[CANCER RESEARCH 45,1973-1977,
May 1985]
In Vitro and in Vivo Light Dose Rate Effects Related to Hematoporphyrin
Derivative Photodynamic Therapy1
Charles J. Gomer,2Natalie Rucker,NicholasJ. Razum, and A. Linn Murphree
Clayton Center for Ocular Oncology [C. J. G., N. R., N. J. R., A. L U.], Childrens Hospital of Los Angeles, and Departments of Pediatrics (Division of HematologyOncology) [C. J. G.], Radiation Oncology [C. J. G.] and Ophthalmology [A. L. M.¡,University of Southern California School of Medicine, Los Angeles, California 90027
ABSTRACT
In vitro and in vivo experiments were performed to evaluate
the parameter of light dose rate as it relates to the efficiency of
hematoporphyrin derivative (HPD)-induced photosensitization.
Exponentially growing Chinese hamster ovary cells were incu
bated with HPD (25 /¿g/ml)and were then exposed to red light
(630 nm) delivered at different dose rates. A total of five dose
rates (0.5, 5.0,15, 23, and 60 milliwatts/sq cm) were examined
following a 1-hr HPD incubation, two dose rates (1 and 20
milliwatts/sq cm) were examined after a 12-hr HPD incubation,
and three dose rates (0.4, 4, and 40 milliwatts/sq cm) were
examined following a 16-hr incubation and a 30-min serum wash
protocol. The effect of light dose rate was determined from cell
survival curves obtained by standard clonogenic colony forma
tion assays. Similar levels of cellular toxicity were obtained when
cells from each HPD incubation group were treated with equal
doses of red light delivered at different dose rates. For in vivo
experiments, albino mice were given injections of HPD (7.5 mg/
kg) and 24 h later the right hind leg of each mouse was treated
with localized red light (630 nm). A total dose of 270 J/sq cm
was delivered to the right hind leg at dose rates of 5, 25, or 125
milliwatts/sq cm. The resulting acute skin damage induced by
HPD photosensitization was scored over a 30-day period, and
skin response curves for the three dose rates were obtained.
Comparable levels of damage were induced in each of the three
experimental groups. The results obtained from both in vitro and
in vivo studies indicate that the photosensitizing efficiency of
HPD photodynamic therapy is not affected by nonthermal varia
tions in clinically relevant dose rates of delivered light.
INTRODUCTION
HPD3 PDT is used clinically in the treatment of various types
of solid tumors (8, 9, 12, 25). The in situ localization of HPD in
tumor tissue and the photodynamic induction of tumor tissue
toxicity are properties responsible for the effectiveness of this
treatment modality (15, 26, 31). Clinical utilization of HPD PDT
began 8 years ago, and was used initially for paliative treatment
following the failure of conventional therapies (7, 9,10, 22). HPD
PDT is currently being used for both palliative therapy and as a
primary modality in the treatment of certain bladder, lung, skin,
1This investigation was performed in conjunction with the Clayton Foundation
for Research, and was supported in part by USPHS Grants CA 31230 and CA
31885, awarded by the National Cancer Institute, Department of Health and Human
Services.
2 To whom requests for reprints should be addressed, at Clayton Center for
Ocular Oncology, Childrens Hospital of Los Angeles, 4650 Sunset Boulevard, Los
Angeles, CA 90027.
'The abbreviations used are: HPD, hematoporphyrin derivative; PDT, photody
namic therapy; CHO, Chinese hamster ovary; PCS, fetal calf serum.
Received 9/13/84; revised 12/11/84; accepted 1/18/85.
and eye tumors (3,4, 6, 8,21).
HPD PDT combines drug administration and visible light irra
diation, and therefore many of the clinical procedures and param
eters used in PDT are similar to those used in conventional
radiation therapy and chemotherapy. Since HPD PDT is a rela
tively new treatment modality, there are still several parameters
which need to be examined. These variables include: (a) dose of
HPD administered; (b) time interval between HPD administration
and PDT treatment; (c) wavelength of light used in treatment; (d)
dose of delivered light; and (e) dose rate of delivered light. In
general, HPD is administered as a single i.v. bolus at a dose of
2.0 to 5 mg/kg (7). Photodynamic treatment is normally initiated
48 to 72 h after HPD administration, although at least one clinical
group has treated patients as early as 3 h following HPD admin
istration (6). Tissue-penetrating red light at 630 nm can be
generated by a tunable dye laser and is used to photoactivate
HPD (14). The dose of delivered light for individual treatments
ranges from 20 to 50 J/sq cm for cutaneous and s.c. lesions to
100 to 400 J/sq cm for pulmonary and ocular lesions (3, 4, 6,
10). The dose rate of delivered light ranges from 20 to 200
milliwatts/sq cm. While several of the procedures related to HPD
PDT are loosely standardized for various treatment sites (8), it
is clear that the parameters related to HPD PDT still need to be
studied and documented.
Improvements in the efficacy of HPD PDT are likely to be
obtained by optimizing the clinical parameters described above.
Clinical randomization of HPD PDT variables would be one
method of addressing the question of treatment optimization.
However, it would not be appropriate at this early stage in the
development of HPD PDT to depend primarily on this procedure
for obtaining needed information. Fortunately, preclinical and
basic studies can be utilized to examine several of the parame
ters listed above. The objective of our study was to examine the
parameter of delivered light dose rate. Specifically, experiments
were performed to evaluate the efficiency of varying light dose
rates in conjunction with HPD PDT-induced phototoxicity. The
effect of light dose rate was documented by in vitro cell killing
and in vivo normal skin toxicity.
MATERIALS AND METHODS
Drugs. HPD was obtained from Photofrin Medical, Inc., Cheektowaga,
NY, as a sterile solution (5 mg/ml) dissolved in 0.9% NaCI solution.
Light Source. A Model 375 dye laser (using Kiton red dye) pumped
by a Model 164 5-watt argon laser (Spectra-Physics, Inc., Mountain
View, CA), and a Model 600 dye laser (DCM dye) pumped by a Model
150 5-watt argon laser (Cooper Laser Sonics, Santa Clara, CA) were the
sources of monochromatic red light (630 nm) used in this study. A
Mm quartz fiberoptic cable was interfaced with the output of the
laser, and a microlens was fitted on the end of the fiber to broaden
even out the intensity of delivered light (14). The light wavelength
CANCER RESEARCH VOL. 45 MAY 1985
1973
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400
dye
and
was
•if.
DOSE RATE EFFECTS IN PDT
documented
with a scanning monochromator
(Model H-20, American
ISA, Metuchen, NJ), and the light dose rate was measured with a
thermopile (Model 210; Coherent, Inc., Palo Alto, CA).
Animals. Eight- to 12-week-old female Swiss albino mice were ob
tained from Bantin-Kingman, Inc., Fremont, CA. The mice were used to
examine light dose rate effects of HPD PDT in normal skin, and were
maintained on standard mouse food and water ad libitum,
Cell Culture Procedures. CHO fibroblasts were used in all in vitro
experiments (14,17,18). The cells were grown in F-10 medium supple
mented with 10% FCS and antibiotics (penicillin and streptomycin). Prior
to treatments, appropriate numbers of exponentially growing CHO cells
were plated onto either 35- or 60-mm plastic Petri dishes and incubated
at 37 °Cfor 4 h to allow for cell attachment. The growth medium in the
dishes was removed and the cells were rinsed once with serum-free F10 medium. The cells were then incubated in the dark for either 1, 12,
or 16 h in F-10 medium containing HPD (25 jig/ml) and FCS (1 or 5%).
Cells incubated with HPD for 16 h also received an additional 30-min
incubation in fresh F-10 medium containing 10% FCS (washout protocol)
immediately after the 16-h incubation. Following the various HPD incu
bation protocols, the medium was removed and the cells were rinsed
with serum-free F-10 medium. The lids of each dish were removed and
the cells were exposed to red light at 630 nm. The delivered light doses
ranged from 0 to 5400 J/sq m, and the dose rates of delivered light
varied from 0.4 to 60 milliwatts/sq cm. The cells were refed with F-10
medium supplemented with 10% FCS immediately following light treat
ment, and were then incubated for 8 to 10 days at 37°C.The surviving
fraction of cells was determined from colony formation (18). Three dishes
were treated at each dose point in each experiment, and experiments
were repeated 3 to 5 times.
Normal Skin Photoradiation Treatment. Mice received a localized
PDT treatment to their right hind leg 24 h following an ¡.p.injection of
HPD (7.5 mg/kg). The mice were placed in styrofoam holders with their
right hind leg extending out of the holder. The treatment leg was shaved
prior to light exposure, and the mice were not anesthetized during the
treatment. Total light doses of 270 J/sq cm were delivered over a 1.5sq cm area of exposed leg. The light dose rate during treatment was
either 5, 25, or 150 milliwatts/sq cm. A total of 10 animals were utilized
in each treatment group. Examination and scoring of the skin response
was started 2 days following treatment, and was carried out 3 times a
week. A numerical scoring system, similar to that used to quantitate skin
response following ionizing radiation or PDT (1, 16) was utilized to
document skin responses following PDT (Table 1). The skin responses
were scored by 2 observers, and the results for each animal were
averaged.
Temperature measurements were obtained s.c. in a second group of
mice which was treated in a manner identical to that previously described.
A 30-gauge hypodermic copper-constantan thermocouple probe and a
Model 400-A digital temperature indicator (Omega Engineering, Inc.,
light varied from 100 to 400 milliwatts/sq cm. Temperature readings
were recorded at intervals of 15 s during the 5-min light exposure and
during the subsequent 4 min.
RESULTS
Charts 1 to 3 illustrate survival curves for CHO cells incubated
with HPD under 3 different protocols and then exposed to 630
nm red light delivered at various light dose rates. These charts
represent the surviving fraction of treated cells as a function of
the dose of delivered light. Five different dose rates (0.5, 5.0,
15.0, 23.0, and 60.0 milliwatts/sq cm) were examined following
a 1-h HPD incubation, as shown in Chart 1. Two light dose rates
(1.0 and 20.0 milliwatts/sq cm) were examined following a 12-h
HPD incubation, as shown in Chart 2. Three light dose rates
(0.4, 4.0, and 40 milliwatts/sq cm) were examined following a
16-h HPD incubation and a 30-min wash, as shown in Chart 3.
The photosensitizing efficiency of HPD PDT (as measured by the
level of cell killing for a given light dose) was similar at all light
dose rates examined for each incubation protocol. The pretreat
ment plating efficiencies for the different experiments ranged
from 68 to 88%.
Chart 4 shows the s.c. temperature measurements obtained
in nonanesthetized mice during light exposure. The individual
curves demonstrate temperature levels during and immediately
following localized leg exposure to 630 nm light delivered at
dose rates ranging from 100 to 400 milliwatts/sq cm. A plateau
in the temperature rise was observed within 3 to 4 min of light
exposure, and the s.c. temperature levels returned rapidly to
pretreatment exposure levels following the light treatment. Light
dose rates of 100 and 200 milliwatts/sq cm induced s.c. tem
perature rises of less than 4°C. Light dose rates from 300 to
400 milliwatts/sq cm induced s.c. temperature
ranged from 6 to 10°C.
rises which
Chart 5 shows the daily skin response to albino Swiss mice
HpD
Photoradiation
Ihr. HpO Incubation
z
o
25.ug HpO/ml. 1%serum
Stamford, CT) were used to document the temperature in mice. The
thermocouple probe was inserted s.c. in the area to be irradiated with
red light. Base-line readings were obtained, and then the hind leg of each
mouse was exposed to 630 nm light for 5 min. The dose rate of delivered
Skin scoring table
Reaction appearing
0
1
2
3
4
Reaction subsiding
3
2
1
0
-
5 .o-
Table 1
Score
o
z
c/3
Observation
Normal
Definite abnormality, slight leg swelling
Marked edema
Slight skin breakdown, moist desquamation in small areas
Breakdown of large areas of skin with moist exúdate
1800
2700
3600
JOULES
Scabs covering treatment field
Epilation with papery skin appearance
Decreased epilatori and slight abnormal appearance
Normal
4500
5400
60 mW/cm1
15 mW/cm1
23 mW/cm'
5 mW/cm1
0.5 mW/cm'
6300
7200
/m?
Chart 1. Surviving fraction of CHO cells as a function of delivered light dose.
Cells were incubated for 1 h in F-10 medium containing HPD (25 ng/m\) and 1%
FCS prior to treatment. Cells were exposed to 630 nm light at dose rates of 0.5,
5,15, 23, or 60 milliwatts/sq cm. Points, mean for 3 to 5 experiments; bars, SE.
CANCER RESEARCH VOL. 45 MAY 1985
1974
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DOSE RATE EFFECTS IN PDT
1.0
HpD
Z
HpD
Photoradiation
t2hr.
HpD
25/ig
HpD/ml.
Photoradiation
16hr HpD Incubation
25MO HpO'ml. 51* Mrum
Incubation
30min. wash. 10% serum
5%serum
10
z
O
g
tü
K
u- io"2
O
O
Z
ce
(lì
10
K
-
20mW/cm2
- 40 mW/cm1
CO
- 04 mW/cm1
- 40mW/cm!
1 mW/cm2
10
900
1800
2700
3600
4500
5400
1600
JOULES/m2
2400
4000
4800
5600
6400
JOULES/m2
Chart 2. Surviving fraction of CHO cells as a function of delivered light dose.
Cells were incubated for 12 h in F-10 medium containing HPD (25 M9/ml)and 5%
PCS prior to treatment. Cells were exposed to 630 nm light at dose rates of 1.0 or
20 milliwatts/sq cm. Bars, SE.
following HPD PDT. The total light dose to the leg of each
experimental mouse was 270 J/sq cm, and the light was deliv
ered at dose rates of 5, 25, or 150 J/sq cm. The treatments
induced moist desquamation encompassing approximately onethird of the treatment field. Similar results were obtained for each
of the 3 light dose rates examined. Damage was not observed
in the legs of mice given injections of HPD and placed in holders
(without light treatment), or in mice treated with red light (without
prior HPD administration).
DISCUSSION
HPD PDT has been in clinical use for 8 years, and has
produced effective responses when used in the treatment of
malignant tumors of the skin, bronchus, bladder, and eye (3, 4,
6, 8, 21 ). However, the majority of patients which have under
gone HPD PDT have been considered late stage, and thus the
follow-up period in most studies is relatively short. As with all
new therapeutic modalities, many of the treatment parameters
have not been fully examined or optimized. The current experi
ments were designed to examine light dose rate as it relates to
the cytotoxic effectiveness of HPD PDT. In vitro studies using
HPD-labeled CHO cells demonstrated that a large range of light
dose rates were equally effective in inducing phototoxicity. This
effect was observed in cells following both short (1 h) and
extended (12 or 16 h) HPD incubation conditions. Since the
subcellular localization of porphyrins can change as a function of
incubation time (23, 27) it was decided to examine the in vitro
effect of light dose rate following a large range of HPD incubation
protocols. The short incubation procedure may induce PDT
Chart 3. Surviving fraction of CHO cells as a function of delivered light dose.
Cells were incubated for 16 h in F-10 medium containing HPD (25 ng/ml) and 5%
FCS. Following HPD incubation and prior to treatment, the cells were incubated
for 30 min in fresh F-10 medium containing 10% FCS. Cells were exposed to 630
nm light at dose rates of 0.4, 4.0, or 40 milliwatts/sq cm. Bars, SE.
damage primarily to the plasma membrane, while the extended
incubation procedures may induce damage primarily to various
subcellular compartments (27). Results from the in vivo experi
ments were in agreement with those from in vitro experiments,
and demonstrated that comparable levels of acute skin toxicity
were induced at all light dose rates examined (28).
Numerous in vitro and in vivo radiation biology studies have
documented that the dose rate of delivered low-linear energy
transfer radiation can be a significant factor in the effectiveness
of a given treatment (2,13,19). It was therefore of both clinical
and scientific importance to determine whether similar results
would be observed for HPD PDT. In the case of ionizing radiation,
the ability of treated cells to accumulate and then repair sublethal
damage is enhanced under conditions of low dose rates (19).
The range of dose rates for maximal variations in cytotoxicity is
reported to be between 1 and 100 rads/min (19). There are
several possible reasons why variations in effectiveness of HPD
PDT were not observed for treatments performed at different
light dose rates. First, HPD PDT may follow the fundamental
photochemical reciprocity law of Bunsen-Roscoe (5). This law
states that the intensity of radiation is inversely related to the
time of exposure needed to produce a given effect; i.e., the
delivered fluence induces the same response regardless of the
fluence rate. If this law holds true for HPD PDT in biological
systems, it would indicate that repair of sublethal damage does
not occur following HPD PDT. A second reason for the lack of a
dose rate effect in our studies may be that the lowest dose rates
examined (0.4 milliwatt/sq cm for In vitro studies and 5.0 milli
watts/sq cm for in vivo studies) were too high for the documen-
CANCER RESEARCH VOL. 45 MAY 1985
1975
Downloaded from cancerres.aacrjournals.org on July 31, 2017. © 1985 American Association for Cancer Research.
DOSE RATE EFFECTS IN PDT
depletion of oxygen or differential photobleaching of HPD.
In vivo light dose rates higher than 150 milliwatts/sq cm were
not examined, in order to avoid possible artifacts due to effects
of hyperthermia (14, 24). Results obtained in our study demon
strated that exposure of albino mouse skin to 630 nm light at
fluence rates between 100 and 200 milliwatts/sq cm causes a
s.c. temperature rise of approximately 3-4°C. However, light
O
>»>•
dose rates of 300 and 400 milliwatts/sq cm induce temperature
rises in s.c. tissue in mice of 7 and 10°C,respectively. While
skin heating at 43°Cfor 1 h does not produce an observable
o
skin reaction in mice (20), a synergistic reaction following HPD
PDT and moderate increases in skin temperature may be pos
sible. A synergistic response of HPD PDT and heat (40.545.5°C)has been reported in the treatment of mouse tumors
a
E
o
I
I
I
I
I
I
I
I
10
Time
(min)
Chart 4. Temperature measurements (s.c.) in albino mice as a function of time
during 630 nm light exposure. Light was delivered at dose rates of 100 (T), 200
(•),300 (A), or 400 (CI) milliwatts/sq cm. Temperature measurements were made
during a 5-min exposure period and for 4 min immediately following treatment.
Points, average measurement from 4 animals.
(29, 30), and therefore a similar phenomenon may occur in skin
tissue. However, while light dose rates which can induce clinically
significant hyperthermia were not examined in this study, it may
occasionally be advantageous to utilize high light dose rates in
order to exploit any synergistic interactions of HPD PDT and
hyperthermia.
Finally, the results of our study are consistent with clinical
observations, in which tumor response following HPD PDT ap
pears to be independent of light dose rates in the range from 20
to 80 milliwatts/sq cm (7). The information on light dose rate
therefore suggests that this parameter of HPD PDT can be
changed for various treatment conditions without altering the
effectiveness of the overall procedure. This would suggest that
large lesions can be treated with a single treatment at reduced
dose rates, while smaller lesions can be equally treated for
shorter periods of time at higher dose rates. However, this would
be true only for lesions having the same thickness, because of
the significant attenuation of visible light by tissue (8).
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CO
O
o.
co
z
co
D -
10
DAYS
5
mW/cm2
O - 25
mW/cm2
•-150
mW/cm2
15
POST
20
25
30
TREATMENT
Chart 5. Daily skin response in albino mice given injections of HPD (7.5 mg/kg)
and exposed 24 h later to 270 J/sq cm of 630 nm light. The treatments were
performed at fluence rates of 5, 25, or 150 milliwatts/sq cm. Points, average
response in 10 to 12 mice.
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watts/sq cm for in vitro studies and 150 milliwatts/sq cm for in
vivo studies) may have been too low to induce any significant
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1977
Downloaded from cancerres.aacrjournals.org on July 31, 2017. © 1985 American Association for Cancer Research.
In Vitro and in Vivo Light Dose Rate Effects Related to
Hematoporphyrin Derivative Photodynamic Therapy
Charles J. Gomer, Natalie Rucker, Nicholas J. Razum, et al.
Cancer Res 1985;45:1973-1977.
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