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H.A.A. AND CONGENITAL BILIARY ATRESIA
398
identify
"
"
responsive state in which therapy with infectious agents can safely be used. It is, however, important to give immunostimulant therapy in combination with conventional (immunosuppressive) therapy, so as to achieve a prolonged state of immune responsiveness, which, in effect, is equatable with prolonged survival.
to
a
COMPARISON OF ANTITUMOUR ACTIVITY OF THREE ANTIVIRAL AGENTS AGAINST WALKER 256 CARCINOSARCOMA
Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
SAMUEL GROSS. *
All drugs tumour
were
given daily intraperitoneally beginning 24 hours after
inoculation and continuing until death.
ANTITUMOUR ACTIVITY OF TWO ANTIVIRAL DRUGS—RIFAMPICIN AND TILORONE SIR,-Failure to achieve permanent remission in acute lymphocytic leukaemia (A.L.L.) may be related to (a) inability to achieve 100% leukasmic-cell kill, (b) the emergence of leukasmic cells resistant to the antitumour therapy, or (c) reinduction of the leukaemia by virus or virus-like agents which are unaffected by antileuksemic drugs currently in use. Suitable models would now exist for testing proposition (c) in animals, and also in man, if drugs were available which would inhibit replication or kill the virus or virus-like agent inducing the leukxmia. An animal system for testing this proposition is the AKR spontaneous lymphoma. This disease is induced by the Gross leukxmia virus 1; it closely resembles human lymphoid leukxmia; and remissions can be obtained with vincristine, cytosine arabinoside, or other agents used clinically. Patients with A.L.L. who do not respond clinically to L-asparaginase or whose cells in vitro do not respond to L-asparaginase may be suspected of having virus-induced disease, since 20 animal leukaemias (including AKR) induced by 4 types of viruses did not respond to L-asparaginase.2,3 In addition, it is reasonable to suppose that, in patients with A.L.L. who have R.N.A.-dependent D.N.A. polymerase4 in their cells, the disease is induced by R.N.A. virus. Therefore, there is a need for drugs that will inhibit the leukxmia virus and/or the R.N.A.-dependent D.N.A. polymerase, and testing of these drugs in combination with the standard antitumour drugs in animals and patients (suspected of having virus-induced disease), whose leukxmia is in remission. I now wish to report the antitumour activity of two antiviral agents-rifampicin and tilorone hydrochloride. Rifampicin has both antiviral and antibacterial activity and also inhibits the R.N.A.-dependent D.N.A. polymerase of human acute-leukaemia cellos. 4-7 Tilorone is a synthetic small-molecular-weight inducer of interferon which has broad antiviral activity against both R.N.A. and D.N.A. viruses.8,9 These two antiviral drugs with different mechanisms of action were tested for antitumour activity against the ascitic Walker 256 carcinosarcoma-a tumour that responds to the antiviral agent poly I-poly C.10 As can be seen in the accompanying table, both rifampicin and tilorone are active against this tumour. Rifampicin was equivalent in antitumour activity to poly I-poly C, against Walker 256 carcinosarcoma, but tilorone was more effective than either rifampicin or poly I-poly C,
giving an increase in median survival of 700% over controls. Therefore these three antiviral agents also have antitumour activity, and their effectiveness in maintaining remission in the AKR system or other suitable animaltumour systems and in human A.L.L. (toxicity studies permitting) should be examined. Some of these studies are in progress. Section of Pharmacology and Experimental Therapeutics, Laboratory of Chemical Pharmacology, National Cancer Institute, National Institutes of Health, RICHARD H. ADAMSON. Bethesda, Maryland 20014.
Gross, L. Acta hœmat. 1960, 23, 259. Adamson, R. H., Fabro, S. Cancer Chemother. Rep. 1968, 52, 617. Adamson, R. H. Unpublished. Gallo, R. C., Yang, S. S., Ting, R. C. Nature, 1970, 228, 927. Bergamini, N., Fowst, G. Arzneimittel-Forsch. 1965, 15, 951. Heller, E., Argaman, M., Levy, H., Goldblum, N. Nature, 1969, 222, 273. Subak-Sharpe, J. H., Timbury, M. C., Williams, J. F. ibid. p. 341. Krueger, R. F., Mayer, G. D. Science, 1970, 169, 1213. Mayer, G. D., Krueger, R. F. ibid. p. 1214. Adamson, R. H., Fabor, S., Homan, E. R., O’Gara, R. W., Zendzian, R. P. Antimicrobial Agents and Chemotherapy, 1969; p. 148. Washington, D.C., 1970.
SIR,—I share Dr. Whitehead’s concern that it can be taken for granted by members of the public that an accused person whom a court finds " unfit to plead " is actually " guilty".4 The fact that a professional journal could adopt that view regarding the manslaughter case cited by Dr. Whitehead, though the verdict " unfit to
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
H.A.A. AND CONGENITAL BILIARY ATRESIA SIR,—The report by Smithwick and Suat Cheng Go1 of absence of Australia antigen (H.A.A.) in cord sera from 2225
deliveries, despite an incidence in maternal sera of 2-5%, provides evidence against the intrauterine transmission of H.A.A. Even so, the virus undoubtedly crosses the placenta in a few cases, causing neonatal hepatitis, as Dr. Gillespie and his colleagues record.2We should like to contribute two unusual cases. We have seen two infants with partial intrahepatic and extrahepatic biliary agenesis (confirmed by laparotomy and liver biopsy) whose mothers had H.A.A. in the serum (detected by Ouchterlony’s technique and Prince’s electrophoretic technique). One was H.A.A.-positive from birth up to the age of 40 days, and the other was negative at the age of 7 months. We believe this is the first time such an association has been found, though the possibility has previously been suggested.3 There have been other cases of neonatal hepatitis and of biliary atresia in both patients’ families. Neither of the patients’ mothers had any symptoms in pregnancy or any previous history of hepatitis. They may therefore be regarded as healthy carriers of H.A.A. It would be of interest to test the sera of all patients with biliary atresia during the first month of life, and also the sera of their mothers, for H.A.A. PAOLO TOLENTINO University Department of Infectious ASSUNTA BRAITO Diseases, ANGELA TASSARA. Genoa, Italy.
FITNESS TO PLEAD AND FITNESS TO BE A VICTIM
1. 2. 3. 4.
Smithwick, M. Elizabeth, Suat Cheng, G. Lancet, 1970, ii, 1081. Gillespie, A., Dorman, D., Walker, J. A., Yu, J. S. ibid. Tolentino, P. G. Mal. infett. parassit. 1959, 11, 1116. Whitehead, J. A. Lancet, Jan. 30, 1971, p. 234.
identify
"
"
responsive state in which therapy with infectious agents can safely be used. It is, however, important to give immunostimulant therapy in combination with conventional (immunosuppressive) therapy, so as to achieve a prolonged state of immune responsiveness, which, in effect, is equatable with prolonged survival.
to
a
COMPARISON OF ANTITUMOUR ACTIVITY OF THREE ANTIVIRAL AGENTS AGAINST WALKER 256 CARCINOSARCOMA
Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
SAMUEL GROSS. *
All drugs tumour
were
given daily intraperitoneally beginning 24 hours after
inoculation and continuing until death.
ANTITUMOUR ACTIVITY OF TWO ANTIVIRAL DRUGS—RIFAMPICIN AND TILORONE SIR,-Failure to achieve permanent remission in acute lymphocytic leukaemia (A.L.L.) may be related to (a) inability to achieve 100% leukasmic-cell kill, (b) the emergence of leukasmic cells resistant to the antitumour therapy, or (c) reinduction of the leukaemia by virus or virus-like agents which are unaffected by antileuksemic drugs currently in use. Suitable models would now exist for testing proposition (c) in animals, and also in man, if drugs were available which would inhibit replication or kill the virus or virus-like agent inducing the leukxmia. An animal system for testing this proposition is the AKR spontaneous lymphoma. This disease is induced by the Gross leukxmia virus 1; it closely resembles human lymphoid leukxmia; and remissions can be obtained with vincristine, cytosine arabinoside, or other agents used clinically. Patients with A.L.L. who do not respond clinically to L-asparaginase or whose cells in vitro do not respond to L-asparaginase may be suspected of having virus-induced disease, since 20 animal leukaemias (including AKR) induced by 4 types of viruses did not respond to L-asparaginase.2,3 In addition, it is reasonable to suppose that, in patients with A.L.L. who have R.N.A.-dependent D.N.A. polymerase4 in their cells, the disease is induced by R.N.A. virus. Therefore, there is a need for drugs that will inhibit the leukxmia virus and/or the R.N.A.-dependent D.N.A. polymerase, and testing of these drugs in combination with the standard antitumour drugs in animals and patients (suspected of having virus-induced disease), whose leukxmia is in remission. I now wish to report the antitumour activity of two antiviral agents-rifampicin and tilorone hydrochloride. Rifampicin has both antiviral and antibacterial activity and also inhibits the R.N.A.-dependent D.N.A. polymerase of human acute-leukaemia cellos. 4-7 Tilorone is a synthetic small-molecular-weight inducer of interferon which has broad antiviral activity against both R.N.A. and D.N.A. viruses.8,9 These two antiviral drugs with different mechanisms of action were tested for antitumour activity against the ascitic Walker 256 carcinosarcoma-a tumour that responds to the antiviral agent poly I-poly C.10 As can be seen in the accompanying table, both rifampicin and tilorone are active against this tumour. Rifampicin was equivalent in antitumour activity to poly I-poly C, against Walker 256 carcinosarcoma, but tilorone was more effective than either rifampicin or poly I-poly C,
giving an increase in median survival of 700% over controls. Therefore these three antiviral agents also have antitumour activity, and their effectiveness in maintaining remission in the AKR system or other suitable animaltumour systems and in human A.L.L. (toxicity studies permitting) should be examined. Some of these studies are in progress. Section of Pharmacology and Experimental Therapeutics, Laboratory of Chemical Pharmacology, National Cancer Institute, National Institutes of Health, RICHARD H. ADAMSON. Bethesda, Maryland 20014.
Gross, L. Acta hœmat. 1960, 23, 259. Adamson, R. H., Fabro, S. Cancer Chemother. Rep. 1968, 52, 617. Adamson, R. H. Unpublished. Gallo, R. C., Yang, S. S., Ting, R. C. Nature, 1970, 228, 927. Bergamini, N., Fowst, G. Arzneimittel-Forsch. 1965, 15, 951. Heller, E., Argaman, M., Levy, H., Goldblum, N. Nature, 1969, 222, 273. Subak-Sharpe, J. H., Timbury, M. C., Williams, J. F. ibid. p. 341. Krueger, R. F., Mayer, G. D. Science, 1970, 169, 1213. Mayer, G. D., Krueger, R. F. ibid. p. 1214. Adamson, R. H., Fabor, S., Homan, E. R., O’Gara, R. W., Zendzian, R. P. Antimicrobial Agents and Chemotherapy, 1969; p. 148. Washington, D.C., 1970.
SIR,—I share Dr. Whitehead’s concern that it can be taken for granted by members of the public that an accused person whom a court finds " unfit to plead " is actually " guilty".4 The fact that a professional journal could adopt that view regarding the manslaughter case cited by Dr. Whitehead, though the verdict " unfit to
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
H.A.A. AND CONGENITAL BILIARY ATRESIA SIR,—The report by Smithwick and Suat Cheng Go1 of absence of Australia antigen (H.A.A.) in cord sera from 2225
deliveries, despite an incidence in maternal sera of 2-5%, provides evidence against the intrauterine transmission of H.A.A. Even so, the virus undoubtedly crosses the placenta in a few cases, causing neonatal hepatitis, as Dr. Gillespie and his colleagues record.2We should like to contribute two unusual cases. We have seen two infants with partial intrahepatic and extrahepatic biliary agenesis (confirmed by laparotomy and liver biopsy) whose mothers had H.A.A. in the serum (detected by Ouchterlony’s technique and Prince’s electrophoretic technique). One was H.A.A.-positive from birth up to the age of 40 days, and the other was negative at the age of 7 months. We believe this is the first time such an association has been found, though the possibility has previously been suggested.3 There have been other cases of neonatal hepatitis and of biliary atresia in both patients’ families. Neither of the patients’ mothers had any symptoms in pregnancy or any previous history of hepatitis. They may therefore be regarded as healthy carriers of H.A.A. It would be of interest to test the sera of all patients with biliary atresia during the first month of life, and also the sera of their mothers, for H.A.A. PAOLO TOLENTINO University Department of Infectious ASSUNTA BRAITO Diseases, ANGELA TASSARA. Genoa, Italy.
FITNESS TO PLEAD AND FITNESS TO BE A VICTIM
1. 2. 3. 4.
Smithwick, M. Elizabeth, Suat Cheng, G. Lancet, 1970, ii, 1081. Gillespie, A., Dorman, D., Walker, J. A., Yu, J. S. ibid. Tolentino, P. G. Mal. infett. parassit. 1959, 11, 1116. Whitehead, J. A. Lancet, Jan. 30, 1971, p. 234.