zyxwvutsrqp
zy
zyxwv
51
Scand J Haematol
Suppl 44, Vol 34, 1986
CELLULAR PHARMACOLOGY AND OPTIMAL THERAPEUTIC CONCENTRATIONS OF 1-@-0-
ARABINOFURANOSYLCYTOSINE 5'-TRIPHOSPHATE I N LEUKEMIC BLASTS DURING TREATMENT OF REFRACTORY LEUKEMIA WITH HIGH-DOSE
SINE
1-8-D-ARABINOFURANOSYLCYTO-
W i l l i a m P l u n k e t t l , Stephen Iacoboni2. Michael J . Keating2
Department o f Chemotherapy Research1
Department o f Hematology2
The U n i v e r s i t y o f Texas M.D. Anderson H o s p i t a l and Tumor I n s t i t u t e a t
Houston, Houston, Texas 77030, USA.
ABSTRACT
The pharmacology o f 1-8-D-arabinofuranosylcytosine 5 ' - t r i p h o s p h a t e
(ara-CTP) has been s t u d i e d i n t h e c i r c u l a t i n g leukemic b l a s t s o f p a t i e n t s
w i t h r e f r a c t o r y leukemia d u r i n g t h e r a p y w i t h h i g h doses o f s i n g l e - a g e n t
ara-C. C e l l u l a r ara-CTP was analyzed by high-pressure l i q u i d chromatography. The median t r o u g h c o n c e n t r a t i o n s o f ara-CTP i n b l a s t s o f p a t i e n t s
who responded t o i n t e r m i t t e n t high-dose ara-C ( 3 g/m2 x 4-12 doses) was
196 vM, whereas 75 VM was t h e l o w e s t t r o u g h ara-CTP c o n c e n t r a t i o n
t h a t d i s c r i m i n a t e d between complete r e m i s s i o n and t r e a t m e n t f a i l u r e
(p=0.03). The median steady s t a t e ara-CTP c o n c e n t r a t i o n s i n t h e b l a s t s o f
p a t i e n t s who responded t o a h i g h dose continuous i n f u s i o n p r o t o c o l ( 2
doses o f 3 g/m2 e v e r y 12 h r f o l l o w e d by a continuous i n f u s i o n o f 3303000 m g / d x 4 d) were c l u s t e r e d between 79 and 206 vM. The values o f
t r e a t m e n t f a i l u r e s were p r e d o m i n a n t l y o u t s i d e t h i s range (p<0.005). These
r e s u l t s suggest t h a t t h e o p t i m a l c o n c e n t r a t i o n range f o r i n t r a c e l l u l a r
ara-CTP i n t h e t r e a t m e n t o f r e f r a c t o r y leukemia may be 75 t o 200 pM.
INTRODUCTION
The most e f f e c t i v e d r u g f o r t h e s u c c e s s f u l t r e a t m e n t o f a d u l t a c u t e
myelogenous
leukemia
is
1-p-arabinofuranosylcytosine
(ara-C)
(1).
Over
t h e years, i n v i t r o s t u d i e s have c o n t r i b u t e d t o a s u b s t a n t i a l understand i n g o f t h e c e l l u l a r metabolism o f ara-C and t o t h e mode o f a c t i o n o f i t s
active
CTP)
metabolite
(2-4).
1-8-D-arabinofuranosylcytosine
However,
5'-triphosphate
(ara-
r e l a t i v e l y l i t t l e information exists t h a t relates
p a t i e n t response t o t h e b i o c h e m i c a l pharmacology o f ara-CTP i n t h e leuke-
Key words: ara-CTP, high-dose ara-C, i n d i v i d u a l i z e d therapy,
leukemia.
Running t i t l e : C e l l u l a r Pharmacology o f ara-CTP
refractory
52
mic c e l l s d u r i n g d r u g a d m i n i s t r a t i o n
(5).
Recent a p p l i c a t i o n o f h i g h -
p r e s s u r e l i q u i d chromatographic procedures t o t h i s problem (6,7)
and t h e
t h e r a p e u t i c use o f ara-C doses 30 t i m e s g r e a t e r t h a n t h o s e a d m i n i s t e r e d
i n c o n v e n t i o n a l c o m b i n a t i o n chemotherapy have f a c i l i t a t e d t h e i n v e s t i g a t i o n o f t h e i n t r a c e l l u l a r metabolism o f ara-CTP i n tumor c e l l s (8,9).
The
g o a l o f t h e p r e s e n t s t u d y was t o g a i n an u n d e r s t a n d i n g o f t h e r e l a t i o n s h i p between t h e c e l l u l a r metabolism o f t h e a c t i v e f o r m t o ara-C and t h e
c l i n i c a l response t o ara-C t h e r a p y .
I n t h e process, we hoped t o i d e n t i f y
a range o f ara-CTP c o n c e n t r a t i o n s
i n leukemic c e l l s t h a t i s a s s o c i a t e d
w i t h p o s i t i v e c l i n i c a l response.
I t i s w i d e l y r e c o g n i z e d t h a t t h e a c t i v e m e t a b o l i t e o f ara-C i s t h e t r i -
phosphate, ara-CTP
(10.11).
Ara-CTP
appears t o have a d i r e c t e f f e c t on
zy
zyxwvut
DNA s y n t h e s i s
because i t competes w i t h dCTP i n t h e i n h i b i t i o n o f DNA
polymerase (11,12)
and i s i n c o r p o r a t e d i n t o DNA (13).
These a c t i o n s a r e
strongly associated w i t h t h e loss o f clonogenicity o f c e l l s i n c u l t u r e
( 1 4 ) . I n a d d i t i o n ara-CTP i s known t o p a r t i c i p a t e i n aspects o f i n t e r m e -
.005
.004.003 -
E
0
a3
.001
hl
I
-
OI
zyxwv
0
0
C
L1
m
In
.004
%I
araCTP
J
I
n
a
.003
.002
.oo 1
0
10
20
Minutes
30
Fig.
1. High-pressure
liquid
chromatographic
separation of
nucleoside triphosphates.
A.
Standard
compounds.
CTP,
1.85 nmol; ara-CTP, 1.80 nmol;
UTP 1.70 nmol; ATP, 2.10 nmol;
GTP, 1.90 nmol.
B. An e x t r a c t o f 1x107 p e r i p h e r a l leukemic b l a s t s f r o m a
p a t i e n t w i t h r e f r a c t o r y acute
myelogenous leukemia sampled 12
h r a f t e r i n f u s i o n o f 3 g/m2
ara-C. The mean c e l l volume was
0.31
pL.
Calculated c e l l u l a r
concentrations
of
nuc 1eos i d e
CTP.
310 vM;
triphosphates:
ara-CTP,
250 pM; UTP,
1.290
vM; GTP, 790 pM.
zyxwvu
53
d i a r y m e t a b o l i s m t h a t i n v o l v e p h o s p h o l i p i d s (15) and g l y c o p r o t e i n s ( 1 6 ) .
These a c t i o n s may e x p l a i n t h e t o x i c i t y o f ara-C
i n v o l v e d i n DNA s y n t h e s i s .
However,
t o c e l l s t h a t are not
a s i n g l e mechanism o f c y t o t o x i c i t y
f o r ara-CTP has n o t been i n d e n t i f i e d . and i t i s l i k e l y t h a t s e v e r a l t o x i c
a c t i o n s c o n t r i b u t e t o c e l l death. F o r t h a t reason, we have chosen t o f o cus on t h e c e l l u l a r m e t a b o l i s m o f ara-CTP i n leukemia c e l l s d u r i n g t h e r a PY.
RESULTS AND DISCUSSION
C i r c u l a t i n g leukemic b l a s t s f r o m p a t i e n t s w i t h r e f r a c t o r y a c u t e l e u k e mia were f r a c t i o n a t e d by F i c o l l - H y p a q u e d e n s i t y c e n t r i f u g a t i o n . A f t e r t h e
c e l l s were counted and t h e i r mean volume was determined, c e l l u l a r n u c l e o t i d e s were e x t r a c t e d w i t h p e r c h l o r i c a c i d and s e p a r a t e d by anion-exchange
h i g h - p r e s s u r e l i q u i d chromatography ( 1 7 ) .
F i g u r e 1 A shows t h e s e p a r a t i o n
o f a m i x t u r e o f r e f e r e n c e compounds. Using t h i s procedure, t h e l o w e r li-
m i t o f d e t e c t i o n o f ara-CTP i s a p p r o x i m a t e l y 25 pmol. A s i m i l a r f r a c t i o n a t i o n o f t h e n u c l e o s i d e t r i p h o s p h a t e s i n an e x t r a c t o f p e r i p h e r a l leuke-
m i c b l a s t s i s o l a t e d f r o m t h e b l o o d o f a p a t i e n t r e c e i v i n g high-dose ara-C
t h e r a p y i s shown i n f i g u r e
IB. T h i s chromatogram demonstrates t h a t even
3 g/m2
12 hours a f t e r i n f u s i o n o f
z
of
ara-C,
ara-CTP
remains a m a j o r
n u c l e o t i d e i n t h e leukemic c e l l s o f t h i s p a t i e n t .
S e r i a l sampling o f p e r i p h e r a l b l o o d d u r i n g and f o l l o w i n g ara-C
infu-
zyxwvu
zyxwvutsr
zyxwvut
s i o n s gave a p h a r m a c o k i n e t i c p r o f i l e o f ara-CTP m e t a b o l i s m i n leukemic
1000
500
5
&l-
o
200
-:
,$<100 -- 4 # A
,**\
50
\'\
-..*.
A
'
-2,
\
F i g . 2. Accumulation and r e t e n t i o n o f ara-CTP by c i r c u l a t i n g leukemic b l a s t s o f f i v e
p a t i e n t s w i t h r e f r a c t o r y acute
myelogenous leukemia a f t e r a
(3
2-hr
infusion
of
ara-C
g/m2).
Cellular
concentrat i o n s of ara-CTP were d e t e r m i '-+ ned f o r each p a t i e n t by t h e
h i g h - p r e s s u r e 1 i q u i d chromatog r a p h i c method shown i n f i g u r e
1. Those i n d i v i d u a l s i n d i c a t e d
by open symbols and s o l i d l i n e s
a c h i e v e d complete r e m i s s i o n i n
, response t o high-dose ara-C
12 t h e r a p y . R e s i s t a n t p a t i e n t s a r e
i n d i c a t e d by c l o s e d symbols and
dashed l i n e s .
-..
$
-z
20
-
10
$
5
zyxwvutsrq
zy
=-
2
1
-++
9
'
/
0
.
a
\
A
I
I
jaZ3-l
4
8
Hours
kk.
\;'. '.
zyxwvu
zyx
54
c e l l s (Fig.
I t i s c l e a r t h a t t h e r e i s g r e a t d i v e r s i t y among p a t i e n t s
2).
w i t h r e s p e c t t o t h e a b i l i t y o f t h e c i r c u l a t i n g leukemic b l a s t s t o accumul a t e and t o r e t a i n ara-CTP.
More d e t a i l e d s t u d i e s have demonstrated good
c o r r e l a t i o n s between t h e ara-CTP c o n c e n t r a t i o n s i n c i r c u l a t i n g b l a s t s and
t h o s e i n t h e marrow b l a s t s f r o m t h e same p a t i e n t (18). . I n a d d i t i o n ,
it
has been p o s s i b l e t o demonstrate t h a t t h e c e l l u l a r pharmacokinetics o f
ara-CTP
i n t h e c i r c u l a t i n g leukemic b l a s t s o f p a t i e n t s w i t h r e c u r r e n t
zy
zyxwvutsrq
a c u t e leukemia were s t r o n g l y c o r r e l a t e d w i t h c l i n i c a l response t o h i g h dose ara-C
t h e r a p y (19).
Although t h e peak c o n c e n t r a t i o n s o f ara-CTP
t h e s e response c a t e g o r i e s were n o t s i g n i f i c a n t l y d i f f e r e n t ,
in
s t r o n g asso-
c i a t i o n s were found between response and t h e r a t e o f ara-CTP e l i m i n a t i o n ,
t h e t r o u g h ara-CTP c o n c e n t r a t i o n , and t h e area under t h e ara-CTP accumul a t i o n and e l i m i n a t i o n c u r v e . I n p a r t i c u l a r ,
t h o s e p a t i e n t s whose c e l l s
r e t a i n e d ara-CTP more e f f e c t i v e l y , which a l l o w e d f o r g r e a t e r i n t r a c e l l u l a r exposure t o t h e t o x i c m e t a b o l i c ,
had a s i g n i f i c a n t l y g r e a t e r chance
o f a c h i e v i n g a complete r e m i s s i o n t h a n d i d t h o s e p a t i e n t s whose c e l l s d i d
n o t r e t a i n ara-CTP
exposure t o ara-CTP (19,20).
findings.
zy
as e f f e c t i v e l y and t h e r e f o r e had a r e l a t i v e l y b r i e f
The d a t a presented i n f i g u r e 2 r e f l e c t t h e s e
zyxwv
zyxwvutsrq
’“7
The t r o u g h c o n c e n t r a t i o n o f ara-CTP,
0
,0°1
* O 0tI
O
0
0,
8
O
Complete
Remission
..
0
Failure
t h a t amount p r e s e n t i n leukemic
Fig.3.
Relationship
between t h e response o f p a t i ents w i t h r e f r a c t o r y acute
leukemia
to
intermittent
high-dose ara-C t h e r a p y and
t h e trough concentration o f
in
circulating
ara-CTP
blasts 12 h r a f t e r infusion
o f t h e f i r s t dose o f ara-C.
The l o w e s t c e l l u l a r ara-CTP
c o n c e n t r a t i o n t h a t marked a
d i s t i n c t i o n between compl e t e r e m i s s i o n and t r e a t ment
failure
(resistant
disease
plus
supportive
care f a i l u r e ) a t a s i g n i f i c a n t l e v e l (p=0.03)
was
75 pM, which i s i n d i c a t e d
by t h e dashed l i n e .
zyxwvut
zyxwvuts
zyxwv
55
c e l l s j u s t b e f o r e t h e n e x t dose o f ara-C i n t h e i n t e r m i t t e n t dose r e g i -
men. It i s p o s s i b l e t h a t t h e lowest trough ara-CTP c o n c e n t r a t i o n t h a t i s
associated
w i t h t h e attainment o f complete remission might serve as an
i n d i c a t o r o f t h e lower l i m i t o f t h e m e t a b o l i t e associated w i t h c l i n i c a l
response.
F i g u r e 3 i s a r e p r e s e n t a t i o n o f t h e t r o u g h ara-CTP concentra-
t i o n s i n 52 p a t i e n t s w i t h relapsed acute leukemia who were t r e a t e d w i t h
i n t e r m i t t e n t high-dose ara-C
doses) (20).
( 3 g/m2 over 2 hr,
every 12 h r f o r 4-12
P a t i e n t s who achieved a complete remission had a median
t r o u g h ara-CTP c o n c e n t r a t i o n o f 196 vM. The t r e a t m e n t - f a i l u r e
category
i n c l u d e s i n d i v i d u a l s who achieved marrow hypoplasia b u t f a i l e d t o regene-
r a t e a normal marrow, and those who d i e d w i t h a p l a s t i c marrows as w e l l as
p a t i e n t s w i t h r e s i s t a n t disease. The lowest trough ara-CTP c o n c e n t r a t i o n
t h a t was s i g n i f i c a n t l y d i f f e r e n t f o r p a t i e n t s who responded and those f o r
whom treatment f a i l e d was 7 5 VM (p=0.03).
Because t h e t r o u g h i s t h e
lowest c e l l u l a r ara-CTP c o n c e n t r a t i o n experienced by t h e c e l l s d u r i n g t h e
course o f therapy,
i t suggests a p o t e n t i a l lower l i m i t o f ara-CTP asso-
c i a t e d w i t h response t o i n t e r m i t t e n t high-dose ara-C therapy.
As an ex-
t e n s i o n o f t h i s reasoning, t h e median value f o r p a t i e n t s w i t h r e s i s t a n t
disease,
23
pM,
must be viewed as being inadequate t o achieve d e s i r e d
therapeutic results.
A subsequent group p a t i e n t s who had disease c h a r a c t e r i s t i c s s i m i l a r t o
t h e p a t i e n t s t r e a t e d w i t h i n t e r m i t t e n t high-dose ara-C,
were t r e a t e d w i t h
zyxwvutsrqpon
40 L
ara-C by continuous i n f u s i o n . Each p a t i e n t ’ s dose was determined by t h e
a b i l i t y o f t h e c i r c u l a t i n g b l a s t s o f t h a t p a t i e n t t o accumulate and r e t a i n
7005
i
A
A
ui
c
u)
Q
5
.-t
“
k
v
g
A
A
300
1
w
A
200
200
al
c
0
Ga
100
75
D
Q
al
Responae
F i g . 4. Steady s t a t e ara-CTP
concentrations
in
1eukemic
b l a s t s d u r i n g pharmacologically
directed
continuous
infusion
ara-C
therapy.
Patients w i t h
e i t h e r relapsed acute leukemia
(n=25) o r chronic myelogenous
leukemia i n b l a s t c r i s i s (n=13)
i n i t i a l l y received an i n f u s i o n
o f 3 g/m2 over 2 h r . The area
under t h e ara-CTP accumulation
and r e t e n t i o n curve was d e t e r mined i n an o n - l i n e fashion.
T h i s i n f o r m a t i o n was used t o
c a l c u l a t e a continuous i n f u s i o n
dose r a t e o f ara-C t h a t would
m a i n t a i n t h e d e s i r e d steady
s t a t e c o n c e n t r a t i o n o f ara-CTP
(19) *
zyxwv
zyxwvut
56
ara-CTP
a f t e r a t e s t dose o f 3 g/m
2 (19,21).
The area under t h e c u r v e
f o r c e l l u l a r a c c u m u l a t i o n and e l i m i n i a t i o n o f ara-CTP was used t o c a l c u -
l a t e a dose o f ara-C t o be i n f u s e d c o n t i n u o u s l y o v e r 96 h r t h a t was p r o jected
as
necessary t o m a i n t a i n t h e
level
of
ara-CTP
i n circulating
b l a s t s a t g r e a t e r t h a n 75 IM d u r i n g t h e i n f u s i o n (19,21).
The median c o n c e n t r a t i o n o f ara-CTP was 75
pM.
The steady s t a t e a r a -
CTP c o n c e n t r a t i o n s t h a t were achieved exceeded t h e c a l c u l a t e d t a r g e t l e -
v e l s by a mean o f 3.3
+-
1.8-fold.
It i s l i k e l y t h a t t h i s was due t o
s a t u r a t i o n o f t h e r a t e o f ara-CTP accumulation d u r i n g t h e b o l u s i n f u s i o n ,
l e a d i n g t o an u n d e r e s t i m a t i o n o f t h e a b i l i t y o f t h e c e l l s t o a n a b o l i z e
ara-C ( 2 2 ) . Pharmacologic e v a l u a t i o n o f t h e p a t i e n t s t r e a t e d on t h i s p r o t o c o l presented t h e o p p o r t u n i t y t o compare t h e steady s t a t e concentrat i o n s o f ara-CTP d u r i n g continuous
i n f u s i o n w i t h t h e response o f each
p a t i e n t ( F i g . 4).
There was a s i g n i f i c a n t c l u s t e r i n g o f steady s t a t e ara-CTP
values f o r
t h e p a t i e n t s who achieved complete r e m i s s i o n between 79 VM and 206 IM
(10 o f 17). We have d e s i g n a t e d t h i s as t h e " t h e r a p e u t i c range".
rast,
o n l y 2 o f 21 p a t i e n t s whose steady s t a t e ara-CTP
I n cont-
concentrations
f e l l o u t s i d e o f t h i s range achieved a complete r e m i s s i o n (p<0.005).
The
c e l l s o f t h e p a t i e n t s w i t h r e s i s t a n t disease appear t o have been e i t h e r
i n c a p a b l e o f m a i n t a i n i n g ara-CTP
l e v e l s up t o t h e t h e r a p e u t i c range o r
f a i l e d t o respond,
d e s p i t e c e l l u l a r ara-CTP
concentrations of
hundred micromolar.
The f o r m e r group may have been r e s i s t a n t t o ara-C
t h e r a p y because o f an i n a b i l i t y t o accumulate ara-CTP.
several
W h i l e t h i s charac-
t e r i z e s o n l y a m i n o r p o r t i o n o f t h e p a t i e n t group s t u d i e d (see a l s o 19),
t h e i r tumor c e l l s may have biochemical p r o p e r t i e s s i m i l a r t o t h e " k i n a s e
d e f i c i e n t " c e l l s . Kinase d e f i c i e n c y i s t h e most common f o r m o f ara-C r e s i s t a n c e seen i n e x p e r i m e n t a l systems (23,24).
The p a t i e n t s w i t h r e s i s -
t a n t disease i n t h e h i g h steady s t a t e ara-CTP group m i g h t have f a i l e d f o r
reasons r e l a t e d t o u n f a v o r a b l e c e l l u l a r k i n e t i c s o r because o f an insens i t i v i t y o f DNA s y n t h e t i c processes t o t h e a c t i v e m e t a b o l i t e . The leukemic c e l l s o f p a t i e n t s who experienced a p r o f o u n d a n t i l e u k e m i c e f f e c t b u t
who d i e d w i t h a p l a s t i c marrow had a wide d i s t r i b u t i o n o f steady s t a t e
ara-CTP
concentrations.
causes,
pharmacologic
While these i n d i v i d u a l s d i e d from a v a r i e t y o f
r e s u l t s *suggest t h a t t h e p o r t i o n o f t h i s group
whose steady s t a t e ara-CTP l e v e l s were w i t h i n t h e t h e r a p e u t i c range m i g h t
have achieved r e m i s s i o n had t h e i r s u p p o r t i v e c a r e been s u c c e s s f u l . A d i f f e r e n t c o h o r t w i t h e x t r e m e l y h i g h steady s t a t e ara-CTP
would n o t have b e n e f i t e d f r o m more i n t e n s i v e t h e r a p y .
values p r o b a b l y
Conversely, t h e i r
57
c l i n i c a l course m i g h t have r e s u l t e d i n remission r a t h e r than a p l a s t i c
death had t h e y received a lower dose o f ara-C.
I n conclusion, s i g n i f i c a n t r e l a t i o n s h i p s e x i s t between pharmacokinetics
o f c e l l u l a r ara-CTP and p a t i e n t response t o s i n g l e - d r u g ara-C therapy f o r
zyxwv
zyx
r e f r a c t o r y leukemia. A c o r r e l a t i o n between t h e c l i n i c a l response w i t h t h e
minimum t r o u g h ara-CTP concentrations d u r i n g i n t e r m i t t e n t high-dose ara-C
therapy and t h e lowest values associated w i t h response d u r i n g continuous
i n f u s i o n t r e a t m e n t i n d i c a t e s t h a t 75 lib! ara-CTP
i s a lower l i m i t f o r
e f f e c t i v e treatment. Median ara-CTP t r o u g h values f o r p a t i e n t s who responded t o i n t e r m i t t e n t high-dose
ara-C
(196 pM)
and t h e upper bounds
f o r responders t o continuous i n f u s i o n therapy i n d i c a t e t h a t 200
yM
may
be t h e upper l i m i t o f t h e t h e r a p e u t i c range. Recognition o f a l i k e l y t h e r a p e u t i c range o f t h e ara-CTP c o n c e n t r a t i o n i n leukemia c e l l s provides an
o b j e c t i v e t a r g e t f o r t h e design o f f u t u r e chemotherapeutic regimens. I n d i v i d u a l i z e d therapy based on t h e c e l l u l a r pharmacology o f ara-CTP i s a
p o s s i b l e approach t o a c h i e v i n g t h e r a p e u t i c c e l l u l a r drug concentrations
(19,Zl).
ACKNOWLEDGEMENTS
This work was supported i n p a r t by g r a n t s CA28153 and CA32839 from t h e
N a t i o n a l Cancer I n s t i t u t e ,
DHHS.
The authors g r a t e f u l l y acknowledge t h e
e x c e l l e n t t e c h n i c a l assistance and d e d i c a t i o n o f Theresa Adams.
Sherri
Chubb, Rodney C r o f t , and B i l l i e Nowak.
REFERENCES
1. Keatlng MJ,
McCredie KB.
Bodey GP.
Smith TL,
Gehan E.
F r e i r e i c h EJ.
Improved prospects f o r long-term s u r v i v a l i n a d u l t s w i t h acute myelogenous leukemia. JAMA 1982;248:2481-6.
2. Creasey
WA.
Arabinosylcytosine.
In:
Sartorelli
A n t i n e o p l a s t i c and Immunosuppressive Agents.
Johns
AC,
Berlin:
06.
Springer-Verlag
1974;Vol 2:257-71.
zy
3 . Cohen SS. The mechanisms o f l e t h a l a c t i o n of a r a b i n o s y l c y t o s i n e ( a r a C) and a r a b i n o s y l adenine (ara-A).
4. P a l l a v i c i n i MG.
Cancer 1977;40:509-18.
Cytosine arabinoside:
molecular,
pharmacokinetic and
c y t o k i n e t i c considerations. Pharmacol Ther 1984;25:207-38.
5. B a r l o g i e B. P l u n k e t t W. Raber
M,
L a t r e i l l e J , Keating MJ, McCredie KB.
I n v i v o c e l l u l a r k i n e t i c s and pharmacological s t u d i e s o f 1-8-D-arab i n o f u r a n o s y l c y t o s ine and 3-deazauridine
acute leukemia. Cancer Res 1981 ;41:1227-35.
chemotherapy
for
relapsing
58
Hug V,
6. P l u n k e t t W,
K e a t i n g MJ.
nofuranosylcytosine
marrow
and
Chubb S.
5'-triphosphate
peripheral
blood
of
Q u a n t i t a t i o n o f 1-p-D-arabi-
zy
zyxwv
i n the
patients
leukemic
c e l l s f r o m bone
receiving
1-8-D-arabino-
f u r a n o s y l c y t o s i n e t h e r a p y . Cancer Res 1980;40:588-91.
7. L i s s e n P, Drenthe-Schronk A, Wessels H, Vierwinden G, Haanen C .
mination o f
cytosine arabinoside triphosphate
h i g h-pe rf ormance
an ion -exc hange
c o 1umn chromatography
1982; 232 2424-9.
8. K a n t a r j i a n H, 8 a r l o g i e 6,
n o s i d e i n non-Hodgkin's
arabinoside
1984 ;20: 227-31
.
c e l l s by
Chromat o g r
J
P l u n k e t t W e t a l . High-dose c y t o s i n e a r a b i -
lymphoma. J C l i n Oncol 1983;1:689-94.
9. K a n t a r j i a n H, D r e i c e r R,
cytosine
i n leukemic
Deter-
zyxwvu
B a r l o g i e 6, P l u n k e t t W, Alexanian R. Highdose
i n m u l t i p l e myeloma.
.
Eur J Cancer
C l i n Oncol
Rosenthal 0. Uptake and p h o s p h o r y l a t i o n o f c y t o s i n e
10. Kessel D , H a l l TC,
a r a b i n o s i d e by normal and leukemic human b l o o d c e l l s i n v i t r o . Cancer
Res 1969;29:459-63.
11. F u r t h JJ, Cohen SS.
triphosphate
of
I n h i b i t i o n o f mammalian DNA polymerase by t h e 5 ' -
1-p-0-arabinofuranosylcytosine
phate o f 9-p-D-arabinofuranosyladenine.
12. D i c o c c i o RA,
S r i v a s t a v a BIS.
cleotide-polymerizing
cells
by
and
the
Cancer Res 1968;28:
Kinetics of
5I-triphos2061-7.
i n h i b i t i o n o f deoxyribonu-
enzyme a c t i v i t i e s f r o m normal and leukemic human
5'-triphosphate
9-8-D-arabinofuranosyladenine
and
1-p-D-
arabinofuranosylcytosine 5 ' - t r i p h o s p h a t e . Eur J Biochem 1977;70:411-8.
13. Graham FL, Whitmore GF. S t u d i e s i n mouse L - c e l l s on t h e i n c o r p o r a t i o n
of
1-p-D-arabinofuranosylcytosine i n t o DNA and on i n h i b i t i o n o f DNA
1-p-0-arabinofuranosylcytosine 5 ' - t r i p h o s p h a t e .
Cancer
polymerase by
Res 1970;30:2636-44.
14. Kufe DW,
Munroe 0,
Herrick D ,
arabinof uranosylcytosine
Egan E,
incorporation
Spriggs D.
on
E f f e c t s o f 1-p-D-
eukaryotic
DNA
template
f u n c t i o n . Mol Pharmacol 1984;26:128-34.
15. Lauzon GJ,
Paterson ARP,
Belch AW.
Formation o f 1-p-D-arabinofurano-
s y l c y t o s i n e diphosphate c h o l i n e i n n e o p l a s t i c and normal c e l l s . Cancer
Res 1978; 38: 1730-3.
16. Hawtrey AO,
Scott-Burden
1 , Robertson 6.
I n h i b i t i o n o f glycoprotein
and g l y c o l i p i d s y n t h e s i s i n hamster embryo c e l l s by c y t o s i n e a r a b i n o s i d e and hydroxyurea. Nature (London) 1974;252:58-60.
zyxwvuts
zyxwvu
zy
59
17. P l u n k e t t W,
Chubb S ,
Barlogie 6.
Simultaneous d e t e r m i n a t i o n o f 1-8-
5'-triphosphate
D-arabinofuranosylcytosine
and 3 - d e a z a u r i d i n e
5 ' -tri -
phosphate i n human leukemia c e l l s by h i g h - p e r f o r m a n c e l i q u i d chromatography. J Chromatogr 1980;221:425-30.
18. I a c o b o n i S , P l u n k e t t W,
noside:
Treatment
K a n t a r j i a n H e t a l . High-dose c y t o s i n e a r a b i -
and
cellular
pharmacology o f
chronic
myelogenous
leukemia b l a s t c r i s i s . Submitted.
19. P l u n k e t t W,
MJ.
Iacoboni S ,
Estey E ,
Danhauser L,
L i l i e m a r k JO,
Keating
P h a r m a c o l o g i c a l l y d i r e c t e d ara-C t h e r a p y f o r r e f r a c t o r y leukemia.
Sem Oncol 1985;12(suppl 3):20-30.
20. K a n t a r j i a n HM, E s t e y EH, P l u n k e t W e t a l . Phase 1-11 s t u d y o f highdose
c y t o s i n e a r a b i n o s i d e i n r e f r a c t o r y leukemia. Amer J Med, i n p r e s s .
21. K e a t i n g MJ, E s t e y E,
Plunkett W e t a l .
Evolution of c l i n i c a l studies
w i t h high-dose c y t o s i n e a r a b i n o s i d e (ara-C)
p i t a l . Sem Oncol 1985;12(Suppl
2 2 . P l u n k e t t W,
Liliemark
JO.
a t t h e M.D.
Evidence t h a t a c c u m u l a t i o n o f ara-CTP
leukemic c e l l s i s s a t u r a t e d d u r i n g h i g h - d o s e ara-C
tions
for
Anderson Hos-
3):98-104.
increased e f f i c i e n c y
of
by
i n f u s i o n : sugges-
drug administration.
Proc Am SOC
C l i n Oncol 1985;4:50.
23. Momparler RL. Chu MY, F i s c h e r GA. S t u d i e s on a new mechanism o f r e s i s t a n c e o f L5178Y m u r i n e leukemia c e l l s t o c y t o s i n e a r a b i n o s i d e . 8iochern
8iophys Acta 1968;161:481-93.
24. K r e i s W,
by
Graham J,
semipurified
Damin L-A.
cytoplasmic
exhibiting
collateral
resistance
(P815/ARA-C)
Phosphorylation o f selected substrates
kinases o f
sensitivity
to
three
(P815/TG),
P815 m u r i n e leukemias
sensitivity
1-8-D-arabinofuranosylcytosine.
(P815)
or
Biochem
Pharmacol 1982;31:3831-7.
Address f o r correspondence:
W i l l i a m P l u n k e t t , Ph.D.
Dept o f Chemotherapy Research
The U n i v e r s i t y o f Texas M.D. Anderson Hospi t a l and Tumor I n s t i t u t e a t Houston
6723 8 e r t n e r Avenue
Houston, Texas 77030. USA