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PROTAMINE IN BREAST CANCERS
833
Letters
to
the Editor
PROTAMINE IN BREAST CANCERS SIR,-We feel that Dr. Jolles (Oct. 5, p. 736) does
us
less than justice when he suggests that we are unaware of the complexities of cancerous stromal growth. In fact, many of the points which he mentions have already received attention in the previous publications listed and others have not been neglected during the course of the studies very briefly recorded in our preliminary communication. The complexities are even greater than Dr. Jolles suspects; for heparin, which he mentions in this context as an anticoagulant, only acts to prevent clotting in the presence of its co-factor which is much reduced in the blood of most cancer cases and almost completely absent in some.! In the absence of its co-factor, heparin acts as a fibrinogen precipitant in suitable circumstances2 and may even promote clotting. In our studies we have not been concerned to apply " anticoagulant therapy " which, from our point of view, is a misnomer. Our aim has been to neutralise the labile coagulative factor which diffuses from cancer cells as they grow. In-vitro tests have shown that protamine combines with and neutralises the factor, and its use in therapy was, therefore, a logical step in the absence of a better alternative which is not immediately available. The order of dosage employed was many. times greater than that used conventionally for such therapeutic purposes as the neutralisation of heparin, and treatment was prolonged, In consequence, it was expected that a sufficient concentration of protamine would reach the tumour to effect an appreciable amount of neutralisation. During the trial no evidence was found that protamine in the form in which we have used it (’ Prolothan A ’) had any anticoagulant or coagulant effect so far as the blood On the other hand, it did appear to was concerned. localise at the site of the tumours as shown by the erythema and regressive changes which it produced in them. These changes were of a similar order to those previously observed by the use of fibrinolytic agents3 which destroy the cancer coagulative factor in vitro. A study of the mast cells and ground substance, in the specimens removed at operation, was made at the time by one of us, and no departure from the usual findings in breast tumours was detected in the mast cells. The ground substance appeared less metachromatic than usual, and this observation, if confirmed, would again point to concentration of protamine in the tumour area. We referred in our article to the fact that protamine combines with acid mucopolysaccharides as well as neutralising the cancer coagulative factor. The work of Dr. Jolles and his associates4 had been studied with great interest when it appeared, because we had some time ago (Dr. Boggust) tested a series of polysaccharide sulphates of composition similar to laminarin sulphate. In the standard test which we use for neutralisation of the cancer coagulative it was found that some of the polysaccharide sulphates have an inhibitory effect which, weight-for-weight, is less than that of protamine. Also, it is apparent that the modus operandi is different because of their very different chemical properties. It is highly probable that laminarin sulphate would show inhibition of the same order, but we have had no oooortunitv of testing it.
factor,
1. Temperley, I. J. J. clin. Path. 1963, 16, 115. 2. Temperley, I. J. Irish J. med. Sci. April, 1963, p. 159. 3. Scientific Exhibition, B.M.A. Meeting, Belfast, 1962. 4. Jolles, B., Remington, M., Anderson, P. Brit. J. Cancer,
1963, 17, 109.
One could, therefore, advance the hypothesis that the results obtained by Dr. Jolles and his associates were attributable to inhibition of the cancer coagulative factor in their mouse tumours. This we would hesitate to do, because our work has been strictly confined to naturally occurring spontaneous cancers in man. Material from human sources has been used throughout in our coagulation studies. The differences, often striking, which are known to exist between the details of the coagulation/ fibrinolytic system in man and other mammals have been so inadequately studied as to make direct comparison, in the complex field with which we are dealing, unjustifiable. School of Pathology, R. A. Q. O’MEARA. Trinity College, Dublin. M. J. O’HALLORAN. St. Luke’s Hospital, Dublin. RADIOACTIVITY IN MILK AND BONE SiR,—The recent statement by Sir John Cockcroft1
about the possible stopping of fresh milk supplies to children at least once during the past two years, because of its high radioiodine content, raises other questions. The Agricultural Research Council has not published the results of radioiodine examinations in milk from the " special areas "2 of Britain-the hills with high rainfall, where nuclear fallout,like the rainfall, is five times or more the national average.33 Should children have been milk from these hills during the period of high given radioiodine content? Canadian levels4 of radio-strontium and radio-cassium in fresh milk in 1963, especially in the summer, have been at record high levels, at which they remain. They are nearly twice the 1962 levels and over twice the 1959 peak. The Canadian level in 1959 was an average yearly figure of 14 ;C of 90Sr per g. Ca, with a maximum of 21, and a minimum of 6.1.5 The average content of 90Sr in whole milk in July, 1963, was 46-4 {J.{J.C per litre. British fallout levels are comparable to the Canadian figures, except that with half-yearly or yearly reports, the British information comes six to twelve months later. There have been no large investigations of radioactive strontium in the bones of infants from the areas of high fallout in Britain. Only 2% or 3% of over one thousand bones examined by the Atomic Energy Research Establishment for the Medical Research Council6 come from children between birth and one year of age in the areas of high fallout. But Dr. J. F. Loutit, of the M.R.C. Radiobiological Research Unit, has shown how an estimate of these levels can be made.’ He has shown that levels of radio-strontium in the bones of infants between birth and one year of age are half that of the level in milk they drink, compared with a figure of one quarter in older children. The recent Canadian report shows that it is probable that milk in areas of high fallout in Britain contains radioactive strontium above a level of 134 {J.{J.C per litre and possibly considerably above this. This means that amounts of radioactive strontium in the bones of infants who are drinking milk from wet areas may well be above the 33-5 {J.{J.C per g. Ca of the Medical Research Council’s " warning level " and the 67 fjC per g. Ca which is the maximum permissible level in the whole population allowed by the International Commission on Radiological Protection.8 1. Guardian, Sept. 30, 1963. 2. Annual Report of Agricultural Research Council Radiobiological Laboratory, 1962-63. 3. Agricultural Research Council: Radiobiological Reports nos. 3 and 4. Strontium 90 in Milk and Agricultural Materials in the U.K. H.M. Stationery Office.
4. Radiation Protection Division of the Canadian Department of National Health and Welfare: August, 1963, and earlier monthly reports. 5. Report of the U.N. Scientific Committee on the Effect of Atomic Radiation. New York, 1962. 6. Assay of Strontium-90 in Human Bone in the United Kingdom. Medical Research Council Monitoring Report Series. H.M. Stationery Office. 7. B.B.C. broadcast, March 2. 1961. 8. Hazards to Man of Nuclear and Allied Radiations. H.M. Stationery Office, 1960.
Letters
to
the Editor
PROTAMINE IN BREAST CANCERS SIR,-We feel that Dr. Jolles (Oct. 5, p. 736) does
us
less than justice when he suggests that we are unaware of the complexities of cancerous stromal growth. In fact, many of the points which he mentions have already received attention in the previous publications listed and others have not been neglected during the course of the studies very briefly recorded in our preliminary communication. The complexities are even greater than Dr. Jolles suspects; for heparin, which he mentions in this context as an anticoagulant, only acts to prevent clotting in the presence of its co-factor which is much reduced in the blood of most cancer cases and almost completely absent in some.! In the absence of its co-factor, heparin acts as a fibrinogen precipitant in suitable circumstances2 and may even promote clotting. In our studies we have not been concerned to apply " anticoagulant therapy " which, from our point of view, is a misnomer. Our aim has been to neutralise the labile coagulative factor which diffuses from cancer cells as they grow. In-vitro tests have shown that protamine combines with and neutralises the factor, and its use in therapy was, therefore, a logical step in the absence of a better alternative which is not immediately available. The order of dosage employed was many. times greater than that used conventionally for such therapeutic purposes as the neutralisation of heparin, and treatment was prolonged, In consequence, it was expected that a sufficient concentration of protamine would reach the tumour to effect an appreciable amount of neutralisation. During the trial no evidence was found that protamine in the form in which we have used it (’ Prolothan A ’) had any anticoagulant or coagulant effect so far as the blood On the other hand, it did appear to was concerned. localise at the site of the tumours as shown by the erythema and regressive changes which it produced in them. These changes were of a similar order to those previously observed by the use of fibrinolytic agents3 which destroy the cancer coagulative factor in vitro. A study of the mast cells and ground substance, in the specimens removed at operation, was made at the time by one of us, and no departure from the usual findings in breast tumours was detected in the mast cells. The ground substance appeared less metachromatic than usual, and this observation, if confirmed, would again point to concentration of protamine in the tumour area. We referred in our article to the fact that protamine combines with acid mucopolysaccharides as well as neutralising the cancer coagulative factor. The work of Dr. Jolles and his associates4 had been studied with great interest when it appeared, because we had some time ago (Dr. Boggust) tested a series of polysaccharide sulphates of composition similar to laminarin sulphate. In the standard test which we use for neutralisation of the cancer coagulative it was found that some of the polysaccharide sulphates have an inhibitory effect which, weight-for-weight, is less than that of protamine. Also, it is apparent that the modus operandi is different because of their very different chemical properties. It is highly probable that laminarin sulphate would show inhibition of the same order, but we have had no oooortunitv of testing it.
factor,
1. Temperley, I. J. J. clin. Path. 1963, 16, 115. 2. Temperley, I. J. Irish J. med. Sci. April, 1963, p. 159. 3. Scientific Exhibition, B.M.A. Meeting, Belfast, 1962. 4. Jolles, B., Remington, M., Anderson, P. Brit. J. Cancer,
1963, 17, 109.
One could, therefore, advance the hypothesis that the results obtained by Dr. Jolles and his associates were attributable to inhibition of the cancer coagulative factor in their mouse tumours. This we would hesitate to do, because our work has been strictly confined to naturally occurring spontaneous cancers in man. Material from human sources has been used throughout in our coagulation studies. The differences, often striking, which are known to exist between the details of the coagulation/ fibrinolytic system in man and other mammals have been so inadequately studied as to make direct comparison, in the complex field with which we are dealing, unjustifiable. School of Pathology, R. A. Q. O’MEARA. Trinity College, Dublin. M. J. O’HALLORAN. St. Luke’s Hospital, Dublin. RADIOACTIVITY IN MILK AND BONE SiR,—The recent statement by Sir John Cockcroft1
about the possible stopping of fresh milk supplies to children at least once during the past two years, because of its high radioiodine content, raises other questions. The Agricultural Research Council has not published the results of radioiodine examinations in milk from the " special areas "2 of Britain-the hills with high rainfall, where nuclear fallout,like the rainfall, is five times or more the national average.33 Should children have been milk from these hills during the period of high given radioiodine content? Canadian levels4 of radio-strontium and radio-cassium in fresh milk in 1963, especially in the summer, have been at record high levels, at which they remain. They are nearly twice the 1962 levels and over twice the 1959 peak. The Canadian level in 1959 was an average yearly figure of 14 ;C of 90Sr per g. Ca, with a maximum of 21, and a minimum of 6.1.5 The average content of 90Sr in whole milk in July, 1963, was 46-4 {J.{J.C per litre. British fallout levels are comparable to the Canadian figures, except that with half-yearly or yearly reports, the British information comes six to twelve months later. There have been no large investigations of radioactive strontium in the bones of infants from the areas of high fallout in Britain. Only 2% or 3% of over one thousand bones examined by the Atomic Energy Research Establishment for the Medical Research Council6 come from children between birth and one year of age in the areas of high fallout. But Dr. J. F. Loutit, of the M.R.C. Radiobiological Research Unit, has shown how an estimate of these levels can be made.’ He has shown that levels of radio-strontium in the bones of infants between birth and one year of age are half that of the level in milk they drink, compared with a figure of one quarter in older children. The recent Canadian report shows that it is probable that milk in areas of high fallout in Britain contains radioactive strontium above a level of 134 {J.{J.C per litre and possibly considerably above this. This means that amounts of radioactive strontium in the bones of infants who are drinking milk from wet areas may well be above the 33-5 {J.{J.C per g. Ca of the Medical Research Council’s " warning level " and the 67 fjC per g. Ca which is the maximum permissible level in the whole population allowed by the International Commission on Radiological Protection.8 1. Guardian, Sept. 30, 1963. 2. Annual Report of Agricultural Research Council Radiobiological Laboratory, 1962-63. 3. Agricultural Research Council: Radiobiological Reports nos. 3 and 4. Strontium 90 in Milk and Agricultural Materials in the U.K. H.M. Stationery Office.
4. Radiation Protection Division of the Canadian Department of National Health and Welfare: August, 1963, and earlier monthly reports. 5. Report of the U.N. Scientific Committee on the Effect of Atomic Radiation. New York, 1962. 6. Assay of Strontium-90 in Human Bone in the United Kingdom. Medical Research Council Monitoring Report Series. H.M. Stationery Office. 7. B.B.C. broadcast, March 2. 1961. 8. Hazards to Man of Nuclear and Allied Radiations. H.M. Stationery Office, 1960.