
also
E 100
0.
followed
a
-5--
of 6 h. When
absorbed;
10
occurred
Cmax
-,--
life
similar
ability
to that
was
40%
The
and
observed
(Table
different
life in
studied.
plasma
ratios
ing
iv.
was than
high
to plasma
of AMD473
increase
in
AUC,
the three
i.v.
5; following
are
(Table
6).
in
i,,ll-
02468
10
20
30
40
50
60
70
80
the
Table
was
be
elimination the halfdecrease
(8.6 detected
-opoUF
E a) C
-
100
a10
followin the
1
I 10
11111
02468
i
j
,
20
30
40
it was
increasing
oral
Time
Fig.
6
Time
course
platinum (bottom) bars, SE.
of plasma platinum following 20 mg/kg
I
50
60
70
80
(h) (top) and plasma ultrafiltrable AMD473. Data points. means:
proportional
ultrafiltrable
kidney, and spleen; Fig. half-life of elimination
ultrafiltrate was always
iv UF
-c-ipUF
the tumor
than
plasma,
-0-
1000
muscle. were in
administration,
in
10000
and
over the time and kidney to
following
seen
in plasma and plasma 0.01). However, Cnax
liver
in skin and tumor levels
6. A less
and paramrapidly
and
with sometimes
not
oral
plasma, and all tissues examined (liver, 8). A significant increase in the platinum was registered doses (P