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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 719 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