toxicology, and pharmacokinetics in mice. novel ...

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.

Updated Version

Citing Articles

E-mail alerts Reprints and Subscriptions Permissions

Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/3/11/2063

This article has been cited by 4 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/3/11/2063#related-urls

Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].

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


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.


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


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


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),


(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


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