Combination Therapy of Malignant Tumors with
Ionizing Radiations and Chemicals: A Review
HARRYN. BANE,*JOHNT. CONRAD,!ANDGEORGES. TARNOWSKI
(Divisiona of Biophysics and Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research,
Memorial Center for Cancer and Allied Diseases, New York SI, N.Y.)
Since the discovery of the damaging effects of
ionizing radiations on cells, attempts have been
made to increase the radiation curability of malig
nant neoplasms by the simultaneous administra
tion of various chemical agents. Three major ave
nues of approach will be reviewed : (a) combining
radiation with agents which themselves have antitumor properties in an attempt to gain a synergistic action; (6) sensitizing the tumor to radiation
by means of a noncarcinostatic agent; (c) intro
ducing into the tumor a compound which will in
crease the radiation dose to the tumor by second
ary radiation or by nuclear disintegration. A re
view of previous experience in these fields is needed
because of the discovery of better chemotherapeutic agents, the increasing knowledge of funda
mental radiobiology, and the advent of biologically
applicable beams of electrons, neutrons, and heavy
particles.
The literature is extensive, and it is impossible
to include reference to all work that has been done,
but an effort has been made to include all the
major trends of experimentation. The authors have
exercised critical discretion as to the material
which is included. Whenever possible, examples of
investigations with human tumors, animal tu
mors, and in vitro technics have been cited.
Reference has been omitted to agents which
have a systemic effect, such as the sex hormones
(16) and cortisone (15) which may alter tumors by
indirect pathways, and to radioactive isotopes
such as P32, I131,and Au198which are of proved
value (5).
CARCINOSTATIC
AGENTS
The alterations in the malignant cell following
irradiation represent a combination of direct and
indirect effects of radiation. The direct effects
comprise a more or less prolonged reduction in the
* Kress Fellow in Radiobiology.
t Present address: Department of Biology, Washington
Square College, New York University.
Received for publication February 1,1957.
number of cells entering mitosis, abnormalities in
the mechanism of cell division, and changes in cell
metabolism. The indirect effects are those induced
in the tumor bed, more especially in the intra- and
peritumoral capillaries, lymphatics, and surround
ing connective tissue. If the radiation dose is
small, the direct effect is of a temporary nature
only and is followed by recovery (131). When the
radiation dose is increased, after temporary inhi
bition of mitotic activity, degenerate cells appear
upon resumption of mitosis. Many cells break
down in the premitotic phase or at the end of prophase, some in telophase, and a few at other stages
of mitosis.
The majority of carcinostatic chemicals exert
their action directly on the tumor cells. Many
chemicals which produce no visible effects on a
cell during interphase can interrupt the mitotic
cycle. Some drugs cause the degeneration of divid
ing or premitotic cells leading to the formation of
pyknotic nuclei; others arrest mitosis in certain
phases (62, 82).
Colchicine.—Colchicinewas the first mitotic in
hibitor used in combination with radiation for
treatment of malignant tumors. Colchicine tempo
rarily arrests mitotic division of animal and plant
cells in metaphase, suppresses spindle-fiber forma
tion, and inhibits separation of the daughter cells
after division (87). The therapeutic value of colchicine in the treatment of malignant diseases is not
great, since tumors can be only temporarily in
hibited, and the drug is too toxic to allow its pro
longed use at higher dose levels. In 1951, Levine
(83) reviewed the literature on the combined use
of colchicine and x-rays for the treatment of ani
mal and human neoplasms. Results obtained on
mouse and rat tumors were inconclusive, though
in some cases better effects were produced by
colchicine and x-rays than when either agent was
used alone. Clinical work reviewed by Levine was
carried out in advanced stages of malignant dis
ease and with a small number of patients.
Additional clinical information has been ob-
551
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Cancer Research
tained, especially by Huant (58, 59), Mallet and
Le Camus (91), and Girgis et al. (40), who reported
the results of treatment with colchicine and x-rays
of larger groups of cancer patients. Clinical im
provement (tumor regression and freedom from
relapse over longer periods of time) was observed
in some of these patients, and this was regarded as
an indication of the enhancement of x-ray effects
by colchicine. However, the authors themselves
recommend caution in the evaluation of their re
sults. Regression of primary tumors and disap
pearance of métastaseswere frequently only of a
temporary nature and were followed by relapses
after remissions of various duration. Absence of
adequate controls further complicated the evalua
tion of these clinical observations. Data on smaller
series of cancer patients treated with colchicine
and x-rays were published by Reviglio (121), Con
stantin (18), Keibl and Loetsch (71), and others.
Huant (60, 61) has recently suggested that addi
tional administration of nicotinamide, ascorbic
acid, and also possibly of thiamine could reduce the
toxic side effects of colchicine and permit the in
crease of the daily dose of the compound to 5-5.5
mg. instead of the usual maximum dose of 4 mg.
A derivative of colchicine, N-deacetylthiocolchicine, has been found to be much less toxic and to
show a 10X greater spread between its toxic and
therapeutically effective doses than colchicine
(63).
The authors (140) have injected 100 mg/kg of
N-deacetylthiocolchicine
intraperitoneally
into
mice bearing 5-day-old implants of Sarcoma 180
or RC mammary carcinoma. Eighteen hours later
the tumors were irradiated with 400-500 r of x-ray.
This double treatment was repeated on 2 con
secutive days. No significant increase in the per
centage of mice showing complete regression of
their tumors 8 weeks after irradiation has been
observed in animals receiving combined treatment
as compared with the regression rate in mice treat
ed with either agent alone.
N-Deacetylthiocolchicine has been used at in
travenous dose levels of 20-30 mg/day in the
treatment of two patients with advanced cancer of
the mouth. The tumors were also irradiated with
2500-3000 r of x-ray. Marked tumor regression
after treatment was reported (63).
Alkylating agents.—Alkylating agents including
sulfur and nitrogen mustards, ethyleneimines, 1,2epoxides, and the esters of sulfonic acids have been
used extensively in the chemotherapy of animal
and human tumors (122, 135). The effects of alkylating agents on sensitive animal tissues re
semble in many respects those of ionizing radia
tions. Both types of agents retard the growth of
some tumors, induce chromosomal abnormalities,
exert mutagenic action, cause characteristic dam
age to the bone marrow, produce bleaching of the
hair and vesication at the site of action on the
skin, etc. However, there are definite differences
in both the chemical mechanism of action and the
cytological effects of radiation and alkylating
agents (72). For example, cells of Walker 256 rat
carcinosarcoma are most sensitive to irradiation
and least sensitive to nitrogen mustard at the end
of the mitotic interphase. Irradiation of solutions
of deoxyribonucleic acid (DNA) leads to a slow
degradation of the molecules and loss of viscosity;
nitrogen mustard alkylates the phosphate groups
of DNA and leads to changes in molecular shape
without depolymerization.
Thus, definite possibilities exist that the simul
taneous treatment of tumors with ionizing radia
tion and alkylating agents could produce not only
additive but synergistic effects by interfering with
cell division in more than one way.
Skipper et al. (128) have observed that the com
bination of nitrogen mustard (and also of
aminopterin) with total-body x-radiation increased
the survival time of Akm mice bearing AK4 leu
kemia slightly more than did each of these agents
alone. Schmermund et al. (124) have treated rats
bearing 7-day-old Yoshida rat sarcoma with single
injections of 1.75 mg/kg of nitrogen mustard oxide
combined with a single x-ray dose of 300 r to the
tumor; 3 days later the mean weight of the tumors
was approximately 50 per cent less than that of
untreated controls, while an x-ray dose of 600 r
alone produced 45 per cent and 1000 r 70 per cent
inhibition. A dose of 1.35 mg/kg of nitrogen mus
tard oxide caused about 40 per cent and a dose of
3.3 to 3.5 mg/kg about 70 per cent inhibition.
Thus, there was no evidence of a synergistic effect
by the combination of these two agents.
Triethylenemelamine (TEM) injected in a single
dose of 1.25 mg/kg and combined with a single
tumor dose of 750 r or 1000 r produced responses
suggestive of synergism in mice bearing Sarcoma
180 or RC mammary carcinoma (140).
Clinical studies of combinations of alkylating
agents and x-rays have been reported by several
authors. The largest group of patients treated in
this way was that of Gil y Gil (39) who reported
good immediate results in some of 100 patients
with different tumors in advanced stages treated
with a combination of x-rays and HN3 (tris-2chloroethylamine) or TEM. Results were of a pal
liative nature, and the observation time was too
short to give a fuller evaluation of results. HN3
and x-rays produced better response in combina
tion than when used alone in cases of Hodgkin's
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BANEet al.—CombinedChemotherapyand Radiotherapy of Tumors
disease, anaplastic carcinoma in general, and some
cases of lung cancer. No beneficial effects were re
ported in cases of tumors of the breast or of the
female genitalia.
Satisfactory remissions of Hodgkin's disease
following the combined use of alkylating agents
and radiotherapy were reported by Holy and
Suchan (57), Linke and Lasch (85), MalaguzziValeri and Di Raimondo (90), Pedro-Botel and
Gaix (113), Truhaut (146), and others. Temporary
improvement was observed in cases of tumors of
the urinary tract (147), choriocarcinoma (4), and
bronchial carcinoma (84) treated with combina
tions of HN2 (methylbis[2-chloroethyl]amine) and
x-rays.
In a review of 700 cases of malignant blood dis
eases and reticuloses, Wilkinson (152) cautions
against the use of HN2 prior to or simultaneously
with radiotherapy in the treatment of Hodgkin's
disease and of lymphatic and myelogenous leukemias. In his experience the use of such combina
tions leads to bone marrow damage and the pro
duction of severe refractory or aplastic anemias.
Phillips et al. (177) treated fourteen cases of
liver métastasessecondary to carcinoma of other
organs with a single intravenous injection of 0.4
mg/kg of HN2 followed by super voltage x-ray
therapy. The whole liver was irradiated to a tumor
dose of 2000-3750 r in 8 days. There was no signifi
cant difference in the results of x-ray therapy alone
compared with combined treatment; whereas ten
out of fourteen patients treated with both modali
ties showed symptomatic improvement, sixteen
out of 22 patients treated with x-ray alone reacted
in the same way. Improvement in liver function
tests was observed, but there was no difference
between the two groups. The patients on combined
therapy showed fewer side effects of treatment.
Urethan.—Urethan produces general disruption
of most aspects of cell division in both isolated ani
mal cells and in the tissues of intact animals (Cornman [21]). A range of mitotic abnormalities is pro
duced: multipolar mitoses, accumulation of metaphases, fragmentation of chromosomes, and, in
some tissues (e.g., in the intestinal crypts), karyopyknosis. Urethan inhibits several experimental
tumors, e.g., mouse leukemias, Sarcoma 180,
Walker rat carcinosarcoma 256; it causes tempo
rary remissions in chronic myelogenous leukemia in
man but is less effective in chronic lymphatic
leukemias (17).
Whitehead and Lanier (151) observed an en
hancement of tumor-inhibitory effects of multiple
x-ray doses of 150-300 r in mouse mammary car
cinoma A-179955 and mouse leukemia L4946
when, in addition to radiotherapy, animals were
553
treated with two to three doses of l,3-dichloro-2isopropyl-N-diethylcarbamate
injected intraperitoneally in doses of 0.0019 cc. every 3d day. The
degree of inhibition of tumors implanted into the
leg muscles was determined by comparing tumor
weights of treated and control mice at the end of
treatment.
In 1949, Dustin (28) reported the results of con
current and alternating treatment with urethan
and x-rays of fourteen cases of chronic myelogenous
and ten chronic lymphatic leukemias. Myelogenous
leukemias are more sensitive to urethan alone than
are lymphatic leukemias. Several patients became
resistant to either urethan or x-rays; no cross-re
sistance was observed. Simultaneous therapy with
both agents was used at some time in the course of
treatment of eleven patients with myelogenous
and of four with lymphatic leukemias. Remissions
were obtained in these cases more rapidly and with
smaller doses of these agents than with either
agent alone. They were also observed in cases re
sistant to urethan or x-rays, and in those who did
not tolerate high doses of urethan. Lings (32) re
ported that the treatment of patients with mul
tiple myelomas with a combination of urethan and
x-rays produced better clinical results than thera
py with x-rays only.
Furine analogs.—-8-Azaguanineis incorporated
in small amounts into the nucleic acids of animal
tumors (mouse Sarcoma 37, mouse Leukemia
L1210) and normal tissues (Mandel [92], Skipper
[127]). It appears that the inhibitory action of 8azaguanine on tumor growth may be caused by
the inability of nucleotides containing this purine analog to perform the still unknown func
tions of the natural purine nucleotides.
Carpender and Lanier (12) treated mouse adenocarcinoma E 0771 with a daily subcutaneous
dose of 1 mg. of 8-azaguanine, combined with
daily x-ray doses of 200-600 r to a total dose of
4600 r in 14 days. With the tumor weight used as
a criterion of therapeutic effects, they found that
combined treatment caused a greater degree of
tumor inhibition than did treatment with either
agent alone.
In experiments with Sarcoma 180, RC carcino
ma, and Bashford mouse Carcinoma 63 (140),
8-azaguanine neither produced any increase in the
number of tumor regressions caused by radiation
alone nor altered the degree of the radiation-in
duced tumor inhibition 1 week after treatment.
Another purine derivative, 6-mercaptopurine,
used in combination with x-rays, produced an en
hancement of both tumor growth retardation and
tumor regressions at 8 weeks in the case of Sarco
ma 180. There was an increase in tumor inhibition
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Cancer Research
at 1 week in the case of the RC carcinoma.
In 1927, Chambacher and Rieder (13) reported
great improvement of therapeutic results obtained
with x-rays in a variety of human tumors when
multiple doses of 0.05 mg. "sodium nucleinate"
were injected subcutaneously
prior to or simulta
neously with irradiation.
Antibiotics.—Antibiotics
have often been used
in conjunction
with radiation therapy of cancer
with the aim of combating the infectious compo
nent of a tumor or of the postirradiation
syn
drome. In addition to this, aureomycin was used
by Bateman et al. (3) in conjunction with radiation
therapy of 39 various advanced human tumors,
since it had been reported that aureomycin inhib
its cell division in tissue cultures and retards cer
tain small animal tumors. Regression of palpable
tumors was observed in 22 patients, clinical im
provement in 39, and healing of ulcerated tumors
in twelve.. Freedom of symptoms was recorded in
nine out of nineteen patients observed for 4-19
months after the beginning of therapy. No com
parison was made with x-ray treatment without
aureomycin.
In 60 cases of Hodgkin's disease, lower doses of
x-rays were required to produce remissions when
radiation was combined with actinomycin C thera
py at dose levels of 250 mg/day for 3-6 weeks.
Good results were observed in two cases of aleukemic lymphadenopathy,
but carcinomas and leukemias responded
poorly (Schulte and Lings
[125]). Magnus and Zeitler (88) published addi
tional observations on eleven cases of Hodgkin's
disease and three leukemic patients treated with
actinomycin
C (Sanamycin)
and x-rays. Seven
cases of Hodgkin's disease and one myelogenous
leukemia showed complete or partial remissions.
No comparisons with the results of radiation ther
apy alone were presented.
Miscellaneous
compounds.—Colchicine,
urethan, alkylating agents, certain purine analogs,
and antibiotics are chemicals the tumor-inhibiting
activities of which have been well established. In
addition to them, several chemicals have been
used in combination with ionizing radiations for
the treatment of human and animal tumors on the
basis of some observed tumor-damaging
properties
or following only certain preconceived ideas about
their possible deleterious effects on tumors.
Failla (33) postulated, on the basis of the fact
that radiation-damaged
cells and their nuclei
swell, that radiation increases the intracellular os
motic pressure. According to this theory, it should
be possible to increase the radiosensitivity
of a
tissue by decreasing the osmotic pressure of the
surrounding extracellular fluids. To test this as
sumption Sugiura (137) injected daily, for 4-5
days, 0.5 cc. of distilled water or Locke-Ringer
solutions of different tonicity into 1-week-old im
plants of Sarcoma 180, previously irradiated with
x-rays. Hypotonie saline and distilled water mark
edly enhanced the tumor damage caused by radi
ation, but water itself, injected intratumorally,
did
not affect the growth of the tumor.
Upon injection into tumor-bearing
animals,
bacterial endotoxins and certain polysaccharides
obtained by their degradation
produce hemor
rhages in the tumors and occasionally cause their
regressions. Lawrence and Duran-Reynals
(81)
treated mice of strain A bearing transplantable
mammary carcinoma with E. coli, paratyphoid,
and typhoid toxins plus x-radiation. Toxins did
not increase prolongation of the survival time of
tumor hosts over that obtained with x-rays alone.
Megaphen —¿
(N - 3 - d imethylam ino) - propyl - 3 chlorophenothiazine—produces
mitotic abnormali
ties in some biological systems. Peters et al. (114,
115) treated mice bearing the Elberfeld strain of
Ehrlich ascites tumor with three injections of 12.5
mg/kg/day
of Megaphen on the 5th, 7th, and 9th
day after tumor inoculation. On the 6th day tu
mor-bearing mice were irradiated. This compound
accentuated
the radiation-induced
depression of
tumor cell mitoses and caused an accumulation of
ana- and telophases due to the prolongation
of
mitotic time, but did not potentiate the tumor in
hibition caused by radiation alone.
Choline (149) and its salts (150), isamine blue
(9), arsenicals (126), and other chemicals were
used with equivocal results in combination with
x-rays in therapy of human tumors on the basis of
such rather vague conceptions as those of stimu
lation of the reticulo-endothelial
system, the gen
eral role of phospholipides in tumor cell metabo
lism, etc.
It appears from the preceding survey of tumorinhibitory chemicals used in combination
with
ionizing radiations for the therapy of tumors that
in certain instances real synergistic effects have
been observed. Further progress in this field can be
expected from more extensive testing of the re
ported and other tumor-inhibiting
chemicals in
combination with ionizing radiations on various
animal tumors, including those occurring in the
ascites form. Better understanding
of the mecha
nisms responsible for the antitumor
activity of
both carcinostatic
chemicals and ionizing radia
tions will permit investigation
on a less empiric
basis.
SENSITIZINGAGENTS
It is necessary to define the word sensitizer in
order to avoid confusion between this class of com-
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BANE et al.—Combined Chemotherapy
pounds and other agents used in combination with
radiation. Quite often an agent is called a "sensitizer" when the actual action is one of direct cell
toxicity. In this review the term radiation sensitizer will specifically include those drugs or treat
ments that produce a condition of hypersusceptibility to the action of ionizing radiation, but when
administered alone do not have a carcinostatic
effect.
Oxygen sensitization.—Prevailing theories of the
mode of action of ionizing radiation on cells as
sume the state of oxygénationof the cell to be of
prime importance. These theories have been re
viewed by other authors (47, 112), and Packard
(111) reviewed the earlier work concerning x-rays
and respiration.
The relation of oxygénationof cancerous tissues
to radiation sensitivity has been suspected for
some time. Mottram and Eidinow (110) found that
bleeding by cardiac puncture lessened the skin
reactions to radiation and also lowered the radia
tion sensitivity of implanted Jensen rat sarcoma.
They suggested that the endothelial cells of the
blood vessels might be altered during irradiation
so that some unspecified toxin entered the tissues
and that bleeding reduced the reaction by diminish
ing the blood flow to the tissues. The increased
capillary permeability produced by radiation is
extremely transient (49, 95), and its role in altering
the state of oxygénationof the tissue is not clear.
More applicable is the observation (1) that any
generalized peripheral hypotension, such as that
produced by bleeding, will result in a reduction of
tumor circulation and a subsequent decrease in
its oxygénation.
Another approach was tried by other workers
(23) who found that anaerobiosis decreased, but
cold (0°C.) increased, the radiation sensitivity of
tumor fragments in vitro. Conversely, later work
(31) showed that chilling newborn rats to 0°C.
tended to protect the skin of these animals from
the damaging effects of radiation. Following this
lead, cold and compression were used in an at
tempt to protect the skin during therapeutic ir
radiation (32), but the results were slight and
variable.
The apparent paradoxical action of cold in the
in vitro and in vivo studies may be resolved if the
physiology of the two systems is kept in mind.
Cold, in vivo, tends to produce anaerobiosis in the
skin by vascular constriction. On the other hand,
the in vitro system tends to have an increased oxy
gen content because of a lowered metabolic de
mand for oxygen as a result of chilling. The oxygen
content of the media is only slightly affected in the
in vitro system, since the physical parameters of
and Radiotherapy
of Tumors
555
oxygénationare only slightly dependent upon
temperature.
Metabolic inhibitors may not be classified as
sensitizers and yet, indirectly, may work as sensi
tizing agents by virtue of their ability to raise the
oxygen tension locally by decreasing metabolic
requirements for oxygen. In this manner KCN,
iodoacetate, and KAg(CN)2 enhanced the action
of x-rays on the mouse Sarcoma 37 in vivo (54). In
vitro, cold (0°C.) and cyanide increased the radiosensitivity of mouse carcinoma fragments from an
LDso of 3000 r to below 1500 r when irradiated in
air (53). Anoxia in conjunction with these agents
prevented the sensitization. The combination of
cold (0°C.) and NaCN does not increase sensitiza
tion much above the increment produced by either
alone (52). This might imply that the maximum
O2 level was reached with one agent so that the
second agent had no further effect.
More significantly, Hollcraft et at. (56) varied
the composition of the inspired air during irradia
tion of the tumors and found that tumor growth
was retarded to a greater degree when irradiated
in an atmosphere of 95 per cent O2with 5 per cent
CO2 than in N2 or air. Interrupting the blood sup
ply to the tumor during irradiation had no effect.
Gray et al. (48) irradiated Ehrlich ascites carci
noma cells in vitro at various oxygen concentra
tions and then inoculated mice with the irradiated
cells. Daily paracentèseswere done, and the num
ber of chromosome abnormalities at anaphase was
taken as a measure of radiation damage. When the
oxygen concentration was increased from 0 per
cent to 21 per cent, the radiation sensitivity in
creased by a factor of three with only a slight fur
ther increase in sensitivity at 100 per cent oxygen.
These results are in accord with earlier observa
tions on nonmammalian systems. When the Ehr
lich carcinoma in its solid form is irradiated in the
leg of the mouse, 100 per cent oxygen inhalation
at the time of irradiation with 1000 r results in as
much tumor regression as does irradiation with
1500 r when the animal is breathing air. However,
the latter results in more epilation and skin dam
age. Preliminary data suggest that there is no
greater response when irradiation is carried out at
three atmospheres of oxygen tension than at one
atmosphere. These authors do not state the exact
gas concentrations in the in vivo experiments, and
it may be that some CO2 was present. In neither
the in vitro nor in the in vivo situations does high
oxygen tension increase the sensitivity to radiation
with neutrons or a-rays.
Other investigators (27) found a marked in
crease of radiation sensitivity of the Ehrlich carci
noma when irradiation was carried out with the
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mouse breathing 95 per cent Oi plus 5 per cent COi
at two atmospheres of pressure. It was also found
(25) that the percentage of mitotic inhibition in
tumors given 330 r while the mouse was breathing
air was 32 per cent, but it was 67 per cent when
pure oxygen was employed. At higher doses, when
the number of abnormalities approached 90 per
cent, the difference was not so marked, but it was
still present. Two strains of Ehrlich ascites carci
noma, designated as 0 and 22, have been irradiated
in vivo (26) by giving the mouse 200 r total-body
irradiation. Strain 0 was a radiation-sensitive
strain and showed twice the number of chromo
some fragments when irradiation was carried out
with the animal breathing pure oxygen; however,
there was no significant increase in the number of
bridges, suggesting that the increased oxygen ten
sion does not increase the number of chromosome
breaks but interferes with the rejoining of frag
ments. Strain 22 was a radiation-resistant strain,
and the number of chromosome fragments pro
duced was unaffected by the oxygen tension of the
inspired gas at the time of irradiation.
Reports on the clinical use of combined oxygen
and radiation therapy are limited. Four patients
were irradiated while breathing 100 per cent oxy
gen at atmospheric pressure (64) ; one half of the
lesion was irradiated while the patient breathed
room air and the other half while pure oxygen was
breathed, and in each case there was greater re
gression with pure oxygen, but the skin reaction
was also more pronounced. Eight patients were
treated with x-rays while oxygen was administered
at three atmospheres of pressure (17), and again
one half of the same tumor was first irradiated while
air was breathed at normal pressure. In six of the
eight patients so treated, there was histological
evidence of greater radiation damage in the part of
the tumor irradiated during the positive pressure
oxygen therapy.
It is obvious that the oxygen tension must be
increased in the tissue and not merely in the in
spired gas. Since no satisfactory method has been
devised for the measurement of oxygen tension in
the tissue, little is known about the factors deter
mining the partial pressure of oxygen at the cell.
Gray (48) has calculated that in normally respiring
tumor the oxygen tension may fall from the
normal value of 40 mm. of Hg found at the venous
end of the capillary to 0 mm. of Hg within a dis
tance of 150 tÃ-.
Both normal and neoplastic cells of squamous
epithelium grow in contact with one another, and
they receive nutrient from capillaries in the stroma
which do not penetrate between the cells. Bron
chial carcinomas arising from these cells tend to
grow in rods with central areas of necrosis so that
histological sections cut at right angles to these
strands show necrotic regions surrounded by a ring
of tumor cells. Thomlinson and Gray (142) have
measured the diameters of the areas of necrosis
and the width of the tumor bands. The average
width of these bands was found to be 169 ju and
was independent of the diameter of the tumor
strand; however, the diameter of the necrotic area
increased linearly with the over-all diameter. This
correlation with the theoretical value suggests that
oxygen tension may be the controlling variable in
the production of tumor necrosis, but these inves
tigations do not rule out the possibility that
catabolito accumulation may play a significant
role.
The diffusion of oxygen into the tissue is directly
related to the diffusion constant and to the envi
ronmental oxygen tension but inversely to the
metabolic rate (52, 53). The time for establishing
equilibrium between the oxygen in blood and in
tissue must also be taken into account, and this
time may be longer than has been appreciated. In
addition to these local factors that influence Û2
concentrations, it should be remembered that
hemoglobin carries the vast majority of the oxygen
to the cells even when moderate pressures of a few
atmospheres are used. It is necessary that the
hemoglobin be able to transfer the oxygen to the
cell. Perturbations of the oxygen-unloading mech
anism may alter the tissue oxygen tension.
Many more factors no doubt control tissue oxy
gen tension, but it is clearly complex; however, its
very complexity makes many variables available
for experimental alteration.
Synkavit.—Originally, work was undertaken
with synthetic vitamin K, tetra-sodium-2-methyl1,4-naphthohydroquinone
disphosphate (Synka
vit), because it was thought that this material
might modify nucleic acid metabolism. However,
it was noticed that in conjunction with x-rays it
potentiated the radiation damage in both chick
fibroblast tissue cultures and in a human tumor
(97, 105), but at that time no particular thera
peutic value was claimed for this combination. A
subsequent paper (96) analyzed the results of a
larger group of 116 patients, all with advanced
malignant tumors other than bronchial carcino
mas. The treatment program was palliative irradi
ation alone, intramuscular Synkavit alone, or both
together. At least 23 out of 73 patients receiving
the combined treatment showed "an unexpectedly
good palliative response" (44). In the combined
treatment of inoperable bronchial carcinoma, the
mean survival time was increased to 7.6 months,
compared with 4.2 months for palliative radio-
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BANE et al.—Combined Chemotherapy
therapy alone (97). Additional papers (68, 69, 99)
reported a larger number of patients with subjec
tive and objective improvement following therapy
with x-rays and Synkavit. The effect of combined
Synkavit and x-rays, with 02 inhalation for 15
minutes before and during radiation, has been
tried, and it was noted that the skin and general
reactions were more severe than those after x-rays
alone (100).
A more detailed study (101) was carried out on
patients with inoperable carcinoma of the bron
chus. Synkavit was given intravenously or intra
muscularly, and patients who received the com
pound had a mean survival time of 8.7 months
from the onset of treatment as compared with 3.8
months for those receiving x-ray therapy alone.
Groups of patients receiving the drug by either
route were considered together even though ani
mal experiments had indicated that intramuscular
administration was without effect. A similar series
of patients (103) was observed in which the "con
trols" were given intramuscular Synkavit. The re
sults were similar to those in the earlier report. The
authors conclude (98) that the combination of
x-ray and Synkavit results in a small increase in
the survival time over that following x-ray alone
in cases of carcinoma of the bronchus.
Synkavit plus x-rays reduced the mitotic figures
in chick fibroblast cultures to 14 per cent of the
number in untreated controls, with Synkavit alone
exerting almost the same effect as x-rays alone
(69.3 per cent versus 64.9 per cent) (105). With
Walker rat carcinosarcoma 256 used as the test
tumor, it was found that the combination therapy
increased by about 25 per cent the number of re
gressions over those caused by 1100 r of x-ray alone
(104). The optimum results were obtained with the
intravenous injection of Synkavit about 30 minutes
before irradiation (102). In addition, it was dem
onstrated that Synkavit plus Û2 plus x-rays
slightly increased the radiosensitivity of the
Walker 256 rat carcinosarcoma (103). As far as the
mode of action of Synkavit is concerned, it is pos
tulated (100) that the Synkavit is selectively con
centrated by tumor cells, especially by the mito
chondria, and that its action is exerted there.
Other investigators have not confirmed the above
results with animal tumors. It was found that
neither Synkavit nor its 2-methyl derivative had
any significant effect on the growth of Jensen rat
sarcoma alone, or in combination with x-rays (37).
In an attempt to confirm Mitchell's thesis of radi
ation sensitization with Synkavit, with the use of
Synkavit obtained from Professor Mitchell, the
work was repeated with the Walker 256 carcino
sarcoma (140). It could not be demonstrated in a
and Radiotherapy
of Tumors
557
large series of animals that Synkavit acts as a
sensitizer to ionizing radiation.
Dyes.—Early attempts at sensitization came
with the introduction of dyestuffs in combination
with radiation. Dyes were utilized, because they
were thought to concentrate in malignant tissue to
a greater extent than in normal tissue. However,
recent work (107) has cast some doubt upon this.
Radioactively tagged dyes were found to be highly
concentrated in kidney, liver, spleen, feces, and to
some extent in tumor, so that the desired selective
concentration is not obtained. The earlier impres
sion of tumor concentration occurred because tu
mor tissue is usually light in color; and, there
fore, when estimated visually, the dye was indi
cated out of proportion to its actual concentration.
Previous workers were not aware of this fact and
believed that the dyes concentrated specifically in
the tumor. The concentration of radioactively
tagged dye can be measured independently of tis
sue color. Clinical attempts were made to treat
cancer more effectively by using "activated"
fluorescein, i.e., fluorescein plus x-rays (19), on the
assumption that the dye produced a "secondary"
radiation that had a lethal effect on tumor cells.
Later papers (20, 46) gave complete details regard
ing administration of the dye in patients with vari
ous diagnoses, including carcinoma of the breast
and esophagus and soft-part sarcomas. The followup in many of these cases was inadequate and too
short for general conclusions; however, in at least
one case, one half of a lesion was given combined
therapy and the other radium gamma irradiation
alone with more marked regression in the portion
given combined treatment. Other authors (141) did
not obtain improved results with dyes.
A slow-growing rat sarcoma irradiated by radium
gamma rays and exposed to fluorescein produced
fewer tumor "takes" upon subsequent implanta
tion than did the sarcoma treated with radium
alone (109), indicating an increase in radiosensi
tivity. Fluorescein itself had no effect on the tumor.
Only nine rats were used in this experiment, but
the results were rather definite. Others found simi
lar results (74, 123) with rat sarcoma F16, Jensen
rat sarcoma, and Kato rabbit sarcoma, using vari
ous dyes and x-rays.
The experimental evidence in favor of combined
tumor therapy with dyes and radiation is some
what equivocal. Modern experimentalists do not
seem inclined to follow these early leads, and little
work appears in the contemporary literature.
Inorganic salts.—Followingthe increased inter
est in the biological effects of various salts upon
protoplasm, it was suggested (2) that NaCl be ad
ministered prior to x-rays without any reasoning
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558
Cancer Research
other than that it might "stimulate" the cells.
However, no experimental observations were re
ported.
Subsequently, it was noticed (22) that the res
piration of Jensen rat sarcoma in vitro decreased
20-30 per cent in phosphate Ringer's solution
compared with bicarbonate Ringer's. Tumor
pieces irradiated in phosphate Ringer's produced
fewer "takes" upon implantation than did pieces
irradiated in bicarbonate Ringer's, and the same
effect was found with mouse carcinoma.
Others (29) attempted sensitization in vivousing
various ions. Magnesium salts did not significantly
increase the x-ray sensitivity of an unspecified rat
sarcoma, but calcium chloride did. The number of
regressions depends on the time elapsed from in
jection to irradiation, decreasing after 30 minutes
subsequent to CaCl2 administration. The authors
postulated that the radiosensitivity was affected in
some "catalytic" manner. Other investigators (93)
increase the tumor radiosensitivity, improve the
general resistance of the host or in some other way
potentiate the effectiveness of radiotherapy. How
ever, very little is known about the mechanisms
involved, and the reports reviewed on the use of
glucose, insulin, and electrolytes for increasing the
effects of tumor radiotherapy are 15-20 years old,
so that this whole field is obviously in need of a
thorough re-investigation and re-evaluation.
CARRIERS,SECONDARY
RADIATORS,AND
THERMALNEUTRONCAPTURE
Many attempts have been made to increase
selectively the dose delivered to the tumor. Three
major lines of investigation have been used:
(a) Heavy metals have been administered in the
hope that these would concentrate in tumors and
hence increase the tumor dose by soft secondary
radiations produced by more energetic primary,
external beams, (b) If compounds could be found
found that an increase in the number of regressions which would be taken up more in tumors than in
could be achieved with concomitant x-ray irradia
normal tissue, these could serve as carriers of
tion and magnesium sulfate injection in the tumor. radioactive isotopes, (c) With the advent of high
Glucose and insulin.—An early clinical observa
intensity neutron beams, nuclear reactions within
tion on tumor therapy with intravenous injections tumors can be achieved if a compound which will
of 25 per cent dextrose solutions and x-rays seemed react with neutrons in the desired manner can be
to indicate that the tumor is thereby sensitized to localized in the tumor.
Secondary radiators.—One of the earliest at
x-rays (94). Others (50) reported four cases that
showed a better x-ray response with dextrose. tempts to enhance radiation sensitivity of tumors
Likewise, rat tumors showed an increased radio- by chemical means was the use of colloidal heavy
sensitivity with intraperitoneal dextrose (120). In
metals. If tumors concentrated heavy metals, ir
creasing sensitivity was demonstrated with the radiation with an external beam would produce
Kato rabbit sarcoma when treated with dextrose secondary radiations from these elements of high
or with dextrose and cesium iodide injections fol atomic number. Such secondary radiation would
lowed by irradiation (66). A regimen of dextrose have low energy and would be absorbed within the
and x-rays followed by insulin was tried clinically tumor with a resultant increase in tumor dosage
and in certain cases appeared to be of benefit and no increase in dosage to surrounding normal
tissue.
(116).
The local application of insulin to a neoplastic
Many metal colloids have been used, including
ulcérationof the breast resulted in prompt pallia
cobalt (75,76), copper (14), bismuth (70), and lead
tive relief. Subsequent x-ray treatment resulted in (6-8, 130, 148). Clinical impressions varied as to
a much more favorable response than was obtained the merits of this treatment but were, in general,
from a prior course of radiation before the local favorable. The numbers of cases in all series were
application of insulin (38). The claim was repeated
small, and no controls were used, so that no objec
subsequently without additional data (44). En
tive conclusion can be made.
However, Todd and Aldwinkle (145) reported
couraging clinical results were obtained by others
who sought to enhance the radiation effect by in that in twelve cases which were given an extensive
course of lead selenide therapy followed by x-ray
sulin in addition to blood transfusions (42). Quan
or radium, the results were "nothing less than dis
titatively, insulin injections increased the per
centage of regressions of rat tumors from a value astrous." Radiation was stopped at one-quarter to
of 18.8 per cent for x-ray alone, to about 52 per one-half of what they considered to be a normal
cent (30). Another attempt at local application of dose, at which time there was ulcération,fistula
insulin resulted in an increase in the radiosensi
formation, and rapid progression of disease. They
tivity of several human tumors (43).
conclude that either the secondary radiation from
the lead is so severe as to cause the side effects or,
It is possible that changes in the carbohydrate
and electrolyte metabolism of tumor tissue may more probably, that the colloidal selenide par-
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BANEet al.—CombinedChemotherapyand Radiotherapy of Tumors
tides are reduced in size by the radiation and be
come more toxic, both in the tumor and stromal
cells. However, excellent results in two cases were
reported by Gosse and Mottram (45).
Sperti and Norris (132) extensively treated the
theoretical aspects of increasing the radiation dose
to tumors by concentrating metals within them.
Fragments of a mouse sarcoma were irradiated in
vitro following the intravenous injection of Csl to
the donor animals, and the number of subsequent
successful transplants was used as a criterion of the
extent of radiation damage. Fewer "takes" were
found at every dose level of x-rays employed. In
travenous injection of colloidal lead enhanced the
action of x-rays on the Flexner-Jobling rat carcino
ma but showed no increased effect when rat Sarco
ma 10 was used (153). It is interesting to note that
part of this positive effect was interpreted as oc
curring because of thrombosis of the arteries and
impairment of the blood supply. This concept is
substantiated in part by the work of Mottram
(108), who found that systemic administration of
colloidal lead, followed by irradiation, showed no
advantage over radiation alone and resulted only
in a reduction in the growth rate of the tumor.
However, postirradiation treatment with lead
showed a marked effect, and some tumors re
gressed completely.
Other metals, ranging in atomic number from
aluminum to uranium, have been used with equiv
ocal results (65, 73, 89). Moreover, animal work
confirmed the clinical experiments of Todd (145)
that prior treatment with lead selenide was contraindicated. Indirect support of this thesis was re
ported by others (51) who used colloidal bismuth
and platinum.
Carriers.—Itcompounds could be found which
were selectively taken up by neoplastic tissue,
radioactive isotopes could be incorporated into
them, and, hence, large doses of radiation could be
given to the tumors. Two important facets of this
concept should be stressed. First, the chemical
compound need not be carcinostatic in itself,
though any tumor action it might have would be
advantageous. Second, these compounds could also
be taken up by distant métastases,whether clini
cally detectable or not. This latter point represents
an advantage over other forms of combined thera
py insofar as this type of treatment would include
the tumor foci which lie outside the beam of exter
nal radiation.
Several investigators tried to inhibit tumor
growth by the injection of naturally occurring
radioactive substances such as RaE in combina
tion with colloidal Bi (80), ThB (24), and radio
active Pb (36). None of the experiments showed
559
any effect on the tumors, though autoradiographs
showed uptake in the kidney, liver, and spleen.
Zahl and Waters (156) suggested that certain
acid dyes that localize in tumor tissue to some de
gree might be used as carriers of radioactivity;
however, they report no experimental work along
these lines. Radioactive Br was incorporated into
several diazo dyes by Tobin and Moore (144) in
such a way that the bond was stable and nonionizable. They showed that these dyes concentrated in
inflammatory lesions (106) and in tumors (107).
The radioactive dyes were given intravenously to
a large number of mice carrying several types of
tumor. The quantity of dye present in the organs
and tumor was determined by the radioactivity
present. By this method the true amount of dye
present is analyzed, and the quantity is not ob
scured by natural pigmentation of the organ. Re
sults are expressed as the percentage of injected
dose per gram of tissue. In tumor-free animals, the
liver, colon, small intestine, bile, and feces ac
counted for about 50 per cent of the injected dose.
Since tumor concentrations were seldom higher
than the liver concentrations, the results of dibromo-trypan blue injection expressed as the tumorliver ratio in C3H mice varied from 0.14 to 0.62
for different tumors tested. Tumor-liver ratios
found after dibromo-Evans blue injection ranged
from 0.29 to 0.66 in various mouse tumors.
The two dyes show about the same concentra
tion in tumors, but the tumor-liver ratio is lower
for dibromo-trypan blue because of greater liver
concentration. On occasion, tumor-liver ratios
greater than 1 are found. These cases occur in
cachectic animals with large tumors where the
liver uptake is small, presumably owing to im
paired hepatic function.
Necrotic areas of tumors which were filled with
clear fluid or which were caseous showed little
staining, whereas hemorrhagic necrosis tended to
pool the dye from the plasma. The authors con
clude that their data cast doubt on the earlier en
thusiastic reports of dye concentration, but the
fact that two closely related dyes have a different
uptake by the liver suggests the possibility that a
more differentially concentrating substance can be
found.
Similar experiments were performed by Stevens
et al. (133) using I131-labeledtrypan blue prepared
by the method of Bloch and Ray (11), who synthe
sized a number of I131-iodinated dyes with the hope
that they might selectively concentrate in neo
plasms, particularly gastric cancer. The dye was
injected intravenously into Swiss albino mice car
rying two mammary carcinomas 15091a of differ
ent size. The I131content of both tumors was pro-
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560
Cancer Research
portional to the amount injected, but no striking
difference was found in the concentrations in the
large and small tumors. As was reported by Moore
et al. (106) for bromine, the concentrations of I131
were highest in the liver, kidney, spleen, and feces.
The tumor:liver ratios were lower than those
reported above.
Bloch and Ray (11) and Kremen and co-work
ers (78) studied the distribution of S35-labeled
methionine in normal and neoplastic tissue in mice
following intraperitoneal injection. Distribution
was studied in normal AK mice, AK mice with
either transplanted lymphosarcoma or spontane
ous leukemias, and in JJB mice bearing spontane
ous mammary carcinoma. In all instances the con
centration was higher in the liver and intestine than
it was in the tumors.
The only therapeutic trial of radioactively
tagged dyes is reported by Sloviter (129), who used
I13I-iodinated Nile blue A, a basic oxazine dye,
which diffusely stains the tumor cells themselves
in contrast to the stromal staining properties of
Evans blue and trypan blue. C3H mice were given
inoculations of either a transplantable fibrosarco
ma which had been originally induced with methylcholanthrene or of a transplantable mammary
carcinoma. Average survival time of animals carry
ing the fibrosarcoma was 20 days for the controls
and 51 days for the animals receiving the radioac
tive dye parenterally. Mice with the mammary
carcinoma had average survival times of 25,36, and
74 days, respectively, for controls, nonradioactive
dye, and I181-tagged dye. The dye was mixed with
the food. It is unfortunate that the values for the
control survival times are taken from the litera
ture and that the amount of radioactivity admin
istered is not stated, nor is it possible to calculate
the dose of radiation because of incomplete knowl
edge of the time interval between the preparation
of labeled dye and the beginning of therapy.
In 1950, Pressman and Eisen (118) described a
technic for attaching one to two atoms of I131per
molecule of antibody of molecular weight 160,000.
Using I131-labeledantibodies, Pressman and Korngold (119) showed that there could be produced in
rabbits antisera that would localize in tumors,
liver, and kidney of mice bearing the Wagner osteogenic sarcoma. They found some indication
that by purification methods some of the tumorlocalizing antibodies could be separated from the
liver- and kidney-localizing antibodies. These
same investigators (77) found similar results with
the Murphy lymphosarcoma in the rat. While I131
was used only as a tracer in these studies to detect
the presence of antibodies, an increase in the de
gree of iodination and specificity of these antibodies
could provide a method of bringing therapeutically significant quantities of radiation to both the
primary tumor and métastases.
Nuclear reactions within tumors.—Immediately
after the discovery of the neutron in 1932, work
was initiated on its biological effects. In 1936,
Locher (86) pointed out that the absorption of low
energy or thermal neutrons did not depend upon
the atomic number, as with x-rays and gamma
rays, but varied widely depending upon the nuclear
structure of the absorbing element. While the ab
sorption of neutrons by the common elements of
tissue is small, he suggested that the highly absorb
ing elements might be introduced into or concen
trated by tumors. Even at very low concentra
tions, this could result in the absorption of a large
amount of energy of a thermal neutron beam
within the tumor. Two of the elements which have
high absorption properties are Li7 and B10; they
react with neutrons according to the nuclear equa
tions :
6B10+ on1-> 3Li7 + 2He4 + 2.8 Mev
and
3Li6
2He4 + 4.6 Mev
It should be pointed out that it is these two iso
topes of lithium and boron that have a high proba
bility of interacting with neutrons. Li6 is only 7.5
per cent of normally occurring lithium, and B'°is
18.4 per cent of naturally occurring boron; how
ever, methods are now available to concentrate
these isotopes so that "enriched"
lithium and
boron containing up to 85 per cent of these iso
topes can be prepared.
These physical considerations
led Kruger (79)
in 1940 to the irradiation of tumors in vitro. A
spontaneous and differentiated mouse sarcoma, a
mouse mammary carcinoma, and a mouse lymphoma were irradiated with a thermal neutron beam
produced by a cyclotron. A control sample of
tumor was exposed to a solution of HsBOs but was
not irradiated. Two other tumor fragments also
were placed in the boron solution. One of these was
exposed directly to the thermal neutron beam, and
this would be the sample which would receive the
highest dose from the neutron-boron reaction. The
other boron-containing
tumor fragment was also
exposed to the cyclotron beam but was shielded by
a B6C shield which effectively stops the thermal
neutrons. However, the neutrons and gamma-ray
contaminants of the beam are not stopped by such
a shield, and, therefore, this sample served as a
control to measure the damage produced by these
higher energy radiations. In some instances a nonboron-containing
sample of tumor was exposed to
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BANE et al.—Combined Chemotherapy and Radiotherapy of Tumors
the thermal neutron beam. Irradiated tumors were
then transplanted to appropriate hosts, and the
failure to "take" was used as a criterion of radia
tion damage. Until very high doses of thermal neu
trons were reached, there was no difference be
tween the number of "takes" in the nonirradiated
controls and the boron-shielded but boron-con
taining samples. Also, in those instances in which a
nonboron-containing specimen was irradiated, the
number of "takes" was the same as in the controls
until very high doses were reached. The number of
"takes" was greatly reduced, and this effect in
creased with increasing exposure. This showed
quite clearly that the lethality of thermal neutrons
to neoplastic cells could be greatly enhanced by
boron.
Even in in vitro work the problem of dosimetry
is very difficult, from both the biological and the
physical point of view, and it is not completely
solved today. With in vivo experiments, dosimetry
becomes even more difficult because of the lack of
knowledge of the boron concentration in the tumor
at the time of exposure. Moreover, the a-particles,
which produce the ionization, have very short
ranges in tissue at these energies. Therefore, more
exact information is needed to determine the intracellular-extracellular partition of boron compounds.
Zahl et al. exposed mice bearing Sarcoma 180 to
sublethal doses of total-body irradiation with slow
neutrons (155). Experimental groups had an oil
suspension of finely pulverized lithium metaborate
injected into the tumors. This technic kept the
boron and lithium atoms localized in the tumor
during the long exposure times used. Whether,
with the short range of the secondary a-particles,
there was a sufficient amount intracellularly to be
effective is questionable. Boron-injected mice
had some regressions of tumors without irradia
tion, but the irradiated animals had an even great
er regression rate. With the use of the survival
curves for animals treated with neutrons or x-rays
and the data of Sugiura for the dose-response
curve of Sarcoma 180 to local x-rays (136), the
authors estimate the presence of boron and lithium
had the effect of 350-600 r.
Theoretical considerations of whether Li, B, or
the pure isotopes Li6and B10offer the best increase
in differential between tumor and surrounding tis
sue have been discussed by Zahl and Cooper (154).
They used lithium carmine, which had previously
been shown to concentrate in tumors. When inject
ed into mice, lithium was found at a maximum con
centration of 0.03 per cent in the tumor 4 hours
after injection. The appearance of lithium was
more rapid and was found in greater concentration
than would be predicted from the observed con
561
centration of dye, suggesting a selective uptake of
inorganic lithium. Using these theoretical consid
erations, they concluded that there would be a
gain of 43 per cent in the dose to the tumor over
the surrounding normal tissues. Unfortunately,
they report no radiation experiments.
No further animal work, by these technics, has
been reported. However, in 1951, Sweet (138)
pointed out that the concentration of P32 and K42
in brain tumors was much higher than in either the
gray matter or the white matter and that these
isotopes might be used for diagnostic localization
of these lesions. At this time, he suggested that the
blood-brain barrier might be utilized for the con
centration of boron in tumors for slow neutron
therapy. Sweet and Javid (139) showed that 15
gm. of borax can be given intravenously without
toxic effects, that concentration ratios of greater
than 3:1 can be achieved in brain tumors com
pared with normal tissue, and that in some in
stances the ratio can be as high as 48:1. Tumor
concentration at these doses is greater than 50
¿igB/gm of tissue; it is 15 jug B/gm in the gray
matter, and even less in the white matter. The
maximum concentrations are achieved within 10
minutes. On the basis of these findings and accord
ing to certain assumptions about the relative bio
logical effectiveness of alpha particles and gamma
rays, Javid et al. (67) concluded that boron would
account for 85 per cent of the radiation effect in
gray matter, 79 per cent in white matter, and 94
per cent in tumor, if the incident beam is a pure
thermal neutron one. Thus, with the concentra
tion ratios observed earlier, at least a 3X higher
dose could be delivered to the tumor than would
be given to the gray matter.
Clinical trial of neutron capture therapy cur
rently is being done at Brookhaven National Lab
oratories by Farr et al. (34). The physical setup
and the dose distributions have been described by
Stickley (134). Fair et al. (35) have reported pre
liminary clinical experience with ten cases of glioblastoma multiforme. The ten patients were given
20 gm. of B10-enriched borax 10 or 15 minutes be
fore being irradiated with a dose of approximately
IO12neutrons/sq. cm. at the skin surface with a
thermal neutron beam from the Brookhaven pile.
Five of the patients received more than one irradi
ation. Of the 21 irradiations, eight resulted in tem
porary palliation, six patients showed questionable
improvement, and seven showed no improvement.
Eight of the ten cases have come to autopsy, and,
in three of the five cases having multiple courses
of radiation, some changes were seen in the normal
brain ; however, nothing could be said about radia
tion effects in the tumor itself (41).
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562
Cancer Research
Though not done on tumors, the work of Tobias
et al. (143) deserves special mention, because it
introduces a new concept. The capture of a ther
mal neutron by Li8 or B10results in the release of
4.6 and 2.8 Mev of energy, respectively, most of
which is given to the resultant a-particles. Capture
of a thermal neutron by U235results in the libera
tion of 159 Mev of energy distributed among the
fission products which are much more densely
ionizing and hence may have a relative biological
effectiveness which is 3-4 times that of the a-par
ticles. UOz colloid prepared from U236-enriched
uranium, given by vein to mice, concentrated pri
marily in the liver and spleen. When these animals
were given sublethal doses of thermal neutrons,
all died within 3 weeks. Animals given comparable
amounts of nonenriched UOz (not fissionable) and
exposed to the same thermal neutron-flux were
alive and well after 6 weeks. Similarly, animals
given comparable doses of either enriched or regu
lar UOa did not die within 6 weeks. To be sure that
it was not the enriched IKh plus the stress of radia
tion which caused death, a group which had re
ceived the enriched U02 was given a comparable
dose of x-rays, and no deaths occurred. The
authors conclude that a dose of radiation from the
fission products of U236was the cause of death.
Clinically, the animals which had received en
riched UC>2followed by irradiation showed the
signs of the radiation syndrome. At autopsy the
spleens were markedly shrunken and gray or black
in color. The livers were pale, some having a
mottled appearance, and some showed areas of
necrosis or hemorrhage. None of the control ani
mals showed similar effects.
DISCUSSION
Investigation of the effects of combined chemical
and radiation therapy of cancer has been mainly
empirical, and many of the theories which exist
have been reached a posteriori.
Some alkylating agents (nitrogen mustards,
TEM) in several instances have shown results in
dicative of potentiation of the radiation response.
Furine antagonists and antifolics in combination
with radiation have been explored very little, but
the results obtained with 6-mercaptopurine seem
to justify further work in this field (140). Combi
nations including colchicine and its derivative,
N-deacetylthiocolchicine, have been studied much
more extensively but did not produce significant
improvement of the therapeutic results. Some pos
sibilities of success may exist in the field of anti
biotics, e.g., actinomycin, azaserine, 6-diazo-5oxonoricucine (DON), but only a little work has
been done in this direction. These empirical inves
tigations should be continued as newer chemotherapeutic agents become available.
Information is being gained about the funda
mental processes involved in the transfer of energy
from the primary ionization produced by the inci
dent radiation to the biologically significant por
tion of the cell. The a priori theories arising from
this knowledge should result in a greater ability to
alter the radiosensitivity of tumors than has been
achieved previously. The role of the oxygen ten
sion at the cellular level in determining radiation
sensitivity has been studied in a wide variety of
biological systems, including tumors, and has been
found to be quantitatively the same. Preliminary
results of treatment with x-rays and high oxygen
tension in the inspired gases have been encourag
ing, and further investigations should be pur
sued. Methods of measuring the tissue oxygen ten
sion are inadequate, and this represents one of
the major difficulties. As was mentioned earlier in
this paper, many factors influence the oxygen ten
sion at the cellular level, and increased knowledge
is needed about cellular permeability to oxygen,
the vascular structure of tumors, and their hemodynamics.
Gray (47) points out that, though the radiomimetic drugs produce cytological damage that is
similar to that from radiation, their toxicity is not
a function of oxygen tension and their modes of
action must be different. Thus, it is possible that
both oxygen and carcinostatic agents in combina
tion with radiation might have a marked effect on
neoplasms without increased systemic reactions.
Secondary radiators are probably of little value,
and certain colloids, such as lead selenide (145),
are probably contraindicated. However, much of
this work was done before modern methods of bio
logical research had been developed, and some of
the concepts may bear re-investigation. The use of
B10and Li6 with external thermal neutron beams
shows promise, particularly if they can be incorpor
ated into compounds which will selectively concen
trate in tumors. Any compound which could do
this, whether carcinostatic or not, could be used as
a carrier of radioactive isotopes to both the pri
mary growth and to the métastases.If any fission
able element could be incorporated into such a
compound, the work of Tobias (143) offers interest
ing possibilities.
In general, while no spectacular results have
emerged from the combined chemical and radia
tion therapy of malignant neoplasms, enough en
couraging results have been obtained to warrant
continued investigations, particularly in view of
the increasing knowledge of fundamental radiobiology and the availability of new radiation sources.
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1957 American Association for Cancer Research.
Combination Therapy of Malignant Tumors with Ionizing
Radiations and Chemicals: A Review
Harry N. Bane, John T. Conrad and George S. Tarnowski
Cancer Res 1957;17:551-566.
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