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[CANCER RESEARCH 50, 15-19, January I, 1990|
Dose-dependent Effects of Hydralazine on Microcirculatory
Hyperthermic Response of Murine FSall Tumors1
Function and
Joachim Kalmus, Paul Okunieff,2 and Peter Vaupel
Department of Radiation Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
which can modulate the effects of heat treatment (4). This
energy depletion is associated with, and in fact may result from,
a declining blood pressure and thus inadequate perfusion (4, 8).
Clinically used, HYD is known as a safe vasodilator which can
lower MABP in a predictable and dose-dependent manner (12).
In low doses the balance between decreased arteriolar resistance
and associated increased cardiac output can outweigh the blood
pressure drop and can cause an improved tissue perfusion.
Hence, there may be opposite effects of HYD at low and high
therapeutic doses, and the precise understanding of the phys
iological and tumor pathophysiological effects of this drug are
critical.
The advantages of HYD for potentiation of HT is likely to
be heat dose dependent since both modalities can modify tumor
perfusion, and at high heat doses the expected shut down of
perfusion might eliminate the theoretical advantages possible
with combined therapy.
The goal of the present study is to examine dose- and timedependent modifications in tumor and normal tissue blood flow
after HYD, and to evaluate the interaction between HYD and
perfusion at constant hyperthermia temperature, but varying
drug doses and heating times.
ABSTRACT
The effects of the vasodilator hydralazine (HYD) on microcirculatory
function and hyperthermic response were studied in early generation
isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma (FSall).
Red blood cell flux (RBC flux) in superficial tumor regions was assessed
using laser Doppler flowmetry. A differential microcirculatory response
was seen between tumor and normal skin after 0.25 Mg/gi-p- HYD, the
tumor showing a transient increase in flow and the skin remaining almost
stable. At 1.0 ^g/g i-P-,the differential response continued, this time with
a transient fall in tumor blood flow but again no change in skin flow.
High dose hydralazine (10.0 Mg/g ¡-P-)
was associated with a dramatic
and prolonged decrease in tumor blood flow but a lesser and only transient
decline in skin flow.
Identical doses of hydralazine were given 30 min prior to heat treatment
(43.5°Cfor 15, 30, or 60 min). Tumor growth was measured daily and
compared to controls (HT without hydralazine). Hydralazine at 0.25 tig/
g i.p. did not affect heat induced growth delay. At 1.0 fig/g i-P- it
significantly increased growth delay upon heat exposures of 15 min, but
not after 30 or 60 min HT. Hydralazine at 10 Mg/gi-P- increased growth
delay for all heat doses (/' < 0.05). Hydralazine alone had no influence
on growth delay of sham-heated tumors. The results obtained clearly
indicate that tumor and normal tissues have microcirculatory differences
in the time-course, degree and/or direction of response after hydralazine,
and that hydralazine has potential for increasing the response of tumor
to HT.
MATERIALS
AND METHODS
Animals and Tumors. Male and female C3Hf/Sed mice, 8-10 weeks
of age, from our defined flora and specific pathogen-free colony were
used (13). Sterilized Wayne Lab Blox and acidified vitamin-K fortified
water were provided ad libitum. All experiments were performed on
conscious mice. Tumors were early generation isotransplants of a
spontaneous C3H murine fibrosarcoma (FSall). Single cell suspensions
were prepared by mincing tumors with scissors, repeated passaging
through needles, filtering, centrifuging, and by resuspending the pellet
in Hanks1 solution. Five p\ (10*-106 cells) were inoculated into the
INTRODUCTION
The potential application of HYD3 to enhance the effect of
HT was first suggested by Voorhees and Babbs (1) and Babbs
et al. (2). The basis of this combined modality treatment centers
on the observation that tumor vasculature is minimally reactive
or unresponsive to such agents, whereas vasodilation in normal
tissues can in some cases allow for an improved tissue perfusion
(leading to better heat dissipation). Furthermore, the effects of
vasodilatory drugs are transient and nontoxic, and allow for the
development of synergistic treatment protocols involving se
quential radiation and vasodilator intensified hyperthermia.
HYD, a powerful and safe vasodilating drug, is among the best
candidates for combination therapy with hyperthermia and
bioreductive drugs, and has recently undergone extensive labo
ratory testing (3-11).
Previous studies have demonstrated that relatively high doses
of HYD can induce an increase in hypoxic cell fraction, and a
reduction of blood flow in tumors (6, 10). HYD also leads to a
dose-dependent decrease in tumor cellular phosphocreatine and
ATP levels, and a decrease in intracellular pH, parameters
subcutis of the hind foot dorsum. Tumor volumes were calculated using
the three orthogonal diameters and the formula V - (tr/6) x d, x rf2x
</3.
Hyperthermia. After immobilization of the animal in a cylindrically
shaped restraint device, local water bath hyperthermia was applied to
the tumor-bearing foot. During hyperthermia the tumor temperature
was 43.5 ±0.1 °Cfor 15, 30, or 60 min, and was not significantly
modified by blood flow induced heat dissipation. HYD was adminis
tered i.p. 30 min before HT. Injection volumes were always 10 ¿¿1/g,
and drug doses were 0.25, 1.0, or 10.0 Mg/B- Saline was used for
controls. Tumors were 100 mm3 at the time of treatment. Tumor
growth was measured daily and growth times were determined at
endpoint volumes of 500 and 800 mm1.
LDF. The Laserflow Blood Perfusion Monitor 403 A (TSI Inc., St.
Paul, MN) was used to measure RBC flux in tumors and in normal
skin. Power at the end of the optical fiber was 1.5 mW (wavelength,
780 nm). The laser Doppler flowmetry allows a stable, reproducible,
and noninvasive method for continuous monitoring of tissue perfusion
in superficial tissue areas within a hemisphere of approximately 2 nun '
Received 1/30/89; revised 5/18/89, 9/26/89; accepted 10/3/89.
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 in part by NIH Grants CA48096 and CA13311, by
the ACS Career Development Award, and by the Deutsche Forschungsgemein
schaft Postdoctoral Fellowship.
2To whom requests for reprints should be addressed, at Department of
Radiation Medicine, Massachusetts General Hospital Cancer Center, Harvard
Medical School, Boston. MA 02114.
3The abbreviations used are: HYD, hydralazine; HT, hyperthermia: LDF,
laser Doppler flow; MABP, mean arterial blood pressure; NMR, nuclear magnetic
resonance.
(14, 15). The microprocessor of this flowmeter computes several vari
ables (RBC flux, RBC velocity, and number of moving cells) which
were recorded simultaneously on a multichannel chart recorder (Type
6514; Linseis, Selb, West Germany). Data are expressed as relative
units which represent percentage values of full scale deflection on the
instrument meter (16).
15
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MODULATION
OF HEAT RESPONSE BY HYDRALAZINE
After immobilization of the animal in the same restraint device as
applied for heat treatment, a 22 ga/0.75-inch Teflon catheter (AngioSet, Deseret Medical, Sandy, UT) was placed i.p. for HYD injection.
Using a flexible metal stand, the fiberoptic probe was fixed adjacent to,
but without skin contact, at central locations over the tumor (size =
186 ±42 mm3, n = 31) or normal tissue (skin at hind foot dorsum).
When a constant baseline was registered for at least 8 min (RBC flux
= 100%), HYD was administered over = 2 min via bolus injection at
the same doses used in the hyperthermia studies. Following a 90-min
observation period, the mice were anesthetized and then sacrificed by
injecting KCI intracardially (RBC flux = 0%).
RESULTS
Modifications in LDF after Hydralazine Loading. The change
of RBC flux in tumors following i.p. injection of saline or
different doses of HYD is shown in Fig. 1. In controls, the
average values of RBC flux remained stable at 100% during the
entire 90-min observation period. HYD at 0.25 ¿ig/g¡-Pslightly
increased RBC flux in tumors, whereas after 1 /¿g/gi.p., RBC
flux was transiently decreased with a subsequent recovery after
40 min. At higher HYD doses, progressively steeper flow de
clines and more pronounced inhibitions of RBC flux were seen.
HYD at 10 Mg/g led to an almost complete shut down of tumor
microcirculation lasting for the entire observation period.
The effects of HYD on RBC flux in normal foot skin is
shown in Fig. 2. Here, saline slightly increased blood flow. For
doses of 0.25 or 1.0 ^g/g ¡.p.,no significant drug induced flow
change was seen. HYD at 10 Mg/g transiently decreased RBC
flux in the skin (P < 0.001).
Skin and tumor both had minimal changes in RBC velocity
after 0.25 or 1.0 ¿zg/gHYD, or after saline. Similarly, the
changes in the number of moving RBCs were small after these
HYD doses. In contrast, tumor and skin demonstrated clear
decreases in the RBC velocities after 10.0 ^g/g HYD. The
number of moving RBCs within the tumor volume investigated,
however, was more variable, and decreased in only 43% of the
tumors measured after high dose HYD. No changes in the
TIME AFTER HYDRALAZINE
(min)
Fig. 2. Laser Doppler flow in murine hind foot dorsum (normal skin) after
i.p. HYD loading at varying doses (0.25, 1.0, or 10.0 >ig/g). Values are means ±
SE. Numbers of mice investigated are given in parentheses.
NaCI 0.25
10.0
1.0
HYDRALAZINE
(|jg/g
¡.p.)
Fig. 3. Growth time required for murine FSall tumors to grow from a treat
ment volume of 100 mm' to an endpoint volume of 500 mm3 after various HYD
(0.25, 1.0, and 10.0 Mg/g i.p.) and heat doses (43.5"C/15, 30, or 60 min). Values
are means ±SE.
60
TIME AFTER
HYDRALAZINE
80
number of moving red blood cells were seen in normal skin at
this dose.
Effect of Hydralazine on Tumor Growth following Hyperther
mia. The effect of different HYD doses in combination with
43.5°CHT on tumor growth time is shown in Fig. 3. There
were no changes in growth time to reach 500 mm3 at any heat
dose studied following 0.25 ¿ig/gHYD. At 1.0 ¿ig/gi.p. com
bined with 15-min hyperthermia, HYD affected tumor growth
significantly (P < 0.05), whereas combinations with 30- or 60-
100
(min)
Fig. 1. Laser Doppler flow in murine FSall tumors after i.p. administration
of HYD at varying doses (0.25, 1.0, or 10.0 (ig/g). Values are means ±SE.
Numbers of tumors investigated are given in parentheses.
16
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MODULATION
OF HEAT RESPONSE BY HVDRALAZINE
min hyperthermia failed to produce significant changes. HYD
at 10 fig/g significantly increased the growth time for all heat
doses (P < 0.05). Similar evaluations were made using a tumor
volume endpoint of 800 mm'. HYD without heat treatment
HYDRALAZINE
0.25 MQ/g ¡-P-
60 -
had no influence on growth time at any doses.
40 20 -
DISCUSSION
1.1,111.
0
The efficiency of blood flow through tumors plays a cardinal
role during heat treatment. Due to poorer perfusion rates, the
convective heat dissipation is reduced in many animal tumors
and allows a quasiselective heating of the malignant tissue (17,
18). Vasodilators, having profound effects upon the distribution
of blood flow between tumor and normal tissue, may enhance
the disproportion of perfusion to therapeutic advantage when
hyperthermia is applied. Heat doses capable of inducing signif
icant vascular shut down in animal tumors can only rarely be
achieved in clinical hyperthermia, and thus supplementing ther
apy with HYD to reduce tumor blood flow, nutrient delivery,
and heat dissipation has theoretical appeal.
Effects of Hydralazine on Tumor and Skin Laser Doppler
Parameters. In the present study, the response of RBC flux in
superficial tumor areas to different doses of HYD was contin
uously and noninvasively monitored by LDF. This technique is
a useful and valid method for measuring microcirculation in
small, discrete tumor areas (16, 19, 20). The method may also
allow for a good estimate of the relative changes of flow in
deeper tissue regions (16, 21).
Low dose HYD (0.25 ¿tg/gi.p.) tended to increase RBC flux
in tumors. These results are consistent with investigations of
energy metabolism. Specifically, low HYD doses produced a
5-10% increase of phosphocreatine/inorganic
phosphate and
nucleoside triphosphate/inorganic
phosphate ratios, and a
slightly higher pH value (4). HYD doses of 1 ng/g decreased
the RBC flux in the malignant tissue significantly, but only for
a limited time (—40min). HYD doses of 10 ng/g i.p. induced
major and prolonged reductions of RBC flux. The dramatic
changes in RBC flux in FSall tumors are similar to perfusion
data obtained in Lewis lung carcinoma (estimated using mean
fluorescence of cells from disaggregated tumor tissue) at HYD
doses of 5 Mg/g (10). The flow changes measured in the skin of
the foot were qualitatively different from that in tumor in both
time course and response intensity (see Fig. 4). Specifically, at
0.25 ng/g HYD, a transient increase in flow occurred in tumor
but not in skin. At 1 ng/g a transient flow decrease was observed
in tumor but not in skin, which again maintained homeostatic
control of cutaneous blood flow. Finally, at 10 ¿¿g/g
HYD a
prolonged and profound decrease in tumor blood flow was
associated with only a transient decrease in skin blood flow.
The differential flow pattern between normal and malignant
tissue seen after HYD are most probably due to a steal phenom
enon (1, 3, 5, 21).
Since perfusion pressure is probably the chief parameter
governing blood flow of tumors (22-26), blood flow through
tumors should show a linear dependence on MABP. In C3H
mice, doses of >1 ng/g i.p. decrease MABP as much as 30
mmHg (4, see Table 1). The nearly complete shut down of
tumor RBC flux after 10 /¿g/gHYD, however, suggest that
secondary effects (e.g., induction of RBC rigidity at low pH,
and homeostatic mechanisms diverting blood flow to critical
organs and away from the extremities) must have contributed
to the flow decline. The postulated redistribution of blood flow
to vital organs is confirmed by HYD induced radioprotection
of the spleen and bone marrow (8). In this case, blood is shifted
-20-
HYDRALAZINE
1.0ng/gi.p.
HYDRALAZINE
10.0 ng/g i.p.
20
-60
80
10
20
30
TIME AFTER
40
50
60
70
HYDRALAZINE
80
90
(min)
Fig. 4. Comparison of RBC flux changes in tumors (•)and normal skin (EH)
after ¡.p.HYD at 0.25 (top). 1.0 (center), or 10.0 >jg/g ¡.p.(bottom). *. P < 0.05,
>
Table 1 Effect ofhydrala:ine and i.p. volume loading on MABP and heart rale
Experiments were performed under pentobarbital anesthesia using an escalat
ing dose schedule (4. 8).
rate"
(beats/min)494
Hydralazine dose (ru <ji.p.)
0.0
±4
±23
0.25
83 ±5
518± 19
1.0
59 ±3
586 ±22
10.0Saline
±290
62
600
3490±1
dose (ml)
0.0
0.1
1.0MABP"(mmHg)92
16°
Values are mean ±SE.
±4
96 ±5
107 ±3Heart
±20
486 ±28
437 ±
away from noncritical organs (e.g., spleen, skin, and extremi
ties) in favor of vital organs, thus causing a radioprotective
hypoxia of hematopoietic tissues.
After high HYD doses, reduction of LDF in normal and
malignant tissues are accompanied by a drop in RBC velocity.
The number of moving red blood cells remained stable in
normal tissue, whereas in many tumors, a drop of the moving
17
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MODULATION
OF HEAT RESPONSE BY HYDRALAZINE
this assumption is supported by both hyperthermic response
and NMR measurements of metabolic parameters (both tech
niques average the entire tumor volume and parallel the RBC
flux measurements). Hence, use of vasodilators to increase the
temperature difference between tumors and surrounding tissues
during HT (1) and to modify the tumor micromilieu, make
them promising enhancers of hyperthermia. The utility of com
bined HT and HYD depends on both the duration of heating
and the dose of HYD employed. Potentiation of HT was seen
at low heat doses, a situation common in clinical hyperthermia.
Since using water bath heating, no significant differences in
convective heat dissipation occur, the clinical utility of supple
menting HT by pretreatment HYD for metabolic "priming" is
red blood cells was observed. This effect probably results from
the relatively increased resistance to RBC flow through the
more acidotic and tortuous tumor microvessels that occurs in
low flow states (23).
The effects of hydralazine on the previously reported (4)
MABP corresponded closely with the changes in laser Doppler
flow observed in the present study. Hydralazine causes an
arterial and venous vasodilation followed by a decrease in
MABP, a regulatory increase in heart rate, and eventually a
stabilization of MABP at a lower level than baseline (see Table
1). These animals were anesthetized, due to technical con
straints, with pentobarbital, possibly augmenting the blood
pressure drop. On the other hand, control animals given saline
volumes of 0, 0.1, and 1.0 ml i.p., had significant MABP
increases and heart rate decreases (4, 8), indicating that the
measured decrease in blood pressure could have been even
greater without the accompanying saline. Studies done on larger
animals including rats (2) and dogs (1) have shown selective
shunting of blood away from the tumor along with an increased
cardiac output and perfusion of normal organs. This increased
perfusion occurred despite a more mild blood pressure drop
than was observed in anesthetized mice. It is not yet clear to
what extent a decrement in blood pressure is required in order
to "steal" tumor blood flow in larger animals. Clinically it is
likely that many older patients will not tolerate the hydralazineinduced blood pressure changes, and all patients will need i.v.
line placement and will have to remain horizontal for the
duration of drug action. To be worthwhile therefore, noninvasive methods will be needed to confirm that the hydralazine is
having the desired effect on tumor metabolism. We have sug
gested that "P-NMR methods might be used to identify those
likely to be even higher. Vasodilators like HYD should also be
useful in potentiating other treatment modalities (e.g., agents
specifically toxic to hypoxic or metabolically deprived cells).
The drop in MABP after HYD is unlikely to be tolerated by
some patients, and HYD should be used with caution in com
bination with treatment modalities for which poor perfusion or
oxygénationmight reduce therapeutic effectiveness, such as
irradiation and many chemotherapeutic drugs.
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patients in whom hydralazine might make a useful contribution
(4).
Effects of Hydralazine on Hyperthermic Sensitivity. Low dose
HYD (0.25 ¿ig/g¡-P-)
had no effect on hyperthermic sensitivity.
This is consistent with the minimal changes seen in tumor
energy metabolism and blood flow at this dose. Doses of HYD
sufficient to significantly reduce arterial blood pressure and
tumor blood flow also enhanced hyperthermic response (Table
1). The mid-range HYD dose (1.0 Mg/g) enhanced only the 15min heating. This was expected since the flow was only reduced
for approximately 40 min at this HYD dose, and the heating
was started 30 min after drug delivery. Longer heating times
themselves induce near maximal flow restrictions, and therefore
heat treatment would be unlikely to further benefit from the
partial reductions induced by this HYD dose. At 10 ¿ig/gi-PHYD, there was prolongation of the growth time at all heat
doses tested. The augmentation of HT-induced tumor growth
time at the highest HYD dose is difficult to fully explain since
blood flow cessation is expected by 30 or 60 min of heat alone
(16, 27). This observation suggests that the marked metabolic
effects of high dose H YD can synergistically enhance cell killing
by heat. One possible mechanism is the induction of a hostile
micromilieu and tumor acidosis which primes the cells for
hyperthermic sensitivity. It should be emphasized that in the
tumor model and heating system used, blood flow does not
significantly influence tumor temperature. Therefore, differ
ences in tissue heat dissipation, likely to be present in human
subjects, would add to the clinical efficacy of HYD observed in
this animal study.
Assuming that the reduction in RBC flux, measuring only
superficial tissue areas, represents the decrease of average total
tissue blood flow, a dose dependent and tumor selective influ
ence on blood flow affected by HYD is obvious. The validity of
18
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MODULATION
OF HEAT RESPONSE BY HYDRALAZINE
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19
Downloaded from cancerres.aacrjournals.org on June 14, 2017. © 1990 American Association for Cancer Research.
Dose-dependent Effects of Hydralazine on Microcirculatory
Function and Hyperthermic Response of Murine FSall Tumors
Joachim Kalmus, Paul Okunieff and Peter Vaupel
Cancer Res 1990;50:15-19.
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