(CANCER RESEARCH 52. 3237-3240, June 1, 1992)
Advances in Brief
Nicotinamide Can Lower Tumor Interstitial Fluid Pressure: Mechanistic and
Therapeutic Implications1
Intae Lee, Yves Boucher, and Rakesh K. Jain
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Abstract
Several investigators have shown that nicotinamide (NA) may increase
the tumor blood flow and/or alleviate temporal fluctuations in tumor
blood flow and, consequently, increase pO2. However, the mechanisms
of these changes in tumor blood flow are not understood, especially
because NA lowers the mean arterial blood pressure in mice. Our
hypothesis is that NA may decrease flow resistance in tumors, which
would lower vascular pressure and tumor interstitial fluid pressure
(TIFP). To test this hypothesis, we measured the physiological parame
ters: mean arterial blood pressure, TIFP, tumor water content, and
hematocrit in C3H mice bearing FSall tumors, before and after treatment
with 500 mg/kg of NA. In control animals, TIFP increased with tumor
growth up to 400 nun ', reached a plateau, and then decreased when the
tumor size was above 1000 mm3 (n = 135). Tumor water content
correlated significantly with TIFT (for tumors <500 mm3) (n = 26). NA
caused approximately a 15% decrease in mean arterial blood pressure (/'
< 0.05) and a 35% decrease in TIFP (P < 0.001) at 2 h postinjection,
without any change in hematocrit. The change in TIFP was found to be
tumor size dependent. Specifically, NA decreased the TIFP by 47% (P
< 0.001) and 39% (P < 0.001) in medium (200 to 500 mm3) and large
(500 to 800 mm3) tumors, respectively. The decrease in TIFP in small
(<200 mm3) and very large (>800 mm3) tumors was not statistically
significant (P > 0.1). Our results may explain the size-dependent en
hancement in pOj and radiation response reported by I. Lee and C. W.
Song (Radiât.Res., 730:65-71, 1992) for this tumor line. If our results
could be confirmed in human tumors in situ, they would have significant
implications in noninvasive measurements of TIFP using NMR and in
cancer treatment using radiation, chemotherapy, and immunotherapy.
Horsman et al. (9) have shown that NA decreases the MABP
of mice. Therefore, the only mechanism of the observed changes
in TBF is a decrease in P\ and/or FR. How is it possible to
lower Pv and FR with NA? FR has two components: geometric
and viscous resistance; both are elevated in tumors (10, 11).
The former results from the peculiar morphology of the tumor
vasculature (10) and the latter from the altered rheology in
tumor vessels (11). If NA decreases the rigidity or adhesion of
RBC, WBC, or cancer cells in the tumor vasculature, it will
lower the transient fluctuations in TBF as well as FR. The Pv
in tumors is also elevated, presumably due to elevated FR, and
is the main source of interstitial hypertension (12).3 Therefore,
if NA lowers FR, we should see a decrease in P\ and, hence, in
TIFP. The goal of this work was to test if NA decreases TIFP.
MABP, TIFP, tumor water content, and HCT were measured
in control and NA (500 mg/kg)-treated C3H mice bearing FSall
tumors. This dose of NA has led to increased pO2 and radiosensitization in this tumor model (4). Furthermore, tumor
oxygénationin response to NA was found to be tumor size
dependent. Therefore, we carried out these studies for tumors
between 100 and 1700 mm1. Since edema may contribute to
interstitial pressure, we also sought possible correlation between
TIFP and tumor water content. Finally, to exclude the possi
bility of a water shift from the vascular compartment to the
peritoneal cavity due to an i.p. injection of NA, we measured
the HCT before and after NA treatment.
Introduction
Materials
Since the original study of Jonsson et al. (I), several investi
gators have shown that NA,2 the amide form of vitamin B.t,can
radiosensitize murine tumors (2-4). This radiosensitization
presumably results from the increased oxygénationby NA, as
directly measured using microelectrodes by Lee and Song (4).
The increased oxygen tension in tumors results from reduced
oxygen utilization and/or increased oxygen availability through
modifications in tumor blood flow (5-7). While there are no
direct measurements of in vivo oxygen utilization following NA
injection, several investigators have shown that NA increases
TBF and/or decreases transient fluctuations in TBF (3, 4).
However, what factors led to these changes in TBF is not
known.
It is well known that TBF is proportional to PA —¿
P\ and
inversely proportional to the FR (7). Stone et al. (8) and
Animals. Female C3Hf/Sed mice, 8 to 10 wk of age, were used in
this study. Animals were kept under pathogen-free conditions in the
animal facility maintained at 25 ±3°C.The mice were allowed food
Received 2/25/92; accepted 4/15/92.
The costs of publication of this article were 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.
1This work was supported by grants from the National Cancer Institute (CA37239, CA-49792. and CA-13311). Presented at the 40th Radiation Research
Society Meeting, Salt Lake City, UT, March 14-18, 1992.
2The abbreviations used are: NA. nicotinamide: TBF. tumor blood flow; TIFP,
tumor interstitial fluid pressure: MABP. mean arterial blood pressure; HCT,
hematocrit; WIN. wicked-in-needle; PA. arterial pressure; Pv. venous pressure.
FR, flow resistance.
and Methods
and water ad libitum.
Tumors. Frozen FSall tumor cells (third generation) were thawed
from the liquid N2, cultured, and grown in vitro in C3Hf/Sed mice. The
FSall (fourth generation) tumors were harvested 7 to 10 days after the
inoculation, and single cell suspensions were prepared using 0.25%
trypsin solution. About 2 x IO5 viable cells suspended in 0.05 ml of
RPMI 1640 medium were injected s.c. into the right thighs of mice.
Experiments were carried out when the tumor volume was between 100
and 1700 mm3. Tumor volumes were calculated using the formula V =
0.4 x ab~, where a and b are the longer and shorter diameters of the
tumors, respectively.
Nicotinamide Treatment. Nicotinamide (Sigma Chemical Co., St.
Louis, MO) was dissolved in sterile saline solution (0.9% NaCI) before
each experiment. The tumor-bearing mice were given i.p. injections at
a dose of 500 mg/kg in a volume of 0.01 ml/g of body weight.
Measurement of MABP. Mice were anesthetized with an i.p. injection
of sodium pentobarbital (60 mg/kg) and placed on a heating pad to
keep the body temperature around 37.5°C.The right carotid artery was
exposed and cannulated with a PE-10 polyethylene catheter (Clay
Adams, Parsippany, NJ), using a binocular microscope. During the
3 Y. Boucher and R. K. Jain. Simultaneous measurements of interstitial and
vascular pressure in tissue-isolated tumors (abstract). Presented at the 40th
Radiation Research Society Meeting. Salt Lake City, UT. March 14-18. 1992.
3237
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INTERSTITIAL
PRESSURE DECREASE BY N1COTINAM1DE
insertion of PE-10 tubing into the artery, the artery was occluded with
a small clamp. The tubing, previously filled with heparin (70 units/ml),
was connected with a three-way stopcock to a pressure transducer
(Gould, Inc., Valley View, OH). The clamp on the artery was then
released, and the PE-10 tubing was checked for blood and tied with
fine silk thread. The stopcock was then turned on to allow communi
cation between the tubing and the pressure transducer. MABP was only
measured in animals with small tumors. In animals with larger tumors,
cannulation of the carotid artery and pentobarbital anesthesia induced
the death of the animals. However, we were able to measure MABP in
animals with larger tumors, anesthetized with ketamine (90 mg/kg)/
xylazine (9 mg/kg).
Measurement of TIFP. TIFP was measured with the WIN technique
using a 23 gauge needle with a side hole 5 mm from the tip (13). The
experimental setup used for the measurements of TIFP was similar to
that described in detail previously (14). Briefly, five nylon surgical
sutures (6-0 ethilon; Ethicon, Inc., Somerville, NJ) were placed within
the needle. To take the pressure measurements, the needle was con
nected to a pressure transducer by PE-50 polyethylene tubing filled
with sterile heparinized (70 units/ml) saline. Before pressure measure
ments in each animal, the calibration of the pressure transducer setup
was verified by applying pressures of 0, 5, 15, and 30 cm of saline (i.e.,
1 mm of Hg = 1.36 cm of saline in height). Possible leaks in the system
were tested by maintaining the pressure of 30 cm of saline for at least
5 min. For this protocol, the animals were anesthetized with 60 mg/
kg, i.p., of sodium pentobarbital, and the skin was carefully removed
above the tumors. The animals were placed on a hot water heating pad
in order to keep the body temperature at 37.5"C. Two needles were
inserted separately into the central region of the tumor, since TIFP as
been shown to be relatively uniform throughout solid tumors growing
as a single nodule (12). In animals not treated with NA, two measure
ments were made by introducing two needles in the central regions of
the tumors. The animals given injections of NA were divided in two
groups. In one group TIFP was monitored continuously with one needle
before and after 2 h following the injection of NA. In the second group
of animals, one measurement was obtained 2 h following injection of
NA using a separate needle. Data of the second group were compared
with those of untreated tumors of similar size. The dynamic changes in
the TIFP signal were continuously monitored and recorded by a chart
recorder. After measurements of TIFP, the WIN system was recali
brated. TIFP values were discarded when the values drifted by more
than 1 mm of Hg.
Measurement of Tumor Water Content (Tw<). Water content in a
limited number of tumors was calculated using the formula
Tw - T,
Results
Fig. \A shows TIFP as a function of tumor volume (100 to
1700 mm') in untreated tumors. Note that TIFP increased with
tumor volume from 100 to 400 mm1 and then leveled off. Over
1000 mm', the TIFP decreased significantly. TIFP differed
considerably among individual tumors of similar size. Fig. IB
shows TIFP and pO2 as a function of the tumor volume in
FSall tumors (<500 mm'). TIFP increased when the tumor
grew; however, pO? decreased showing an inverse relationship
20
(FSall Tumors)
60
X
E
E IO
0
500
1000
1500
Tumor volume (mm3)
2000
B
(FSall Tumors)
200
.ino
400
Tumorvolume(nunJ )
500
600
(FSall Tumors)
x 100%.
Tumors were weighed immediately after the excision for the wet weight
(Tw) and after a drying period of 2 days at 50°Cfollowed by 5 days at
room temperature for the dry weight (Td). The dry weight was not
significantly different at 2 and 5 days at room temperature for tumors
< 500 mm3.
Measurement of HCT. The HCT was measured before and after the
i.p. administration of nicotinamide (500 mg/kg) in a 70-^1 sample of
blood (approximately 3.0 to 3.5% of total blood volume) collected from
the orbital sinus of each mouse in a 75-^1 capillary tube. The capillary
tubes were centrifuged for 10 min at 12,500 rpm, and separate bands
of HCT were read.
Data Analysis. All values are shown as the mean ±SE of each group
and time points for the parametric statistic. The changes by percentage
were determined individually for each mouse, based on pretreatment
values, and then averaged. The significance of the differences within a
group before and after the nicotinamide treatment was evaluated with
a paired Mest. Significant differences between treatment groups were
checked with an unpaired t test.
75
io
TIFP (mm Hg)
Fig. 1. A, TIFP as a function of the tumor volume in FSall tumors, ranging
from 100 to 1700 mm'. The mean TIFP increases with tumor volume from 100
to 400 mm5 and then levels off (see Fig. 4). Over 1000 mm1. TIFP decreases
significantly (each point represents a single measurement: n = 135). B, TIFP and
pO2 as a function of the lumor volume in FSall tumors (<500 mm'). TIFP
increased when the tumor grew: however, pO2 decreased showing an inverse
relationship between pO: and TIFP (pO2 data from Ref. 4). C tumor water
content as a function of the mean TIFP. for tumors ranging from 100 to 500
mm' (each point represents a single tumor: n = 26). A line was determined by
linear regression analysis. Note that water content increased from ~79% to ~85%
as TIFP increased from ~2 to ~14 mm of Hg for tumors (<500 mm3).
3238
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INTERSTITIAL
50
PRESSURE
DECREASE BY NICOT1NAMIDE
after treatment with NA (500 mg/kg), reaching 85% of the
control value by 30 min (P < 0.05) and then fluctuated slightly
for 2 h posttreatment. Fig. 2B shows the percentage of changes
in TIFP after treatment with NA. TIFP also rapidly decreased
within 10 min of treatment with nicotinamide, reaching a
minimum of 60% of the control value by 2 h. In a few animals
TIFP was measured for 4 h, and it did not return to the
pretreated control value. For subsequent analysis, we chose
values of MABP and TIFP at 2 h after an i.p. injection of
nicotinamide, i.e., approximately a 35% decrease in TIFP (P<
0.001) and a 15% decrease in MABP (P< 0.05). In the salinetreated control group, no changes in MABP or TIFP were
observed (data not shown).
To delineate the effectiveness of nicotinamide in TIFP reduc
tion in the same animals, we divided the tumors into four
groups: small (100 to 200 mm3); medium (200 to 500 mm3);
large (500 to 800 mm3); and very large (800 to 1700 mm3). The
(C3Hf/Sed mice)
CL.
03
I
e
}''HiT+^-^Mr+ÃU
•¿Mean ±SE
T
a
0
50
100
ISO
Time after the treatment of nicotinamide (min)
B so
(FSalI tumors)
drop in TIFP was significant for tumor volumes ranging from
200 to 800 mm3; the pressure decreased by 47 ±9% (P <
•¿
Meant SE
00
C
a
j=
o
e
u
y
-50
O
50
100
150
Time after the treatment of nicotinamide (min)
Fig. 2. A, percentage of changes in MABP as a function of time after an i.p.
injection of 500 mg/kg of NA in C3H mice. Points, mean of the MABP from 8
animals; bars, SE. B, percentage of changes in TIFF as a function of time after
an i.p. injection of 500 mg/kg of NA in FSall tumors (tumor volume, from 100
to 800 mm3). The points are the mean of TIFP from 27 animals; bars, SE.
0.001) and 39 ±6% (P < 0.001) in medium and large tumors,
respectively. A 13% reduction in TIFP was found in small
tumors (P> 0.1). Nicotinamide did not influence the TIFP of
very large tumors (Fig. 3).
Fig. 4 compares TIFP as a function of tumor volume for
animals treated and untreated with NA. TIFP in untreated
animals increased as a function of tumor size between 100 and
400 mm3. In animals given injections of NA. the increase in
TIFP associated with tumor growth disappeared. The mean
TIFP decreased to values between 2.8 and 3.8 mm of Hg as
compared with untreated animals with TIFP between 4.5 and
9.0 mm of Hg. Also the major drop in TIFP of 5 mm of Hg
was observed in tumors with a volume between 350 and 450
mm3.
The HCT of the control mice was 49 ±0.7%, and that of
mice bearing about 150-mm3 tumors was similar to the HCT
of the control mice. However, as the tumors grew to about 700
mm3 and 1400 mm3, the HCT declined to 45 ±0.9% (P <
0.05) and 42 ±0.4% (P< 0.05), respectively. However, a single
IS
0
•¿50
100-200
200-500
500-800
(FSall Tumors)
Untreated
•¿ Ninnili.uniili
III .llril
xoo-1500
Tumor volume (mm3 )
Fig. 3. Tumor volume-dependent changes in TIFP after treatment with 500
mg/kg of NA in small (100 to 200 mm3, n = 7). medium (200 to 500 mm3, n =
13), large (500 to 800 mm3, n = 7), and very large tumors (800 to 1700 mm3, n
= 7). A significant drop in TIFP was found for tumor volumes between 200 and
800 mm3 (P < 0.001). Note that TIFP was monitored continuously for 2 h in
these studies. Bars, SE.
between pOz and TIFP. The relationship between tumor wet
weight (mg) and tumor volume (mm3) was linear ( Y = 40.6 +
Q.99X, r = 0.92). Fig. 1C shows the tumor water content as a
function of TIFP for tumors ranging from 100 to 500 mm3.
Note that water content increased from ~79% to ~85% as
TIFP increased from ~2 to ~14 mm of Hg for tumors <500
mm3 (n = 26, Y = 11A + Q.60X, r = 0.74). The average value
of water content in larger tumors (>500 mm3) was about 82%
and did not correlate with TIFP.
Fig. 2A shows the percentage of changes in MABP after
treatment with nicotinamide. MABP was 74 ±3 mm of Hg in
anesthetized mice. MABP rapidly decreased within 10 min
a »i
i
E
o.
H
200
400
600
Tumor volume (mm-1)
so«
1(10(1
Fig. 4. Interstitial fluid pressure in FSall tumors in untreated control and 2 h
after an i.p. injection of 500 mg/kg of NA. TIFP in the untreated control tumor
increased significantly between 150 and 400 mm3; however, following the NA
treatment the significant increase in TIFP associated with tumor growth disap
peared between 150 and 600 mm3. The most significant drop in TIFP of 5 mm
of Hg was observed in tumors with a volume of 350 and 450 mm3. Note that
TIFP was measured by inserting the needle (two measurements per animal;
however, in some cases only one measurement was accepted due to the bad fluid
communication) for the untreated control group and at 2 h posttreatment with
NA (one measurement per animal) for the NA-treated group. The values in
parentheses represent the number of animals; bars, SE.
3239
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INTERSTITIAL
PRESSURE DECREASE BY NICOTINAM1DK
injection of 500 mg/kg of nicotinamide did not alter the hematocrit for 2 h posttreatment (P> 0.1).
Discussion
The first goal of this study was to measure TIFP in FSall
tumors as a function of tumor size. Similar to prior studies
with experimental and human tumors (14, 15), TIFP increased
with tumor size up to 400 mm'. However, unlike previous
studies, TIFP decreased somewhat in tumors > 1000 mm1. The
clonal antibodies). Also, TIFP and pO2 are inversely related.
TIFP measurements are considerably easier to perform than
pO2 distribution; therefore, they may be useful in individualiz
ing therapy and predicting the outcome of radiation therapy
(18). Furthermore, a positive relationship between TIFP and
water content in tumors was determined in this study. If this
correlation is found in other experimental and human tumors,
then water content as measured by 'H-NMR could be used to
only other study where TIFP was found to decrease beyond a
critical size of the tumor was done using a chronic implant of
micropore chambers pioneered by Cullino (5).4 Possible expla
nations of this decrease in TIFP are (a) decrease in microvascular pressure due to a large tumor burden and (b) ulcération
of tumors resulting in increased tissue hydraulic conductivity
(16). However, in this tumor model, MABP did not decrease
when tumors grew up to 1700 mm'.
The second goal of this study was to check if there is a
correlation between TIFP and water content as postulated by
Steen (17). Water content increased from ~79% to ~85% as
TIFP increased from 2 mm of Hg to 14 mm of Hg, in support
of Steen's hypothesis. On the other hand, water content was
nearly constant (82%) for larger tumors (>500 mm') and did
not correlate with pressure. If this hypothesis is true for other
experimental and human tumors, then the tumor water content
as measured by 'H-NMR could be used to estimate TIFP,
noninvasively.
The third goal of this study was to test the hypothesis that
NA can lower TIFP. Indeed, the increase in TIFP in tumor
with a volume between 100 and 400 mm' disappeared after the
treatment with NA. Recently, Lee and Song (4) have shown in
FSall tumors that the decrease in pO2 associated with tumor
growth was abolished by NA. Interestingly, an inverse relation
ship between TIFP and pO2 has also been seen in human
cervical carcinomas by Roh et al. (18).
Since tumors have high vascular permeability and they lack
functioning lymphatics (12, 14, 16), the TIFP is primarily
governed by microvascular pressure.' Microvascular pressure
in tumor vessels in sandwich tumor preparation has been found
to vary between 5.8 and 6.7 mm of Hg (19), and in tissueisolated tumors it is very close to TIFP.4 Based on the current
results we expect microvascular pressure to go down following
NA injection in a size-dependent manner. Simultaneous meas
urements of microvascular pressure and interstitial pressure
after treatment with NA are needed to confirm this hypothesis.
In addition to providing insight into the NA-induced TBF
modification, our results suggest that NA may be useful for
improving the delivery of novel therapeutic agents to tumors.
Both hyperthermia (20) and photodynamic therapy5 can lower
the TIFP but at the cost of lowering the tumor blood flow rate.
On the other hand, NA can improve the blood supply and also
lower TIFP, which is a major obstacle to the delivery of anti
bodies and other macromolecules (21). Since NA is relatively
nontoxic in humans (22), its effects on the pathophysiology of
human tumors in situ should be examined to check if the data
from murine tumors can be extrapolated to humans.
In conclusion, N A can lower the elevated TIFP, which is a
major obstacle to the delivery of macromolecules (e.g., mono' A. Belton and R. K. Jain, unpublished results.
5 M. Leunig, A. E. Goetz, F. Gamarra. G. Zetterer, K. Messmer. and R. K.
Jain. Tumor interstitial pressure and volume changes following photodynamic
therapy: mechanistic and prognostic implications, submitted for publication.
estimate TIFP noninvasively.
Acknowledgments
The authors express their thanks to Dr. Michael Leunig and Dr.
Robert Melder for their help in this project and for reviewing this
manuscript.
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3240
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Nicotinamide Can Lower Tumor Interstitial Fluid Pressure:
Mechanistic and Therapeutic Implications
Intae Lee, Yves Boucher and Rakesh K. Jain
Cancer Res 1992;52:3237-3240.
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