IS INTERFERON ANY GOOD FOR CANCER?
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1037 However, the mechanisms by which such post-exposure protection is accomplished are by no means clear; vaccine- induced interferon and cellular responses as well as antibody may be involved. Considerable evidence also indicates that some immunological responses of the host are concerned in the pathogenesis of rabies, and a report by Prabhakar and Nathanson3 implicates rabies antibody. The role of antibody as the sole mediator of protection against rabies has been contentious for more than a decade.4 Passive immunisation with rabies antibody alone only marginally reduces mortality in experimentally infected animals and usually prolongs the incubation period.4,5 Conversely, in some animals in which only low levels of antibody have been induced, the incubation period is reduced. Such animals die earlier than unimmunised controls when challenged with rabies virus.6,7 This phenomenon of "early death" was first noted in monkeys during early vaccine trials.6 In a commentary on the article by Prabhakar and Nathanson, Porterfield8 cites several other viral diseases in which sub-neutralising doses of antibody enhance viral replication and stimulate infection rather than protecting the host. Several explanations have been advanced for early death2 in rabies. One well documented possibility is that antibody-mediated early death is analogous to immune cytolysis which occurs when antibody is applied to rabies- infected cell cultures in the presence of complement.9 The destruction of neurons either by immune cytolysis or by direct viral replication may have the same lethal outcome but differ in timing. 10 Lytic and neutralising antibodies are found in the same 7S immunoglobulin fraction of human and animal sera but vary in concentration.9 Porterfield8 discusses the possible involvement of macrophages and opsonisation of virus-antibody complexes. Other workers suggest that T or K cells might operate through some antibody-dependent cellular, cytotoxic mechanism." Prabhakar and Nathanson3 show quite convincingly that only the transfer of antibody or B cells induced early death in their mouse model; but, as they say, the mechanism is not obvious and needs further study. Extrapolation of the results to man should be cautious; the strain of attenuated virus used differs greatly in biological characters from typical street virus and the experimental conditions are hardly those of the naturally acquired disease. Prabhakar and Nathanson refer to reports12,13 in which patients who were unsuccessfully vaccinated died earlier than did those who were never vaccinated; nevertheless, other factors which influence incubation times cannot be ignored-for instance, the site and severity of the victims’ 3. Prabhakar BS, Nathanson N. Acute rabies death mediated by antibody. Nature 1981; 290: 590-91. 4 Koprowski H. Pre and post exposure prophylaxis: present status and current trends. In: Nagano V, Davenport FM, eds. Proceedings of working conference on rabies. Tokyo University of Tokyo Press, 1970: 111-26. 5. Baer GM, Cleary WF. A model in mice for the pathogenesis and treatment of rabies. J Inf Dis 1972; 125: 520-27. 6. Sikes RK, Cleary WF, Koprowsky H, Wiktor TJ, Kaplan MM. Effective protection of monkeys against death from street virus by post exposure administration of tissue- culture rabies vaccine. Bull World Health Org 1980, 45: 1-11. Blancou J, Andral B, Andral L. A model in mice for the study of the early-death phenomenon after vaccination and challenge with rabies virus J Gen Virol 1980; 50: 433-35. 8. Porterfield JS Rabies virus. Nature 1981; 290: 542. 9. Wiktor TJ, Kuwert EK, Koprowski H Immune lysis of rabies virus-infected cells. J Immunol 1968, 101:1271-82. 10. Murphy FA Rabies pathogenesis. brief review. Arch Virol 1977; 54: 279-97. Tignor GH, Mifune K, Smith AL. Immunopathology of rabies. In: Symposium on advances in rabies research Atlanta. Center for Disease Control, 1976: 13-19. 11. Centro Panamericano de Zoonosis. Human rabies vaccination in the Americas 1969-75. Vigilancia Epidemiologica 1976, 8: no. 9 12. Held JR, Tierkel ES, Steel JH Rabies in man and animals in the United States 1946-65. Publ Health Rep 1967, 82: 1009-18. bites, their ages, how promptly vaccine was applied, and how potent the vaccine was. Immunisation with potent cell-culture vaccine and human rabies immunoglobulin is the best treatment we can offer to those exposed to rabies infection. There have so far been no reports of rabies deaths in man when these measures have been applied as recommended. While the findings discussed here may lead to a better understanding of the pathogenesis of rabies they cast no doubt whatever on the efficacy of existing methods for immunoprophylaxis. IS INTERFERON ANY GOOD FOR CANCER? THE excitement and the unjustified enthusiasm for using interferon to treat cancer in man have already subsided greatly and one is already hearing comments that it was all hot air and interferon will never have any use in practical cancer therapy. This week we publish three papers from a Yugoslav group who have been working on interferon for some years, though out of the limelight much of the time. Their experiences may help to balance our views and since interferon is difficult to get and studies are laborious and slow it is valuable to have results of studies which will take a long time for anyone else to repeat. They have used human leucocyte interferon which has been concentrated but not purified and they have therefore been giving quite modest doses of interferon and large amounts of unknown other contaminants. Their main mode of treatment was to infiltrate 2 x 106 units of interferon preparation into a localised but clearly malignant tumour. For instance, 8 patients with recurrent bladder papillomas were treated daily for three weeks and in 4 the tumours regressed completely while in 4 others there was improvement, in 2 making electrocautery possible. Similarly, of 30 patients with carcinomas of the head and neck, mostly of the skin, 10 were completely cured clinically and histologically after a few months of treatment which was daily for two or three weeks and thereafter given 2 or 3 times a week. Of 15 patients with carcinoma of the cervix treated for three weeks before surgery 6 showed either no tumour cells or fewer. One would not have expected any of these patients to improve spontaneously and these reports do provide a prima facie case that the disease was favourably influenced by the treatment given. Of course, many questions are unanswered. Would the apparent "cures" persist? What was the value of the systemic treatment given to a few patients? Did the interferon produce the effect, or one of the contaminants-and hence would the same effect be produced by more refined material? How was the effect produced-by a direct effect on tumour cells, or through the stromal response? Some of the general effects produced by crude interferon are encountered also with very pure interferon,2 so the effects on tumours, if real, could be due to interferon itself.3 We are in debt to some persistent and courageous doctors and some public-spirited and stoical Yugoslav patients for findings which may yet lead to a way of using interferon as part of the treatment regimen for some malignant conditions. 1. Proceedings of Symposium on Clinical Use of Interferon. Zagreb. Yugoslav Academy of Sciences and Arts, 1975 2. Scott GM, Secher DS, Flowers D, Bate J, Cantell K, Tyrrell DAJ. The toxicity of interferon. Br Med J 1981; 282: 1345-48 3. Gresser I, ed. Interferon 1980 London Academic Press, 1980.
Transcript of IS INTERFERON ANY GOOD FOR CANCER?
1037
However, the mechanisms by which such post-exposureprotection is accomplished are by no means clear; vaccine-induced interferon and cellular responses as well as antibodymay be involved. Considerable evidence also indicates thatsome immunological responses of the host are concerned inthe pathogenesis of rabies, and a report by Prabhakar andNathanson3 implicates rabies antibody.The role of antibody as the sole mediator of protection
against rabies has been contentious for more than a decade.4Passive immunisation with rabies antibody alone onlymarginally reduces mortality in experimentally infectedanimals and usually prolongs the incubation period.4,5Conversely, in some animals in which only low levels ofantibody have been induced, the incubation period isreduced. Such animals die earlier than unimmunised controlswhen challenged with rabies virus.6,7 This phenomenon of"early death" was first noted in monkeys during early vaccinetrials.6 In a commentary on the article by Prabhakar andNathanson, Porterfield8 cites several other viral diseases inwhich sub-neutralising doses of antibody enhance viral
replication and stimulate infection rather than protecting the
host. Several explanations have been advanced for earlydeath2 in rabies. One well documented possibility is thatantibody-mediated early death is analogous to immune
cytolysis which occurs when antibody is applied to rabies-infected cell cultures in the presence of complement.9 Thedestruction of neurons either by immune cytolysis or bydirect viral replication may have the same lethal outcome butdiffer in timing. 10 Lytic and neutralising antibodies are foundin the same 7S immunoglobulin fraction of human andanimal sera but vary in concentration.9Porterfield8 discusses the possible involvement of
macrophages and opsonisation of virus-antibody complexes.Other workers suggest that T or K cells might operatethrough some antibody-dependent cellular, cytotoxicmechanism." Prabhakar and Nathanson3 show quiteconvincingly that only the transfer of antibody or B cellsinduced early death in their mouse model; but, as they say, themechanism is not obvious and needs further study.Extrapolation of the results to man should be cautious; thestrain of attenuated virus used differs greatly in biologicalcharacters from typical street virus and the experimentalconditions are hardly those of the naturally acquired disease.Prabhakar and Nathanson refer to reports12,13 in which
patients who were unsuccessfully vaccinated died earlier thandid those who were never vaccinated; nevertheless, otherfactors which influence incubation times cannot be
ignored-for instance, the site and severity of the victims’
3. Prabhakar BS, Nathanson N. Acute rabies death mediated by antibody. Nature 1981;290: 590-91.
4 Koprowski H. Pre and post exposure prophylaxis: present status and current trends. In:Nagano V, Davenport FM, eds. Proceedings of working conference on rabies.Tokyo University of Tokyo Press, 1970: 111-26.
5. Baer GM, Cleary WF. A model in mice for the pathogenesis and treatment of rabies. JInf Dis 1972; 125: 520-27.
6. Sikes RK, Cleary WF, Koprowsky H, Wiktor TJ, Kaplan MM. Effective protection ofmonkeys against death from street virus by post exposure administration of tissue-culture rabies vaccine. Bull World Health Org 1980, 45: 1-11.
Blancou J, Andral B, Andral L. A model in mice for the study of the early-deathphenomenon after vaccination and challenge with rabies virus J Gen Virol 1980; 50:433-35.
8. Porterfield JS Rabies virus. Nature 1981; 290: 542.9. Wiktor TJ, Kuwert EK, Koprowski H Immune lysis of rabies virus-infected cells. J
Immunol 1968, 101:1271-82.10. Murphy FA Rabies pathogenesis. brief review. Arch Virol 1977; 54: 279-97.Tignor GH, Mifune K, Smith AL. Immunopathology of rabies. In: Symposium on
advances in rabies research Atlanta. Center for Disease Control, 1976: 13-19.11. Centro Panamericano de Zoonosis. Human rabies vaccination in the Americas
1969-75. Vigilancia Epidemiologica 1976, 8: no. 912. Held JR, Tierkel ES, Steel JH Rabies in man and animals in the United States
1946-65. Publ Health Rep 1967, 82: 1009-18.
bites, their ages, how promptly vaccine was applied, and howpotent the vaccine was.Immunisation with potent cell-culture vaccine and human
rabies immunoglobulin is the best treatment we can offer tothose exposed to rabies infection. There have so far been noreports of rabies deaths in man when these measures havebeen applied as recommended. While the findings discussedhere may lead to a better understanding of the pathogenesis ofrabies they cast no doubt whatever on the efficacy of existingmethods for immunoprophylaxis.
IS INTERFERON ANY GOOD FOR CANCER?
THE excitement and the unjustified enthusiasm for usinginterferon to treat cancer in man have already subsidedgreatly and one is already hearing comments that it was all hotair and interferon will never have any use in practical cancertherapy. This week we publish three papers from a Yugoslavgroup who have been working on interferon for some years,though out of the limelight much of the time. Theirexperiences may help to balance our views and sinceinterferon is difficult to get and studies are laborious and slowit is valuable to have results of studies which will take a longtime for anyone else to repeat.They have used human leucocyte interferon which has
been concentrated but not purified and they have thereforebeen giving quite modest doses of interferon and largeamounts of unknown other contaminants. Their main modeof treatment was to infiltrate 2 x 106 units of interferonpreparation into a localised but clearly malignant tumour.For instance, 8 patients with recurrent bladder papillomaswere treated daily for three weeks and in 4 the tumoursregressed completely while in 4 others there was
improvement, in 2 making electrocautery possible. Similarly,of 30 patients with carcinomas of the head and neck, mostlyof the skin, 10 were completely cured clinically andhistologically after a few months of treatment which was dailyfor two or three weeks and thereafter given 2 or 3 times aweek. Of 15 patients with carcinoma of the cervix treated forthree weeks before surgery 6 showed either no tumour cells orfewer.One would not have expected any of these patients to
improve spontaneously and these reports do provide a primafacie case that the disease was favourably influenced by thetreatment given. Of course, many questions are unanswered.Would the apparent "cures" persist? What was the valueof the systemic treatment given to a few patients? Didthe interferon produce the effect, or one of thecontaminants-and hence would the same effect be producedby more refined material? How was the effect produced-by adirect effect on tumour cells, or through the stromal
response? Some of the general effects produced by crudeinterferon are encountered also with very pure interferon,2so the effects on tumours, if real, could be due to interferonitself.3 We are in debt to some persistent and courageousdoctors and some public-spirited and stoical Yugoslavpatients for findings which may yet lead to a way of usinginterferon as part of the treatment regimen for some
malignant conditions.
1. Proceedings of Symposium on Clinical Use of Interferon. Zagreb. Yugoslav Academyof Sciences and Arts, 1975
2. Scott GM, Secher DS, Flowers D, Bate J, Cantell K, Tyrrell DAJ. The toxicity ofinterferon. Br Med J 1981; 282: 1345-48
3. Gresser I, ed. Interferon 1980 London Academic Press, 1980.
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