Investigative Ophthalmology & Visual Science, Vol. 33, No. 2, February 1992
Copyright © Association for Research in Vision and Ophthalmology
Boron Neutron Capture Therapy of Anterior Chamber
Melanoma With p-Boronophenylalanine
Samuel Packer, *f Jeffrey Coderre,t Sharad Saraf,f Ralph Fairchild,t Julia Hansrote,* and Henry Perry*
Boron neutron capture therapy (BNCT) is a form of radiation therapy that requires selective uptake of
boron by the tumor and irradiation with thermal neutrons. Phenylalanine is an amino acid precursor of
melanin and when boronated (p-boronophenylalanine [BPA]) was found to be selectively taken up by
Greene melanoma cells in the anterior chamber of rabbits. This tumor model was irradiated 24 hr after
oral administration of BPA and was used for biodistribution studies that compared BPA and sodium
pentaborate. Three groups were irradiated: group 1 (11 rabbits) received BPA followed by thermal
neutron irradiation, group 2 (9 rabbits) received thermal neutron irradiation only, and group 3 (9
rabbits) served as unirradiated, undrugged control animals. Eight of the 11 tumors in group 1 were
treated successfully; all tumors in groups 2 and 3 grew. Histopathologic examination did not reveal
vascular or retina damage in group 1. These preliminary experiments confirm that newer boronated
compounds, such as BPA, used in BNCT and improved neutron beams can provide selective irradiation
of ocular melanomas. Invest Ophthalmol Vis Sci 33:395-403,1992
blastoma multiforme were done between 1953 and
1961 at Brookhaven National Laboratory and the
Massachusetts Institute of Technology; the results
were disappointing.12 Poor results were attributed to
two major factors: (1) the use of boron-containing
compounds without selective accumulation in the tumor and (2) the rapid attenuation in tissue of the incident thermal neutron beam. Efforts to deliver therapeutic neutron doses to deep tumors resulted in excessive damage to the normal brain and/or the skin. The
high boron concentrations in the blood contributed to
the damage to the vasculature of the brain. The
BNCT clinical trials were discontinued in the United
States in 1961.
In the intervening years since the first American
clinical trial of BNCT, improvements in both areas
have allowed BNCT to reemerge as a viable method
for selective tumor irradiation. Epithermal neutron
beams, which use tissue as a moderator to slow the
neutrons into the thermal energy range at depth, provide an improved depth-dose distribution profile for
thermal neutrons.3 Both thermal and epithermal neutron beams are now available at the Brookhaven Medical Research Reactor (BMRR).3 Since the end of the
first American trial of BNCT, progress has been made
in the development of tumor-selective boron-containing compounds. In Japan, two of the more promising boron compounds currently are being used in two
separate clinical trials of BNCT: one since 1968 for
treatment of patients with glioblastoma and, more recently, one for patients with cutaneous melanoma.4'5
In theory, the full potential of BNCT should be realized when thermal and/or epithermal neutron beams
can be combined with boron-containing compounds
Boron neutron capture therapy (BNCT) is a form
of radiation therapy that has two components. The
first is the delivery of boron to the tumor. This is accomplished by chemically boronating a tumor-seeking compound. The boronated agent must be stable in
vivo and selectively deposit adequate amounts of
boron in the tumor but not in normal tissues. The
second is to irradiate with thermal neutrons. Only the
thermal neutron will interact with the boron and give
rise to an alpha and a lithium particle. These highly
ionizing particles, released preferentially in the tumor, create the selective irradiation of the tumor
compared with other structures in the eye (or body).
The reaction products from the 10B(n,a)7Li reaction
have a range of approximately 10 ^m in tissue and are
known to have a high relative biologic effectiveness (RBE).
Clinical trials of BNCT for the treatment of glio-
From the *Department of Ophthalmology, North Shore University Hospital-Cornell University Medical College, Manhasset, and
the tMedical Department, Brookhaven National Laboratory, Upton, New York.
Supported in part by National Eye Institute (Bethesda, Maryland) grant RO1 EYO856O and the Department of Energy under
contract DE-AC02-76CH00016.
Presented in part at The Radiation Research Meeting, New Orleans, Louisiana, April 3, 1990, at The Association for Research in
Vision and Ophthalmology, May 4, 1990, Sarasota, Florida, and at
The 4th International Symposium on Neutron Capture Therapy,
December 11,1990, Sydney, Australia.
Submitted for publication: May 17, 1991; accepted September
24, 1991.
Reprint requests: Samuel Packer, MD, Department of Ophthalmology, 300 Community Drive, Manhasset, NY 11030.
395
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INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Februory 1992
396
that selectively accumulate in the tumor and are retained, without accumulation in normal tissues.
The use of BNCT first was explored in ophthalmology 20 years ago, using a boron compound (sodium
pentaborate) which had no selectivity for tumor tissue.6 We reevaluated this report and present distribution data showing an improved tumor-localizing ability with the boron-containing amino acid p-boronophenylalanine (BPA).
This article describes the use of BPA as a boron
delivery agent for BNCT of amelanotic Greene melanoma cells carried in the anterior chamber of the rabbit eye. The compound BPA is an analogue of the
melanin precursor tyrosine. As such, it accumulates
in melanoma tissue as a result of the increased metabolic demand for melanin precursors. It has been
shown to enhance the killing effect of thermal neutrons on both pigmented and nonpigmented B16 melanoma in vitro.7 In addition, BPA has been used to
treat superficial melanoma successfully in various animal tumor models.89 Our results describe the use of
BNCT to irradiate a tumor selectively (melanoma in
the anterior chamber) in the presence of radiosensitive tissues. The dose delivered to the tumor exceeded
the dose to normal eye structures by a factor of 3.
Materials and Methods
Tumor Model
The Greene melanoma cell line has been maintained in our laboratory for 15 years. Originally a
hamster melanoma, this tumor has been adapted for
growth in the rabbit eye. 10 " The tumor will grow either in the anterior chamber (iris melanoma) or as a
subchoroidal transplant in the posterior chamber.
This neoplasm has been used to evaluate several experimental therapies, such as the use of radioactive
plaques and hyperthermia.1213 In the experiments we
report, we used only the anterior chamber model.
During surgical procedures, the rabbits were anesthetized with intramuscular ketamine hydrochloride and
xylazine (20 mg/kg). A 2-mm incision was made in
the cornea, just anterior to the limbus, with a No. 11
blade. Approximately 1 mm3 of freshly dissected tumor tissue was deposited onto the iris through the
incision, which then was closed with a single suture.
Antibiotic ointment was applied at the end of the procedure and daily thereafter for 5 days. When the anterior chamber tumor became visible at about 7-10
days postimplantation, photographic documentation
was begun. Tumor size was measured with a handheld caliper; two dimensions, 90° apart, were recorded. The measurements were made two to three
times per week by a single observer.
Vol. 33
Biodistribution Studies
Sodium pentaborate (Na2B10O,6), 95% enriched in
B, was obtained from Oak Ridge National Laboratory (Oak Ridge, TN). The sodium pentaborate was
administered to tumor-bearing rabbits in two ways:
(1) as an intracameral injection (0.05 ml of a 9% solution) and (2) as an intravenous injection (23 mg l0 B/
kg body weight). The BPA, 95.3% enriched in 10B, was
synthesized according to published procedures with
some minor modifications.1415 This drug has a limited solubility at physiologic pH. Previous work in our
laboratory showed that oral administration as an
aqueous slurry at neutral pH (by intragastric intubation) is an effective administration route.16 The rabbits received 750 mg BPA/kg body weight (35 mg 10B/
kg body weight) as a single oral dose in 15 ml of water.
The boron concentration was analyzed by the
prompt-gamma spectroscopic method.17 The intraocular boron distribution pattern was determined by the
method of neutron capture radiography.'5>'8 This technique allows visualization of the boron distribution in
50-/xm thick cryosections.
10
Neutron Irradiations
Neutron irradiations were done using the thermal
neutron facility at BMRR. Dosimetry measurements
for the rabbit eye tumor geometry were done using
gold foils and thermoluminescent dosimeters in a
plastic phantom and by positioning gold foils on an
anesthetized rabbit. The dosimetric parameters of the
BMRR thermal neutron irradiation facility are listed
in Table 1. A RBE of 2.5 was used for the 10B reaction,
2.0 for protons from the 14N(n,p)14C reaction, and 2.0
for fast neutrons. The IOB dose was 79.4% of the total
dose. The thermal neutron port (25 X 25 cm) was
collimated with a 2.7-cm thick 6LiF-epoxy insert to a
1.55-cm aperture. The animals were anesthetized and
positioned with the eye centered in the collimator aperture.
A 10-min videotape record of the eye of an anesthetized rabbit, taken from the other side of the collimator with the rabbit in place, established that the eye
did not move significantly. During irradiation, online eye monitoring was not possible; therefore, the
possibility of movement and a geographic miss cannot be excluded with the existing positioning apparatus. (This would not be the case with clinical irradiation.)
Three groups of animals were studied. Group 1 received BPA orally and then was irradiated. Group 2
did not receive BPA but was irradiated. Group 3 (control group) received no BPA and was not irradiated.
Table 2 gives the tumor size at time of irradiation.
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DNCT OF ANTERIOR CHAMBER MELANOMA / Packer er al
No. 2
Table 1. Average tissue dose* using BMRR
thermal neutron beamf
Dose components
With BPA
Without BPA
1. 10B dose (20 ppm, tumor)
2. Fast neutron dose
3. Gamma dose, from
reactor
4. I4N (n, p) (2.6% N2)
5. Gamma capture 'H(n, a)
dose (10.3% H)
6. 10B dose to normal tissue
(3 ppm IOB)
2307
312
923
156
50
206
50
103
30
30
346
138
* In centigray (cGy).
2
t Totalfluencewas 5.33 X 1012n,h/cm .
Our investigations with rabbits adhered to the
ARVO Resolution on the Use of Animals in Research.
Results
Boron Distribution Studies
The only previous use of BNCT for the treatment
of ocular melanoma in rabbits used intracameral injections of sodium pentaborate immediately before
irradiation. We did a comparative evaluation of the
intraocular boron distribution produced by intracameral or intravenous injection of sodium pentaborate
and the boron distribution produced by orally administered BPA.
Figure 1 is a neutron capture radiogram (NCR) that
shows the boron distribution in a tumor-bearing eye
after intracameral injection of sodium pentaborate.
In such images, bright areas represent high boron concentrations. Aqueous humor had been removed, and
0.05 ml of sodium pentaborate 9% solution was injected into the anterior chamber. The interval between injection and death was 10 min, the same as
397
that used in an earlier study.6 The large arrow in Figure 1 indicates relatively high concentrations of boron
in the anterior chamber. The small arrow points to
the anterior chamber tumor nodule growing on the
iris. Under these conditions, the boron has not penetrated to the interior of the tumor and remains in the
anterior chamber.
Figure 2 shows the boron accumulation and washout in the blood and in the anterior chamber tumor
after a single oral dose of BPA (35 mg 10B/kg). At 24
hr postadministration, the boron concentration in the
tumor was in the therapeutic range (> 15 ppm) with a
tumor/blood boron concentration ratio of approximately 4. When sodium pentaborate was administered as a single intravenous injection (23 mg l0B/kg),
the boron concentrations observed in tumor and
blood reached approximately 30 ppm at 30 min postinjection and decreased with a clearance half-time of
2.5 hr (data not shown). The tumor/blood boron concentration ratio after intravenous injection of sodium
pentaborate never exceeded 1.
We compared the intraocular boron distribution
patterns obtained after systemic administration of
both BPA and sodium pentaborate in tumor-bearing
rabbits. Figure 3 shows a NCR prepared from a coronal section of a tumor-bearing eye. The rabbit received intravenous BPA 7 hr before death. The large
arrow points to the anterior chamber tumor. The
boron concentration in the tumor shown in Figure 3
was approximately 20 ppm. Other radiosensitive ocular structures of interest in the treatment volume include the cornea, the lens, the retina, and the optic
nerve (the optic nerve is not visible in this section).
The estimated boron concentrations in the normal
eye structures in Figure 3 are approximately 3-4 ppm.
Figure 4 shows the corresponding intraocular boron
distribution produced by sodium pentaborate. This
NCR was obtained 7 hr after intravenous injection of
sodium pentaborate. The boron distribution was non-
Table 2. Treatment data for Group 1 (BPA + NCT)
Animal no.
Date
irradiated
Date
enucleated
Initial size*
(mm X mm)
Final size*
(mm X mm)
299
740
323
275
169
167
432
503
097
555
824
3/23/89
3/23/89
3/23/89
3/23/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
5/24/89
5/24/89
6/30/89
7/23/89
9/27/89
7/26/89
9/11/89
7/31/89
11/22/89
01/26/90
—
6X3
1.5 X 1.5
1.5 X 1.5
1.5 X 1.0
2X2
6.5 X 6.5
6.5 x 5.5
3X4.5
6.5 X 3.5
3.0 X 3.0
4.5 X 4.5
NVf
NV
1.0X0.5
NV
NV
12X8
12X6
9X6
NV
NV
NV
* Base dimensions 90° apart.
t NV = Not visible.
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398
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1992
Vol. 33
Fig, 1. Neutron autoradiograph of anterior chamber melanoma
taken after sodium pentaborate was given intracamerally. The melanoma (short arrow) has no accumulation of boron (white), while
the anterior chamber remainsfilledwith boron (long arrow).
selective; the tumor/normal tissue boron concentration ratios were approximately 1.
BNCT Irradiations
Fig. 3. Neutron autoradiograph of anterior chamber melanoma
taken 7 hr after a single dose of BPA (750 mg/kg). The melanoma
(arrow) has significant accumulation of BPA compared to the rest
of the eye. Whiteness reflects boron accumulation.
A total of 29 rabbits with anterior chamber melanomas were divided into three groups. Group 1 (11
rabbits) received a single oral dose of BPA followed by
thermal neutron irradiation 24 hr after the BPA administration. Table 2 gives data as to the size of the
tumor at the time of treatment and the response of the
tumor to the BNCT irradiation. Figure 5 shows the
individual growth curves of the tumors in Group 1.
Three of 11 tumors grew; the remaining tumors were
monitored for various periods of time (Table 2, for the
time of enucleation). Rabbits with controlled tumors
were killed after increasing intervals, and the eyes
c
o
o
c
o
<L>
Q.
CO
•£
o
OL
10
15
20
25
30
Time, hrs
Fig. 2. Biodistribution of BPA (750 mg/kg) given orally as a single
dose to rabbits containing an anterior chamber Greene melanoma.
Fig. 4. Neutron autoradiograph of anterior chamber melanoma
taken 6 hr after a single dose of sodium pentaborate (750 mg/kg).
The melanoma (arrow) has accumulated amounts of sodium pentaborate similar to other ocular structures. Whiteness reflects boron
accumulation.
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DNCT OF ANTERIOR CHAMBER MELANOMA / Packer er ol
No. 2
175
O — O299
— »740
A
A 323
•
A 275
D — D169
• — B503
<? — V824
80
100
Time, d
Fig. 5. Group 1 received BPA (750 mg/kg) and was irradiated 24
hr later with thermal neutrons (see text). Three animals had tumor
that continued to grow (#167, #503, and #432).
were examined histologically. At approximately 6090 days postirradiation, cataract formation was observed in treated eyes that were otherwise free of visible signs of radiation damage. Group 2 (nine rabbits)
received thermal neutron irradiation only (Table 3,
for details as to tumor size and irradiation dates). Figure 6 shows that all nine melanomas grew. Group 3
(nine rabbits) served as an untreated control group
and received neither BPA nor reactor irradiation. Figure 7 shows that all nine control tumors grew.
399
cataract formation or any damage to normal ocular
tissues. Figure 8 (bottom figures) shows animal 321
(Group 2) 12 and 23 days postirradiation. The tumor
was measured from 2 days before irradiation to this
point (Table 3). Thus, the small size of this tumor
would favor a good therapeutic response. The opposite, however, occurred (Fig. 8, bottom right), as
shown 23 days postirradiation. Histopathologic examination of animal 321 revealed areas of necrosis alternating with areas of viable-appearing tumor (Fig. 9).
The histopathologic examination of the BNCT
group was significant because the vasculature of the
eye remained normal. The major toxicity in the early
BNCT trials was vascular toxicity. Thus, the lack of
adverse ocular vascular events is evidence of the improved tumor/blood ratios achieved with the new
boronated compounds. This is noteworthy because
the thermal beam we used delivered a similar nonBNCT radiation dose to the anterior and posterior
segments of the eye; thus, rabbit eyes in groups 1 and
2 received the same non-BNCT radiation exposure.
Therefore, the lack of damage to the vascular structures of the eyes in group 1 indicates that they contained inadequate amounts of boron to result in radiation damage. Figure 10 shows the retina of a rabbit
(321) that received BNCT with BPA. The retinal vasculature appears normal 3 months after irradiation.
Discussion
Clinical and Histopathologic Correlations
Figure 8 (top left) shows animal 097 (group 1) 1 day
after irradiation; the tumor measured approximately
3 X 5 mm in base diameter. Figure 8 (top right) was
taken 19 days after irradiation. A cataract was visible
at 1 month. Histopathologic examination of animal
097 confirmed the cataract and did not reveal any
residual tumor or any other evidence of radiation
damage to normal ocular structures. Treated tumors,
which were enucleated at periods less than 60 days
(Table 2) and examined histologically, did not show
A previous study6 was the only other attempt to
apply BNCT to the treatment of ocular melanoma to
our knowledge. There were several significant differences between this earlier study and the results we
report that deserve discussion. In the previous report,
sodium pentaborate was administered as the boron
delivery agent. Sodium pentaborate was one of the
boron delivery agents used during the initial trials of
BNCT in the 1950s and early 1960s and was shown to
distribute rapidly in body water with no selectivity for
Table 3. Treatment data for Group 2 (NCT only)
Animal no.
318
325
006
147
310
321
347
367
621
• Base dimensions 90° apart.
Date
irradiated
Date
enucleated
Initial size*
(mm X mm)
Final size*
(mm X mm)
3/24/89
3/24/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
7/11/89
4/4/89
4/4/89
7/24/89
7/24/89
7/24/89
8/13/89
9/27/89
7/24/89
7/26/89
4X3
4.5X3
5X4
6X4
5.5X4
2X2
5X2
6X4
4.5 X 2.5
5X4*
9X5*
11 X 8.5
"whole AC"f
9X7.5
11 X 6.5
"whole AC"f
t AC = anterior chamber.
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11X9
12X7
400
INVESTIGATIVE OPHTHALMOLOGY G VISUAL SCIENCE / February 1992
30
40
50
60
70
80
Time, d
Fig. 6. Group 2 received no boron-containing compound and
were irradiated with thermal neutrons (see text). All animals had
tumors grow.
tumor tissue. A cell suspension was injected into the
anterior chamber, and the eye underwent experimentation 2-5 days later when the tumor existed as a thin
sheet or perhaps small nodules. In our study, we implanted tumor fragments that were allowed to grow
for approximately 14 days; thus, we were treating a
well-vascularized, solid tumor. The other group injected the sodium pentaborate directly into the anterior chamber and commenced reactor irradiation
within 10 min. They intended to show that the intensely ionizing reaction products from BNCT were
tumoricidal. Their study showed complete tumor
control with minimal radiation damage in 6 of 25
treated eyes, complete tumor control with significant
radiation damage in 8 of 25 treated eyes, and significant growth delay in an additional 6 treated eyes.
Our intent was to demonstrate the ability of the
boron delivery agent BPA to accumulate in tumor
sites selectively after systemic administration. We
chose to treat vascularized solid tumors with this approach as an approximation of the clinical situation.
The management of choroidal melanoma is still
controversial. However, when we consider primarily
the techniques for irradiation of choroidal melanoma,
BNCT offers several worthwhile advantages. First, it
is a selective form of irradiation, ie, the tumor is irradiated preferentially compared with normal ocular
structures. Thus, large choroidal melanomas that
currently would not be considered for radiation therapy might benefit, as would tumors located close to
the macula or optic nerve. Second, the lack of manipulation (no surgery required) would obviate any need
to consider the possibility that tumor manipulation
might cause metastasis.19
The drug BPA is absorbed by cells that synthesize
melanin. Our group showed that this uptake depended more on amino acid transport than on the
Vol. 33
degree of pigmentation.9 In addition, we demonstrated that this uptake did not occur in metabolically
active normal tissue.16 This study demonstrated the
superiority of orally administered BPA to the intracameral technique previously used and confirmed the
selectivity of BPA when given systemically. Its potential significance is the treatment of metastatic foci.
Radiation therapy has been partially effective for
palliative treatment of malignant melanoma of the
skin and metastases. However, BNCT delivers
densely ionizing radiations that should be more effective (higher RBE) than either the x-rays or fast neutrons that have been used clinically.20 This, combined
with the selective delivery of radiation to the tumor,
the possibilities of dose fractionation, and an epithermal beam, highlights a potentially exciting new treatment of malignant melanoma not only of the eye but
elsewhere in the body.
An international committee convened to advise on
clinical applications of neutron capture recommended that four to six fractions be tried in such therapy.21 Further advantages then should be obtained for
a number of reasons: (1) the usual benefits which are
obtained after fractionation as represented by the "4
Rs" (repair, reassortment, repopulation, and reoxygenation); (2) selective repair in normal tissues from
the preponderance of low linear energy transfer (LET)
radiation damage in the latter compared with high
LET damage in the tumor;22 and (3) redistribution of
boron compounds as a consequence of compound
readministration. Fractionation also will facilitate using different boronated melanoma-seeking agents.23
For example, BPA may be used with a boronated
monoclonal antibody.
There are 35 potential neutron sources in the
United States. Therefore, this technique would be
available at many locations.24
Our results are encouraging, but further studies are
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Fig. 7. Group 3 received no boron-containing compound, nor
any radiation, and served as our control group. All animals had
tumors grow.
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No. 2
DNCT OF ANTERIOR CHAMBER MELANOMA / Pocker er ol
401
Fig. 8. Comparison of results, Group 1 vs. Group 2. Top left, #097 1 day after irradiation. Top right, #097 19 days after therapy, tumor
(arrow) smaller than at 1 day. Bottom left, #321 12 days after receiving irradiation and no BPA. Bottom right, #321 23 days after irradiation,
tumor (arrow) significantly larger.
needed. The problems remaining with BNCT are related to optimization of boron delivery and neutron
beam characteristics. As highlighted by others,22 an
adequate tumor concentration of boron is required
(> 35 Mg/g l0B/g tumor), and higher uptake by the
tumor compared with normal tissue is desirable. This
will require pharmacokinetic and biodistribution studies because the absolute amount of 10B in the tumor
will influence the tumor/normal tissue ratio required
to assure a therapeutic gain. The alpha particle has a
range of one cell diameter; therefore, cells without
boron may not be treated successfully. Thus, the uni-
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402
INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / February 1992
Vol. 03
Fig. 9. Histopathologic examination of repressed tumor (#321) reveals areas of
viable-appearing melanoma
cells with areas of necrosis.
form cellular distribution of boron in a tumor is critical. This problem is similar to that faced in radiation
therapy where it is generally considered that treatment requires reduction of the surviving cell fraction
to 1CT9. Given the heterogeneity of malignant melanoma, this is a formidable task and may require ma-
nipulation of boron delivery (perhaps with multiple
agents, eg, melanin precursors or monoclonal antibodies), multiple-dose schedules including fractionation,
and the judicious use of thermal and epithermal neutron beams.5 The latter will decrease the radiation
dose to the anterior structures of the eye further and
Fig. 10. The retina and retinal vasculature appear histologically normal 3 months
after boron neutron capture
therapy.
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No. 2
DNCT OF ANTERIOR CHAMBER MELANOMA / Packer er al
increase the therapeutic gain, ie, allow a tumoricidal
dose to be delivered with less radiation.to the normal
anterior segment of the eye.
Key words: boron neutron capture, melanoma, phenylalanine, rabbit, radiation therapy
Acknowledgments
The authors thank Dennis Greenberg and Peggy Micca
for their technical assistance, Mrs. Cynthia Pearlberg for
preparation of this manuscript, and Dr. David Krohn for
providing the tumor model.
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