Download COLCHICINE IN THE CHEMOTHERAPY OF CANCER

718 SEPT. 23, 1950
CONGENITAL HEART DISEASE
uncomplicated septal defects or a patent ductus arteriosus
when the shunt is from left to right, although occasionally the sudden rise of pressure in the right auricle after
the injection would cause a temporary reversal of the
shunt through an atrial septal defect. Re-circulation of
the dye through the right heart in this type of case was
difficult to demonstrate, since some of the " diodrast "
was often held up in the vein used for injection and
might reach the heart at the time when re-circulation was
likely -to be occurring.
*
In cases of coarctation of the aorta or patent ductus
arteriosus it is difficult sometimes to obtain satisfactory
pictures of the aorta, because dilution of the bolus
of diodrast in its passage through the right heart and
lungs has occurred. Injection into the pulmonary artery
through a cardiac catheter may overcome this difficulty,
but the length and narrow bore of the catheter slow the
speed of injection so that poor-contrast films may still
be obtained. Direct injection into the arch of the aorta
gives better results, and this has been carried out either
by inserting a needle into the ascending aorta or by
retrograde arterial catheterization. Burford, Carson, and
Scott7 have carried out direct aortography on 23 patients,
using the left common carotid artery. Temporary occlusion of the artery distal to the point of injection prevented the dye passing directly into the cerebral circulation, and no complications were observed in any of their
patients. They were able to demonstrate the detailed
anatomy of the aorta and the exact site and extent of
the stricture in patients with coarctation after injection
of 20 ml. of dye. A patent ductus arteriosus could also
be outlined, and this might be of help in differentiating
those patients with an aortic septal defect or rupture of
an aneurysm of the sinus of Valsalva into the pulmonary
artery; in such cases clinical examination and the use of
the cardiac catheter may give identical results. Fatti and
Gilroy8 have approached the same problem from a different direction: they inspected the arch of the aorta and
the gap between it and the pulmonary artery with a
thoracoscope. After induction of a small pneumothorax
with 400-500 ml. of air they inserted the thoracoscope
anteriorly into the second left interspace in the midclavicular line and obtained a satisfactory view. They
were able to inspect the site of a coarctation and to
demonstrate the presence of a patent ductus, while in
one patient the pressure in the pulmonary artery was
measured by needle puncture under dcrect vision.
Many patients with congenital heart disease are now
treated surgically, and though the diagnosis of the
malformation is usually possible by routine methods of
examination the purpose of all these special investigations is to provide accurate details of the anatomy of
the defect. The task of the surgeon is thus made less
difficult.
MEDICAL JOURNAL
COLCHICINIE IN THE CHEMOTHERAPY OF
CANCER
Coichicine, which was mentioned last week in the leading article about a secret remedy for cancer,' is a mitotic
poison which has been much used in research as a
chemotherapeutic agent for cancer. This alkaloid, which
is extracted from the autumn crocus, is probably the
most powerful " radiomimetic " drug known-that is, it
reproduces the cellular changes induced in cells by
x rays. Even at dilutions of 1 in 100,000,000 it can
bring about the typical mitotic arrest at the metaphase
stage. Microscopically, areas of a tissue treated with
colchicine will sometimes show more cells in arrested
division than in the resting state. Ludford,2 who has
ably reviewed the literature on this subject, examined
the mode of action of colchicine on tissues grown in
vitro and observed that the drug does not differentiate
between embryonic and neoplastic tissue, which are
equally sensitive to its mitosis-arresting activity. Other
chemical and physical agents can inhibit mitosis, but,
Ludford wrote, " colchicine is unique in that it does not
arrest the initial phase of division but brings the process
to a standstill at the metaphase in a remarkably wide
range of concentrations." There is little evidence that
colchicine stimulates mitosis as well as blocking it at
metaphase, and, indeed, it has been reported that in high
dilution it slows down the rate at which cells enter the
mitotic cycle. Macroscopically, the most obvious effect
of the drug on a tumour is to induce haemorrhage of the
kind also caused by polysaccharide fractions of bacterial
filtrates-for instance, from Serratia marcescens. Even
in minute amounts, of the order of 0.1 ju, these cause
necrosis and haemorrhage.3 The similarity of the effects
of colchicine and bacterial filtrates is close enough to
have suggested that they inhibit tumour growth by the
same mechanism-by attacking the sensitive cells of the
capillary system of a rapidly growing tumour. One of
the principal conditions of chemotherapy is maximal
injury to tumour cells with minimal effect on normal
tissue, and the use of colchicine appeared promising
when examination by dark-ground illumination showed
little alteration in the mitochondria and in the cytoplasmic granulation, indicating that the metabolic
mechanism had escaped injury. Ludford found that
mitosis could be blocked with dilutions of colchicine far
below that required for metabolic disturbance: in one
experiment a thousandth of the concentration needed
for metabolic effect sufficed to arrest mitosis.
1
2
British Medical Journal, 1950, 2, 663.
J. nat. Cancer Inst., 1945, 6, 89.
3 See annotation in the British Medical
4 Natue, Lond., 1935, 135, 266.
5
Brit. J. Cancer, 1948, 2, 75.
6 Cancer Res., 1950, 10, 420.
7 Surgery, 1940, 7, 696.
JourniJ, 1950, 2, 32.
SEPr. 23, 1950
COLCHICINE IN CHEMOTHERAPY OF CANCER
Amoroso4 was one of the first to try the effect of
colchicine on tumours in animals. He found that transplantable mouse carcinoma No. 63 responded by complete regression, and he successfully treated a carcinoma
of the buccal mucous membrane in a dog. Among other
early experiments with colchicine in animals the regression of multiple skin tumours in a mare has been
recorded, and also of the Shope rabbit papilloma after
the injection of a few milligrammes of the drug. In the
latter case the treatment induced immunity to further
infection by the virus. Colchicine has been used with
success in experiments on the regression of a lymphoid
tumour of the C3H strain of mice and on the FlexnerJobling rat carcinoma. Ludford, after studying 17
different strains of transplantable tumours and 47
spontaneous mammary carcinomas, concluded that the
lethal and chemotherapeutic doses are close to one
another and that soft, highly cellular, rapidly growing
tumours are the most responsive, the reaction of slowgrowing tumours being negligible. In a detailed investigation' of the factors determining the action of colchicine
on tumour growth he used a rapidly growing carcinosarcoma of the Strong A strain of mice. The transplants
were treated with a 1 in 10,000 solution of the alkaloid,
the total dose of 0.7 mg. being divided and spread over
a few hours. The injections were repeated on the 26th
and 35th day. After a sudden decline in the size of the
tumour grafts growth was resumed, and on the 50th day
after transplantation the experimental tumours were the
same size as the controls on the 30th day. A spindlecelled sarcoma growing in Strong A mice was treated
with a total of 0.154 mg. of colchicine. Two out of
three tumours regressed completely. Nevertheless
Ludford considers such success exceptional, the more
typical result with colchicine being regression followed
by recurrence. Among other factors which influence
the effect of colchicine, he found that young adult mice
are more resistant to the toxic action of the drug than
very young or old mice, and that tumour regression is
more obvious in strain A mice than in C57 mice. The
results of treatment of mice bearing carcinoma 63-a
soft, highly cellular tumour with a large number of
mitotic figures-was to produce total regression in 5
mice out of 10. Three died of toxic effects, and the
tumours of 2 continued to grow. The tumours which
regressed showed extensive haemorrhage, just as in the
case of tumours treated by bacterial filtrates. It has been
suggested that the haemorrhage may be caused by pressure exerted on the newly formed capillaries by the
tumour cells, which become swollen after colchicine treatment. Bass and Probet6 in the U.S.A. recently reported
the satisfactory treatment with colchicine of C3H hybrid
mice bearing lymphosarcoma, the drug being given in
doses of 0.5-0.75 mg. per kg. of body weight daily for
EDI¶SOH
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2 to 23 days. The regressions, expressed as fractions,
were 8 out of 10 mice, 4/9, 12/20, and 10/28 in different
experiments. The mice whose tumours regressed were
observed for five months; immunity lasted at least 173
days after the original transplantation.
Although there is a close parallel between the nucleotoxic action of colchicine and of x rays-for instance, in
the acquired tolerance of tumour cells to the drug and
the acquired radio-resistance of tumours which were
previously radio-sensitive-yet there are certain differences in the toxic effects on the nuclear chromatin.
Colchicine is much more specific in its action on the
nuclear structures. Ludford states that one of the outstanding difficulties, in the colchicine treatment of
tumours is the lack of cell-,type specificity. Tests with
the aim of supplementing the action of colchicine with
radiotherapy have been, on the whole, without success.
Several workers have investigated the action of colchicine in the treatment of cancer in man, but it was
found that the drug caused very unpleasant symptoms,
and sometimes death from colchicine poisoning. One
woman was treated with colchicine combined with x rays
for an adenomedullary carcinoma of the breast. The
tumour at first shrank to a third of its original size, but
then rapidly began to grow again, with fatal results.
Another patient with an anaplastic carcinoma of the
neck reacted in much the same way; the central portion
of the tumour necrosed, but the peripheral layers grew
with increasing speed.
Seed, Slaughter, and Limarzi,7 after investigating the
action of colchicine on human subjects and on laboratory animals, concluded that, "although the rapidly
growing cancer cells are much more susceptible to the
poison, the concomitant general toxic effect is much too
great to expect any curative effect."
THE TREATMENT OF VOMITING
In the opening pages of this issue we publish the paper on
the antihistamine compounds which Professor J. H. Burn
read at the Annual Meeting of the B.M.A. in Liverpool.
In his lucid review of the pharmacological action of this
interesting group of drugs Professor Burn refers to a substance named " dramamine" which was introduced last
year in the U.S.A. for the prevention and cure of se*sickness. Those who were present at the Liverpool meeting also had the benefit of hearing Dr. Leslie Gay, of
Baltimore, describe his original work with this drug.' Little
attention has been given to its composition, but it is in fact
a combination of " benadryl" with theophylline (into
which a chlorine atom has been introduced). Both benadryl
and dramamine are said to relieve the nausea and vomiting of pregnancy. Finch2 believed that the success he had
with benadryl was adequate proof that this symptom complex was an allergic reaction. The investigation of the