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IS PHENYTOIN CARCINOGENIC ?
323 enzyme in favour of
GM2 ganglioside. There is, however, doubt that the two enzymes are closely related structurally since we find that antisera raised to one is cross reactive to the other. An alternative proposal might be that these enzymes consist of sub-units of two kinds, one carrying the enzyme site and subject to inactivation by mutation in GM2 gangliosidosis type 2, while the other sub-unit is an acidic ’" specifier glycoprotein directing the enzymic activity specifically towards GM2. A mutation in this sub-unit would result in hexosaminidase A activity being lost while the B activity remains. The two distinct mutations would thus not be in the same gene. no
immediate carcinogenic action, we assume that a concurrent persistent antigenic stimulation and partial immunosup-
pression causes lymphoma development. This model was successfully applied also in other experiments to induce malignant lymphomas. 6-9 Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
"
Department of Biochemistry, Queen Elizabeth College, Atkins Building, Campden Hill, London W.8.
D. ROBINSON M. CARROLL.
IS PHENYTOIN CARCINOGENIC ?
SIR,-Iread with great interest your editorial (Nov. 13, 1071) on this question in which you discuss the possible carcinogenicity of diphenylhydantoin (phenytoin, ’Dilantin’,Epanutin ’). May I draw your attention to the fact that we have proposed a similar theory,1,2 and have prep.
experimental evidence for it ? The assumption that phenytoin may cause chronic antigenic stimulation, and at sented
time probably also interfere with the immune prompted several experiments which are in part published.2,3 Female young adult mice of strains C3Hf, C57Bl, and SJL/J were fed phenytoin in a liquid diet (0-06-36-1 mg. per 100 g. mouse) in acute and chronic experiments. Routine necropsies at intervals between 2 and 64 weeks showed early thymic atrophy, lymph-node structural distortion, partial atrophy, and hyperplastic changes. 3,4 The hyperplastic lesions included atypical histiocytic giant cells. A few early lymphosarcomas were found after a 3-5 month latent period in mice susceptible to spontaneous tumour development in lymphoreticular tissues (SJL/J strain). Later in the experiment, spontaneously arising Hodgkin-like lesions (reticulum-cell sarcoma, type B, of Dunn 5) occurred in this mouse strain earlier in phenytoin-treated mice than in untreated animals. the
same
response,
Mice with
a
medium
or
low spontaneous incidence of
lymphoreticular malignancies (C57Bl, C3Hf) also showed4 several lymphomas after a latent period of about 10 months. All tumours were thymic lymphomas, and, therefore, differed histologically from tumours developing spontaneously in these mice (Hodgkin-like lesion and plasmacell neoplasm). Moreover, their time of onset was much earlier than that of spontaneous lymphoreticular neoplasms. Immunological studies with phenytoin included sensitisation of animals by skin painting with this drug, and thereThe humoral fore confirmed its haptenic character.33 immune response was evaluated by bovine-serum-albumin sensitisation and passive hxmagglutination microassays. Dilantin-fed mice showed variable levels of antibodies, but no significant reduction in titres after two months of feeding. The cellular immune response at this time, as measured by histological evaluation of foot-pad tests, was absent. The microscopy of immunocompetent tissues with phenytoin suggested a sequence of during treatment antigenic " over-stimulation ", atrophy (primarily of thymus and thymic-dependent paracortex of lymph-nodes), and hyperplasia of previously atrophic areas. Phenytoin seems to favour the development of malignant lymphomas in immunocompetent tissues. Rather than an 1. 2. 3. 4. 5.
Kruger, G. Dt. med. J. 1970, 21, 28. Kruger, G. Verh. dt. Ges. Path. 1970, 54, 175. Kruger, G. Virchows Arch. path. Anat. Physiol. 1970, 349, 297. Kruger, G., Harris, D., Sussman, E. Unpublished. Dunn, T. B. J. natn. Cancer Inst. 1954, 14, 1281.
GERHARD R. F. KRUGER DURAN HARRIS.
PHENYTOIN AND DEPRESSION OF IMMUNOLOGICAL FUNCTION
SIR,-The paper by Dr. Sorrell and others (Dec. 4, 1233) raises some important questions. It is well known that patients with systemic lupus not infrequently have seizures. In a group of 25 patients with untreated systemic lupus I find that 4 have IgA levels less than 84 mg. per p.
100 ml. It seems to me that one would have to have before-and-after data to be certain that the phenytointreated group did not represent a selected group of individuals containing a significant fraction of patients having so-called autoimmune disease. On the opposite side of the coin, one could discontinue therapy because of allergic reactions and other reasons and see whether IgAantibody levels rose. In only one systemic-lupus patient with seizures was this done, and after one year the IgA had changed from less than 73 to 90 mg. per 100 ml.still a significant reduction. For the moment, I am inclined to believe the abnormalities in the analeptic group represent part of the basic immune deficit in these individuals rather than the result of the drug per se. Rockwood
Clinic, Eighth Avenue, Spokane, Washington 99204, U.S.A. 312 West
S. K. MCILVANIE.
QUINACRINE FLUORESCENT SURVEY JAPANESE JUVENILE DELINQUENTS SIR,-In our previous letter 10 we reported that no XYY individual was found among 100 tall juvenile delinquents in Tokyo Juvenile Detention and Classification OF
After that time we changed the method from blood-culture to quinacrine staining of buccal smears, and 2 XYY individuals were detected among the next 56 tall juvenile delinquents. The frequency was thus 1-28% (2 XYY individuals out of 156 tested). The 156 were selected for height (approximately taller than 1.5 s.D. for age) from among 1833 entrants in the period Jan. 1 to Dec. 31, 1971. This figure is less than, but not significantly different from, pooled data of the frequency (3’09%,3 5/162) 11-13 of XYY individuals among tall juvenile delinquents outside Japan. Another XYY individual was found Home.
by quinacrine fluorescence among 76 juvenile delinquents selected for height in another institution. Racial differences in the frequency of the XYY complement, as suggested in our earlier letter,10 should be reconsidered.
not
Institute of Brain Research, University of Tokyo School of Medicine.
AKIO ASAKA.
Kruger, G., Malmgren, R. A., Berard, C. W. Transplantation, 1971, 11, 138. 7. Kruger, G. Verh. dt. Ges. Path. 1971, 55, 200. 8. Kruger, G., Heine, U. Cancer Res. (in the press). 9. Kruger, G., O’Connor, G. T. in Current Problems in the Epidemiology of Cancer, Lymphoma and Leukemia (edited by E. Grundmann). Recent Results in Cancer Research (in the press). 10. Asaka, A., Inouye, E., Kabaya, T., Honma, M. Lancet, 1971, ii, 985. 11. Hunter, H. ibid. 1968, i, 816. 12. Baker, D., Telfer, M. A., Richardson, C. E., Clark, G. R. J. Am. med. Ass. 1970, 214, 869. 13. Jacobs, P. A., Price, W. H., Richmond, S., Ratcliff, R. A. J. med. Genet. 1971, 8, 49. 6.
GM2 ganglioside. There is, however, doubt that the two enzymes are closely related structurally since we find that antisera raised to one is cross reactive to the other. An alternative proposal might be that these enzymes consist of sub-units of two kinds, one carrying the enzyme site and subject to inactivation by mutation in GM2 gangliosidosis type 2, while the other sub-unit is an acidic ’" specifier glycoprotein directing the enzymic activity specifically towards GM2. A mutation in this sub-unit would result in hexosaminidase A activity being lost while the B activity remains. The two distinct mutations would thus not be in the same gene. no
immediate carcinogenic action, we assume that a concurrent persistent antigenic stimulation and partial immunosup-
pression causes lymphoma development. This model was successfully applied also in other experiments to induce malignant lymphomas. 6-9 Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
"
Department of Biochemistry, Queen Elizabeth College, Atkins Building, Campden Hill, London W.8.
D. ROBINSON M. CARROLL.
IS PHENYTOIN CARCINOGENIC ?
SIR,-Iread with great interest your editorial (Nov. 13, 1071) on this question in which you discuss the possible carcinogenicity of diphenylhydantoin (phenytoin, ’Dilantin’,Epanutin ’). May I draw your attention to the fact that we have proposed a similar theory,1,2 and have prep.
experimental evidence for it ? The assumption that phenytoin may cause chronic antigenic stimulation, and at sented
time probably also interfere with the immune prompted several experiments which are in part published.2,3 Female young adult mice of strains C3Hf, C57Bl, and SJL/J were fed phenytoin in a liquid diet (0-06-36-1 mg. per 100 g. mouse) in acute and chronic experiments. Routine necropsies at intervals between 2 and 64 weeks showed early thymic atrophy, lymph-node structural distortion, partial atrophy, and hyperplastic changes. 3,4 The hyperplastic lesions included atypical histiocytic giant cells. A few early lymphosarcomas were found after a 3-5 month latent period in mice susceptible to spontaneous tumour development in lymphoreticular tissues (SJL/J strain). Later in the experiment, spontaneously arising Hodgkin-like lesions (reticulum-cell sarcoma, type B, of Dunn 5) occurred in this mouse strain earlier in phenytoin-treated mice than in untreated animals. the
same
response,
Mice with
a
medium
or
low spontaneous incidence of
lymphoreticular malignancies (C57Bl, C3Hf) also showed4 several lymphomas after a latent period of about 10 months. All tumours were thymic lymphomas, and, therefore, differed histologically from tumours developing spontaneously in these mice (Hodgkin-like lesion and plasmacell neoplasm). Moreover, their time of onset was much earlier than that of spontaneous lymphoreticular neoplasms. Immunological studies with phenytoin included sensitisation of animals by skin painting with this drug, and thereThe humoral fore confirmed its haptenic character.33 immune response was evaluated by bovine-serum-albumin sensitisation and passive hxmagglutination microassays. Dilantin-fed mice showed variable levels of antibodies, but no significant reduction in titres after two months of feeding. The cellular immune response at this time, as measured by histological evaluation of foot-pad tests, was absent. The microscopy of immunocompetent tissues with phenytoin suggested a sequence of during treatment antigenic " over-stimulation ", atrophy (primarily of thymus and thymic-dependent paracortex of lymph-nodes), and hyperplasia of previously atrophic areas. Phenytoin seems to favour the development of malignant lymphomas in immunocompetent tissues. Rather than an 1. 2. 3. 4. 5.
Kruger, G. Dt. med. J. 1970, 21, 28. Kruger, G. Verh. dt. Ges. Path. 1970, 54, 175. Kruger, G. Virchows Arch. path. Anat. Physiol. 1970, 349, 297. Kruger, G., Harris, D., Sussman, E. Unpublished. Dunn, T. B. J. natn. Cancer Inst. 1954, 14, 1281.
GERHARD R. F. KRUGER DURAN HARRIS.
PHENYTOIN AND DEPRESSION OF IMMUNOLOGICAL FUNCTION
SIR,-The paper by Dr. Sorrell and others (Dec. 4, 1233) raises some important questions. It is well known that patients with systemic lupus not infrequently have seizures. In a group of 25 patients with untreated systemic lupus I find that 4 have IgA levels less than 84 mg. per p.
100 ml. It seems to me that one would have to have before-and-after data to be certain that the phenytointreated group did not represent a selected group of individuals containing a significant fraction of patients having so-called autoimmune disease. On the opposite side of the coin, one could discontinue therapy because of allergic reactions and other reasons and see whether IgAantibody levels rose. In only one systemic-lupus patient with seizures was this done, and after one year the IgA had changed from less than 73 to 90 mg. per 100 ml.still a significant reduction. For the moment, I am inclined to believe the abnormalities in the analeptic group represent part of the basic immune deficit in these individuals rather than the result of the drug per se. Rockwood
Clinic, Eighth Avenue, Spokane, Washington 99204, U.S.A. 312 West
S. K. MCILVANIE.
QUINACRINE FLUORESCENT SURVEY JAPANESE JUVENILE DELINQUENTS SIR,-In our previous letter 10 we reported that no XYY individual was found among 100 tall juvenile delinquents in Tokyo Juvenile Detention and Classification OF
After that time we changed the method from blood-culture to quinacrine staining of buccal smears, and 2 XYY individuals were detected among the next 56 tall juvenile delinquents. The frequency was thus 1-28% (2 XYY individuals out of 156 tested). The 156 were selected for height (approximately taller than 1.5 s.D. for age) from among 1833 entrants in the period Jan. 1 to Dec. 31, 1971. This figure is less than, but not significantly different from, pooled data of the frequency (3’09%,3 5/162) 11-13 of XYY individuals among tall juvenile delinquents outside Japan. Another XYY individual was found Home.
by quinacrine fluorescence among 76 juvenile delinquents selected for height in another institution. Racial differences in the frequency of the XYY complement, as suggested in our earlier letter,10 should be reconsidered.
not
Institute of Brain Research, University of Tokyo School of Medicine.
AKIO ASAKA.
Kruger, G., Malmgren, R. A., Berard, C. W. Transplantation, 1971, 11, 138. 7. Kruger, G. Verh. dt. Ges. Path. 1971, 55, 200. 8. Kruger, G., Heine, U. Cancer Res. (in the press). 9. Kruger, G., O’Connor, G. T. in Current Problems in the Epidemiology of Cancer, Lymphoma and Leukemia (edited by E. Grundmann). Recent Results in Cancer Research (in the press). 10. Asaka, A., Inouye, E., Kabaya, T., Honma, M. Lancet, 1971, ii, 985. 11. Hunter, H. ibid. 1968, i, 816. 12. Baker, D., Telfer, M. A., Richardson, C. E., Clark, G. R. J. Am. med. Ass. 1970, 214, 869. 13. Jacobs, P. A., Price, W. H., Richmond, S., Ratcliff, R. A. J. med. Genet. 1971, 8, 49. 6.