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VITAMIN-E DEFICIENCY AND POLYUNSATURATED FATTY ACIDS
380 contained much more; sugar, of course, is completely fat-free. These alterations in animal and vegetable foods are both in a direction known to induce arterial changes in experimental animals. Both involve a change in the balance of structural lipid components towards the non-essential features. Furthermore, there is now good evidence that classical competition exists between fatty acids during their metabolism to structural constituents. 34-37 Much is also known about the biochemical response to high carbohydrate diets. In relating these facts to man it could be argued that animal systems have wide tolerances, but there must be a limit, and an ideal balanced diet. I suggest that the balanced diet is more likely to be found in our diverse evolutionary context than in recent developments. We now know that structural lipids are used in every cell, in phospholipids, cerebral gangliosides and prostaglandins. We know that man is genetically polymorphic. When the balance of structural lipid changes, and when the limits of tolerance are approached, surely we would expect degenerative changes to increase in tissues where these structural components are critical ? Nuffield Institute of Comparative Medicine, The Zoological Society of London, Regent’s Park, N.W.1.
MICHAEL CRAWFORD.
VITAMIN-E DEFICIENCY AND POLYUNSATURATED FATTY ACIDS SIR,-In your annotation last February entitled " A Syndrome of Vitamin-E Deficiency?" 38 there are two points I should like to comment on: firstly, the significance of the haemolysis in vitro in relation to vitamin-E deficiency, and secondly, the effect of polyunsaturated fatty acids (P.U.F.A.) on vitamin-E requirement. The red-cells of vitamin-E-deficient patients h2emolyse in vitro when hydrogen peroxide or dialuric acid is added, but this phenomenon may also occur spontaneously. We have found 39 that 4 i.u. of vitamin E per C. of food were needed to prevent spontaneous haemolysis in male rats. This requirement remained constant over a period of 15 months. Of the organs and tissues which were investigated histologically the skeletal muscles proved to be the most sensitive to lack of vitamin E. The amount of vitamin E needed to prevent muscular dystrophy was somewhat lower than the amount required to prevent haemolysis in vitro. Therefore, at least in rats, a positive haemolysis test indicates that the vitamin-E status is so low that it may predispose to muscular dystrophy if maintained for a sufficiently long
period. Using
the same haemolysis test we also investigated 40 41 the effect of P.U.F.A. on the vitamin-E requirements of male rats fed vegetable oils freed from vitamin E, and found that only high doses of linoleic acid increased (slightly) the need for vitamin E. The calculated increased requirement was less than 0.1 mg. D-oc-tocopheryl acetate per g. linoleic acid. This extra need, however, is more than sufficiently covered by the natural vitamin-E content of vegetable oils rich in linoleic acid. Unilever Research Laboratory, F. C. JAGER. Vlaardingen, The Netherlands. 34. 35. 36. 37. 38. 39. 40. 41.
Klenk, E.J. Am. Oil Chemists’ Soc. 1965, 42, 580. Christiansen, K., Marcel, Y., Gan, M. V., Mohrhauer, H., Holman, R. T.J. biol. Chem. 1968, 243, 2969. Blix, G. (editor) Symp. Swedish Nutrition Foundation, 1966, no. 4. Holman, R. T. Prog. Chem. Fats, 1968, 19, 275. Lancet, 1969, i, 405. Jager, F. C. Nutritio Dicta, 1968, 10, 215. Jager, F. C. ibid. (in the press). Jager, F. C. Paper read at the Ninth Congress of the International Society for Fat Research, Rotterdam, September, 1968.
L-ASPARAGINASE AND BURKITT’S LYMPHOMA SIR,-L-asparaginase has been shown to be an effective antitumour agent against a variety of murine lymphoid tumours, the majority of which were either induced by radiation or occurred spontaneously.1 Canine lymphosarcoma, which resembles Burkitt’s lymphoma histologically, has also been successfully treated with L-asparaginase.2 Initial clinical trials with Escherichia coli L-asparaginase
suggested that the antineoplastic activity of this enzyme was confined primarily to neoplasms of the lymphoreticular system, especially acute lymphoblastic leukaemia of childhood.33
It was therefore of interest to proceed with therapeutic trials in patients with Burkitt’s lymphoma, who were refractory to other chemotherapeutic agents. 8 Ugandan patients with advanced lymphosarcoma, 6 of whom had Burkitt’s lymphoma, were treated with L-asparaginase (obtained from Squibb and Co., or Merck, Sharp & Dohme) at the lymphoma treatment centre, Kampala, Uganda. All patients had measurable tumours, and had relapsed following intensive chemotherapeutic regimens with cyclophosphamide, methotrexate, vincristine, cytosine arabinoside, and other agents. L-asparaginase was administered (after appropriate sensitivity testing) as: 1500 i.u. per kg. intravenously (i.v.) as a single weekly dose for 2 weeks (4 patients); or 200 i.u. per kg. i.v. daily for 4-6 days (3 patients); or 500 i.u. per kg. i.v. daily for 7 days (1 patient). None of these patients had an objective or subjective response to L-asparaginase after a minimum of 7 days’ observation. The only side-effect observed was transient fever following injection. This lack of response by advanced Burkitt’s lymphoma, a tumour which is usually sensitive to most of the chemotherapeutic agents, was unexpected in the light of the relatively high response-rate of acute lymphoblastic
leukaemia. It has been demonstrated in murine and human
neoplastic cells that the capacity for biosynthesis of L-asparagine might determine its sensitivity to L-asparaginase.4-8 Burkitt-lymphoma cells have been observed to grow readily in vitro in media which is essentially L-asparagine free.9 10 The lack of clinical effect of L-asparaginase in the treatment of Burkitt’s lymphoma may reflect the lack of exogenous L-asparagine dependence of the tumour cells for growth. Medicine Branch, National Cancer Institute, Bethesda, Maryland, U.S.A. Lymphoma Treatment Centre,
Kampala, Uganda.
G. P. CANELLOS P. P. CARBONE. Z. L. ZIEGLER.
DIVERSION OF FUNDS
SiR,ńThe letter from the chairman of the Clwyd and Deeside Medical Committee (August 2, p. 267) illustrates yet again the devious manoeuvrings of the Department of Health and Social Security, and I fully support this protest. We are all well aware that there must be a limit to the finances available, but the continuous robbing of Peter to pay Paul is exceptionally bad management. Each allocation 1. 2. 3.
4. 5. 6. 7. 8. 9. 10.
Adamson, R. H., Fabro, S. Cancer Chemother. Rep. 1968, 52, 617. Old, L. J., Boyse, E. A., Campbell, H. A., Brodey, R. S., Fidler, J., Teller, J. D. Cancer, N.Y. 1967, 20, 1066. Oettgen, H. F., Old, L J., Boyse, E. A., Campbell, H. A., Philips, F. S., Clarkson, B. D., Tallal, L., Leeper, R. D., Schwartz, M. K., Kim, J. H., Cancer Res. 1967, 27, 2619. Sobin, L. H., Kidd, J. G. Proc. Soc. exp. Biol. Med. 1965, 119, 325. Broome, J. D., Schwartz, J. H. Biochim. Biophys. Acta, 1967, 138, 637. Prager, M. D., Bachynsky, N. Biochim. biophys. Res. Commun. 1968, 31, 43. Horowitz, B., Madras, B. K., Meister, A., Old, L. J., Boyse, E. A., Stockert, E. Science, N.Y. 1968,160, 133. Haskell, C. M., Canellos, G. P. Biochem. Pharmac. (in the press). Epstein, M. A., Barr, Y. M.J. natn. Cancer Inst. 1965, 34, 231. Ziegler, J. L. Unpublished.
MICHAEL CRAWFORD.
VITAMIN-E DEFICIENCY AND POLYUNSATURATED FATTY ACIDS SIR,-In your annotation last February entitled " A Syndrome of Vitamin-E Deficiency?" 38 there are two points I should like to comment on: firstly, the significance of the haemolysis in vitro in relation to vitamin-E deficiency, and secondly, the effect of polyunsaturated fatty acids (P.U.F.A.) on vitamin-E requirement. The red-cells of vitamin-E-deficient patients h2emolyse in vitro when hydrogen peroxide or dialuric acid is added, but this phenomenon may also occur spontaneously. We have found 39 that 4 i.u. of vitamin E per C. of food were needed to prevent spontaneous haemolysis in male rats. This requirement remained constant over a period of 15 months. Of the organs and tissues which were investigated histologically the skeletal muscles proved to be the most sensitive to lack of vitamin E. The amount of vitamin E needed to prevent muscular dystrophy was somewhat lower than the amount required to prevent haemolysis in vitro. Therefore, at least in rats, a positive haemolysis test indicates that the vitamin-E status is so low that it may predispose to muscular dystrophy if maintained for a sufficiently long
period. Using
the same haemolysis test we also investigated 40 41 the effect of P.U.F.A. on the vitamin-E requirements of male rats fed vegetable oils freed from vitamin E, and found that only high doses of linoleic acid increased (slightly) the need for vitamin E. The calculated increased requirement was less than 0.1 mg. D-oc-tocopheryl acetate per g. linoleic acid. This extra need, however, is more than sufficiently covered by the natural vitamin-E content of vegetable oils rich in linoleic acid. Unilever Research Laboratory, F. C. JAGER. Vlaardingen, The Netherlands. 34. 35. 36. 37. 38. 39. 40. 41.
Klenk, E.J. Am. Oil Chemists’ Soc. 1965, 42, 580. Christiansen, K., Marcel, Y., Gan, M. V., Mohrhauer, H., Holman, R. T.J. biol. Chem. 1968, 243, 2969. Blix, G. (editor) Symp. Swedish Nutrition Foundation, 1966, no. 4. Holman, R. T. Prog. Chem. Fats, 1968, 19, 275. Lancet, 1969, i, 405. Jager, F. C. Nutritio Dicta, 1968, 10, 215. Jager, F. C. ibid. (in the press). Jager, F. C. Paper read at the Ninth Congress of the International Society for Fat Research, Rotterdam, September, 1968.
L-ASPARAGINASE AND BURKITT’S LYMPHOMA SIR,-L-asparaginase has been shown to be an effective antitumour agent against a variety of murine lymphoid tumours, the majority of which were either induced by radiation or occurred spontaneously.1 Canine lymphosarcoma, which resembles Burkitt’s lymphoma histologically, has also been successfully treated with L-asparaginase.2 Initial clinical trials with Escherichia coli L-asparaginase
suggested that the antineoplastic activity of this enzyme was confined primarily to neoplasms of the lymphoreticular system, especially acute lymphoblastic leukaemia of childhood.33
It was therefore of interest to proceed with therapeutic trials in patients with Burkitt’s lymphoma, who were refractory to other chemotherapeutic agents. 8 Ugandan patients with advanced lymphosarcoma, 6 of whom had Burkitt’s lymphoma, were treated with L-asparaginase (obtained from Squibb and Co., or Merck, Sharp & Dohme) at the lymphoma treatment centre, Kampala, Uganda. All patients had measurable tumours, and had relapsed following intensive chemotherapeutic regimens with cyclophosphamide, methotrexate, vincristine, cytosine arabinoside, and other agents. L-asparaginase was administered (after appropriate sensitivity testing) as: 1500 i.u. per kg. intravenously (i.v.) as a single weekly dose for 2 weeks (4 patients); or 200 i.u. per kg. i.v. daily for 4-6 days (3 patients); or 500 i.u. per kg. i.v. daily for 7 days (1 patient). None of these patients had an objective or subjective response to L-asparaginase after a minimum of 7 days’ observation. The only side-effect observed was transient fever following injection. This lack of response by advanced Burkitt’s lymphoma, a tumour which is usually sensitive to most of the chemotherapeutic agents, was unexpected in the light of the relatively high response-rate of acute lymphoblastic
leukaemia. It has been demonstrated in murine and human
neoplastic cells that the capacity for biosynthesis of L-asparagine might determine its sensitivity to L-asparaginase.4-8 Burkitt-lymphoma cells have been observed to grow readily in vitro in media which is essentially L-asparagine free.9 10 The lack of clinical effect of L-asparaginase in the treatment of Burkitt’s lymphoma may reflect the lack of exogenous L-asparagine dependence of the tumour cells for growth. Medicine Branch, National Cancer Institute, Bethesda, Maryland, U.S.A. Lymphoma Treatment Centre,
Kampala, Uganda.
G. P. CANELLOS P. P. CARBONE. Z. L. ZIEGLER.
DIVERSION OF FUNDS
SiR,ńThe letter from the chairman of the Clwyd and Deeside Medical Committee (August 2, p. 267) illustrates yet again the devious manoeuvrings of the Department of Health and Social Security, and I fully support this protest. We are all well aware that there must be a limit to the finances available, but the continuous robbing of Peter to pay Paul is exceptionally bad management. Each allocation 1. 2. 3.
4. 5. 6. 7. 8. 9. 10.
Adamson, R. H., Fabro, S. Cancer Chemother. Rep. 1968, 52, 617. Old, L. J., Boyse, E. A., Campbell, H. A., Brodey, R. S., Fidler, J., Teller, J. D. Cancer, N.Y. 1967, 20, 1066. Oettgen, H. F., Old, L J., Boyse, E. A., Campbell, H. A., Philips, F. S., Clarkson, B. D., Tallal, L., Leeper, R. D., Schwartz, M. K., Kim, J. H., Cancer Res. 1967, 27, 2619. Sobin, L. H., Kidd, J. G. Proc. Soc. exp. Biol. Med. 1965, 119, 325. Broome, J. D., Schwartz, J. H. Biochim. Biophys. Acta, 1967, 138, 637. Prager, M. D., Bachynsky, N. Biochim. biophys. Res. Commun. 1968, 31, 43. Horowitz, B., Madras, B. K., Meister, A., Old, L. J., Boyse, E. A., Stockert, E. Science, N.Y. 1968,160, 133. Haskell, C. M., Canellos, G. P. Biochem. Pharmac. (in the press). Epstein, M. A., Barr, Y. M.J. natn. Cancer Inst. 1965, 34, 231. Ziegler, J. L. Unpublished.