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Immunomodulating agents
J. Descotes and J.C1. Evreux
39
Immunomodulating agents
The use o f agents with immunostimulating properties is now widely accepted and many workers have already reported their own experiences with such agents in cancer immunotherapy and certain other fields. Besides substances of bacterial origin, such as BCG or Corynebacterium parvum, recent years have witnessed considerable developments in chemically defined drugs capable of enhancing or restoring immune competence (1R). This first chapter of the-SEDA series devoted to immunomodulating agents will therefore be an attempt to review current knowledge concerning the reported side effects of these promising new drugs. For much information on levamisole, still largely used as an anthelminthic rather than as an immunostimulant, the reader is referred to Chapter 32 in this and previous volumes. UNTOWARD CONSEQUENCES OF IMMUNOMODULATION Theoretically, immunomodulating agents are used because of their capacity to enhance or restore decreased immunocompetence. Patients with primary immunodeficiency, autoimmune disease or malignant conditions seem likely to benefit from such a therapeutic approach. However, the issue should not be oversimplified; the immunological mechanisms involved and their regulatory counterparts are manifold; quite different processes may thus underlie clinically similar conditions. One given immunopharmacological action of a drug may have diametrically opposite consequences, depending on conditions; for instance, well-known immunostimulants such as BCG may exert immunodepressive activity in certain circumstances (2 R ). Immune facilitation due to overproduction of antibodies blocking the recognition sites of lymphocytes, the induction of suppressor cells or macrophages, or a kinetic response to immunomodulation with depression and stimulation phases, are all possible mecha-
nisms underlying this poorly elucidated phenomenon. Immunodepression and exacerbation o f the primary underlying disease have been reported with levamisole but one may reasonably infer that the same holds true for more recently introduced agents. Thome (3 C) observed reappearance of psoriatic lesions in three patients with dormant disease after starting levamisole and two cases of severe exacerbation of brucellosis. Immune complex-induced vasculitis (4 C, 5 C) and arthritis (6 c ) may be interpreted as aggravations of rheumatoid arthritis and Crohn's disease respectively, in relation to levamisole therapy. Tumor growth enhancement is another possible consequence of levamisole use and has also been reported with thymosin (7 C). Hypersensitivity reactions have been observed following the use of most immunomodulating agents (see below). However, several authors have provided evidence that an Arthus phenomenon might be involved in levamisole-induced hypersensitivity reactions (8 c - 1 0 c). Hence, the question arises whether i m m u n o m o d u l a t i o n itself might n o t be a factor facilitating this kind of infrequent side effect. Febrile reactions are the most frequent complications of immunomodulation. Pyrexia up to 3 9 - 4 0 ~ associated with headache, malaise and asthenia has been often reported with chemically poorly defined drugs such as glucans (1 l c), but nearly any immunomodulating agent is likely to be involved. Several hypotheses have been put forward in an attempt to explain this undesirable property; pyrogenicity is naturally a possible cause when bacterial extracts or even their synthetic analogues, e.g. muramyl-dipeptide (12), are concerned. Interferon administration has, however, also been shown to induce a similar febrile response (13), hence most immunomodulators which induce interferon production may act this way (14R). Finally, macrophage and leukocyte activation, a conse-
367
]mmunomodulating agents quence of immunostimulation, is known to result in secretion of pyrogenic substances into the peripheral blood (13).
this volume, have only recently been introduced. Hence current data derive mainly from phase II and III clinical trials. Azimexone
DRUG INTERACTIONS It is now well established that cytochrome P450-dependent drug oxidizing agents in the endoplasmic reticulum of the liver are of prime importance in the biotransformation of chemicals. Any change in the cytochrome P450 steady-state level may account for drug toxicity. Several experimental and clinical reports have clearly demonstrated that administration of non-specific immunostimulants like BCG or Corynebacterium parvum (15 R) or influenza vaccine (16 C - 17 c ) results in inhibition of hepatic microsomal drugmetabolizing activity. The exact mechanism of this action is not yet elucidated (18R): a direct hepatotoxic effect seems to be involved, at least with immunoadjuvants such as Bordetella pertussis vaccine (19). Interferon deserves particular attention in this respect, since increased interferon production was shown to be associated with decreased hepatic biotransformation activity (15 R). Furthermore, some interferon-inducing agents like tilorone (20), poly (rI. rC) ( 1 9 ) o r pyran copolymers (21) delay hepatic biotransformation of drugs. The liver is not the only target of immunomodulating agents with relevance to biotransformation inhibition: there is some evidence that drugs which alter the phagocytic function of reticuloendothelial ceils are capable of modifying drug metabolism (15R). The actual consequences of these findings in clinical situations remain to be determined. Indeed, antipyrine (16 c ) and theophylline (17 c ) disposition are clearly influenced in humans. The potential importance of this phenomenon in the field of combined cancer chemo-immunotherapy is obvious (15R).
EFFECTS RELATED COMPOUNDS
TO
INDIVIDUAL
Most immunomodulating agents except levamisole, the specific side effects of which are reviewed in another chapter of
Although low doses, e.g. 300 mg, of azimexone are well tolerated, higher doses (900 mg) may induce toxic hemolytic anemia (22c). Bestatine
Serrou et al. (23 C) have reported one case of skin rash in a phase I patient after ingesting a six-months supply o f bestatin in a single dose. These authors concluded, however, that in normal use bestatin is safe, a view so far confirmed by others (24r). Diethyldithio carbamat e (DTC)
Patients complained of burning sensations in the epigastric area and in the limbs, which persisted for a few minutes, following excessively rapid injection of DTC via the intravenous route. Clinical and biological tolerance was otherwise good (25r). Glucan
The intralesional administration of glucan in 11 patients with cutaneous and subcutaneous metastatic tumors was associated with painful local reactions. Fever was observed in five out of six patients receiving doses above 100 mg; it rose to a maximum 39~ in 6 - 1 2 hours after injection and returned to normal within 48 hours. Two of these patients complained of headaches and asthenia (26c). Similar findings were reported by Mansell et al. (27c). Isoprinosine
Isoprinosine is an antiviral agent with immunostimulating capacity. A number of clinical trials have shown the good tolerance of isoprinosine in healthy volunteers as well as in patients with cancer or viral infections (28 R, 29R); the only untoward effects seen were occasional nausea and a transient rise in serum and urinary uric acid with no sequelae. Segond et al. (30c), in the course of an open trial in 14 patients with rheumatoid arthritis, observed nausea with abdominal
368 discomfort in one case, isolated eosinophilia in two cases and l y m p h a d e n i t i s in one case, the latter persisting over a six-month followup period. Po lyinosinic-polycytid ylic acid This double-stranded R N A has been associated with a low t o x i c i t y level so far, nausea, v o m i t i n g and fever having been described (31 R, 32C).
J. Descotes and J.Cl. Evreux
Thymosine and thymic hormones A d m i n i s t r a t i o n o f t h y m o s i n e or t h y m i c factors has usually been associated with few side effects or none. However, Costanzi et al. (33 c ) n o t e d a generalized urticarial rash o n the seventh day o f t h y m o s i n e t r e a t m e n t at a dose o f 50 m g / m 2 ; the rash subsided w i t h o u t therapy over 24 hours. T w o additional patients complained o f a mild febrile reaction and one o f painful local reaction.
REFERENCES 1. Arrigoni-Martelh, E. (1981): Developments in drugs enhancing the immune responses. Meth. Find. exp. clin. PharmacoL, 3, 247. 2. Mathe, G., Schwarzenberg, L., Halle-Panenko, O. and Simmler, M.C. (1976): Experimental and clinical immuno-pharmacology data applicable to cancer immunotherapy. Ann. N.Y. Acad. ScL, 277, 467. 3. Thorne, R.D. (1978): Interpretation and management of levamisole-associated side-effects. In: Immune Modulation and Control of Neoplasia by Adjuvant Therapy, p. 157. Editor: M.A. Chirigos. Raven press, New York. 4. Macfarlane, D.G. and Bacon, P.A. (1978): Side effects of drugs. Levamisoleqnduced vasculitis due to circulating immune complexes. Brit. med. J., 1,407. 5. Scheinberg, M.A., Gomez Bezerra, J.B., Almeida, F.A. and Silveira, L.A. (1978): Cutaneous necrotizing vasculitis induced by levamisole. Brit. med. Z, 1,408. 6. Siklos, P. (1977): Levamisoleqnduced arthritis. Brit. reed. J., 2, 773. 7. Patt, Y.Z., Hersh, E.M., Schafer, L.A. et al. (1978): Clinical and immunological evaluation of the use of thymosin plus BCG • DTIC in adjuvant treatment of stage 3B melanoma. In: Immune Modulation and Control of Neoplasia by Adjuvant Therapy, p. 357. Editor: M.A. Chirigos, Raven Press, New York. 8. Secher, L., Permin, H., Skov, P.S. et al. (1977): Levamisole-induced hypersensitivity. Lancet, 11, 932. 9. Parkinson, D.R., Cano, P.O., Jerry, L.M. et al. (1977): Complication of cancer immunotherapy with levamisole. Lancet, I, 1129. 10. Christiansen, F.T., Ng, K.C., Zilko, P.J. and Dawkins, R.L. (1977): Levamisole-induced hypersensitivity. Lancet, I, 1111. 11. Mansell, P.W.A., Rowden, G. and Hammer, C. (1978): Clinical experience with the use of glucan. In: Immune Modulation and Control Neoplasia by Adjuvant Therapy, p. 255. Editor: M.A. Chirigos. Raven press, New York. 12. Dinarello, C.A., Elin, R.J., Chedid, L. and
Wolff, S.M. (1978): The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues. J. infect. Dis., 138, 760. 13. Bocci, V. (1980): Possible causes of fever after interferon administration. Biomedicine, 32, 16. 14. Pollard, R.B. (1982): Interferons and interferon inducers. Drugs, 23, 37. 15. Mullen, P.W. (1977): Cancer immunotherapy and drug disposition. Brit. J. clin. PharmacoL, 4, 695. 16. Kramer, P. and MeClain, C.J. (1981): Depression of aminopyrine metabolism by influenza vaccination. New Engl. Z Med., 305, 1262. 17. Renton, K.W., Gray, J.D. and Hall, R.I. (1980): Decreased elimination of theophylline after influenza vaccination. Canad. med. Ass. J., 123, 288. 18. Renton, K.W. (1981): Effects of infection and immune stimulation on theophyliine metabolism. Sere. PerinatoL, 5, 378. 19. Renton, K.W. (1979): The deleterious effect of Bordetella pertussis vaccine and poly (rI. r.C) on the metabolism and disposition of phenytoin. J. Pharmacol. exp. Ther., 208, 267. 20. Renton, K.W. and Mannering, G.J. (1976): Depression of the hepatic cytochrome P 450 mono-oxygenase system by administration of tilorone. Drug Metab. Dispos., 4, 223. 21. Giampetri, A., Puccetti, P. and Contessa, A.R. (1981): Depression of hepatic biotransformations by chemical immuno-adjuvants, or. lmmunopharmacol., 3, 251. 22. Bicker, U. (1981): The immunopharmacology of azimexone. In: Advances in Immunopharmacology, p. 457. Editors: J. Hadden, L. Chedid, P. Mullen and F. Spreafico. Pergamon press, New York. 23. Serrou, B., Cupissol, D., Caraux, J. et al. (1980): New immunomodulating agents with immunorestorative potential in cancer patients. In: Cancer Immunology and Parasite Immunology, p. 153. Editors: L. Israel, P. Lagrange and J.C. Salomon. INSERM, Paris. 24. Umezawa, H. (1982): Recent studies on anti-
Immunomodulating agents biotics and small molecular immunomodulators with potential usefulness in treating lung cancer. lnt. J. din. Pharm. Ther. Toxicol., 20, 19. 25. Renoux, G. and Renoux, M. (1981): Immunologic activity of DTC: potential for cancer therapy. In: Augmenting Agents in Cancer Therapy, p. 427. Editor: E.M. Hersh. Raven Press, New York. 26. Israel, L. and Edelstein, R. (1978): Treatment of cutaneous and subcutaneous metastatic tumors with intralesional glucan. In: lmmune
Modulation and Control of Neoplasia by Adjuvant Therapy, p. 249. Editor: M.A. Chirigos. Raven press, New York. 27. Mansell, P.W.A., Rowden, G. and Hammer, C. (1978): Clinical experiences with the use of glucan. In: lmmune Modulation and Control of Neoplasia; by, Adjuvant Therapy, p. 255. Editor: M.A. Chirigos. Raven Press, New York. 28. Chang, T.W. and Heel, R.C. (1981): Rebavirin and inosiplex: a review of their present status in viral diseases. Drugs, 22, 111. 29. Hadden, J.W. and Giner-Sorolla, A. (1981):
369 Isoprinosine and NPT 15392: modulators of lymphocyte and macrophage development and function. In: Augmenting Agents in Cancer Therapy, p. 497. Editor: E.M. Hersch, Raven Press, New York. 30. Segond, P. and Salliere, D., Clerc, D. et al. (1982): Essai de traitement de la polyarthrite rheumatofde par l'isoprimosine. Rev. Rhumat., 49, 45. 31. Pollard, R.B. (1982): Interferon inducers. Drugs, 23, 37. 32. Crane, L.R., Levy, H.B. and Lerner, A.M. (1982): Topical polyinoxinic-polycydiglic and complex in the treatment of recurrent genital herpes. Antimicrob. Agents Chemother., 21, 481. 33. Constanzi, J.J., Harris, N. and Goldstein, A. (1978): Thymosin in patients with disseminated solid tumors: phase I and II results. In:
Immune modulation and Control of Neoplasia by Adjuvant Therapy, p. 373. Editor: M.A. Chirigos. Raven press, New York.
39
Immunomodulating agents
The use o f agents with immunostimulating properties is now widely accepted and many workers have already reported their own experiences with such agents in cancer immunotherapy and certain other fields. Besides substances of bacterial origin, such as BCG or Corynebacterium parvum, recent years have witnessed considerable developments in chemically defined drugs capable of enhancing or restoring immune competence (1R). This first chapter of the-SEDA series devoted to immunomodulating agents will therefore be an attempt to review current knowledge concerning the reported side effects of these promising new drugs. For much information on levamisole, still largely used as an anthelminthic rather than as an immunostimulant, the reader is referred to Chapter 32 in this and previous volumes. UNTOWARD CONSEQUENCES OF IMMUNOMODULATION Theoretically, immunomodulating agents are used because of their capacity to enhance or restore decreased immunocompetence. Patients with primary immunodeficiency, autoimmune disease or malignant conditions seem likely to benefit from such a therapeutic approach. However, the issue should not be oversimplified; the immunological mechanisms involved and their regulatory counterparts are manifold; quite different processes may thus underlie clinically similar conditions. One given immunopharmacological action of a drug may have diametrically opposite consequences, depending on conditions; for instance, well-known immunostimulants such as BCG may exert immunodepressive activity in certain circumstances (2 R ). Immune facilitation due to overproduction of antibodies blocking the recognition sites of lymphocytes, the induction of suppressor cells or macrophages, or a kinetic response to immunomodulation with depression and stimulation phases, are all possible mecha-
nisms underlying this poorly elucidated phenomenon. Immunodepression and exacerbation o f the primary underlying disease have been reported with levamisole but one may reasonably infer that the same holds true for more recently introduced agents. Thome (3 C) observed reappearance of psoriatic lesions in three patients with dormant disease after starting levamisole and two cases of severe exacerbation of brucellosis. Immune complex-induced vasculitis (4 C, 5 C) and arthritis (6 c ) may be interpreted as aggravations of rheumatoid arthritis and Crohn's disease respectively, in relation to levamisole therapy. Tumor growth enhancement is another possible consequence of levamisole use and has also been reported with thymosin (7 C). Hypersensitivity reactions have been observed following the use of most immunomodulating agents (see below). However, several authors have provided evidence that an Arthus phenomenon might be involved in levamisole-induced hypersensitivity reactions (8 c - 1 0 c). Hence, the question arises whether i m m u n o m o d u l a t i o n itself might n o t be a factor facilitating this kind of infrequent side effect. Febrile reactions are the most frequent complications of immunomodulation. Pyrexia up to 3 9 - 4 0 ~ associated with headache, malaise and asthenia has been often reported with chemically poorly defined drugs such as glucans (1 l c), but nearly any immunomodulating agent is likely to be involved. Several hypotheses have been put forward in an attempt to explain this undesirable property; pyrogenicity is naturally a possible cause when bacterial extracts or even their synthetic analogues, e.g. muramyl-dipeptide (12), are concerned. Interferon administration has, however, also been shown to induce a similar febrile response (13), hence most immunomodulators which induce interferon production may act this way (14R). Finally, macrophage and leukocyte activation, a conse-
367
]mmunomodulating agents quence of immunostimulation, is known to result in secretion of pyrogenic substances into the peripheral blood (13).
this volume, have only recently been introduced. Hence current data derive mainly from phase II and III clinical trials. Azimexone
DRUG INTERACTIONS It is now well established that cytochrome P450-dependent drug oxidizing agents in the endoplasmic reticulum of the liver are of prime importance in the biotransformation of chemicals. Any change in the cytochrome P450 steady-state level may account for drug toxicity. Several experimental and clinical reports have clearly demonstrated that administration of non-specific immunostimulants like BCG or Corynebacterium parvum (15 R) or influenza vaccine (16 C - 17 c ) results in inhibition of hepatic microsomal drugmetabolizing activity. The exact mechanism of this action is not yet elucidated (18R): a direct hepatotoxic effect seems to be involved, at least with immunoadjuvants such as Bordetella pertussis vaccine (19). Interferon deserves particular attention in this respect, since increased interferon production was shown to be associated with decreased hepatic biotransformation activity (15 R). Furthermore, some interferon-inducing agents like tilorone (20), poly (rI. rC) ( 1 9 ) o r pyran copolymers (21) delay hepatic biotransformation of drugs. The liver is not the only target of immunomodulating agents with relevance to biotransformation inhibition: there is some evidence that drugs which alter the phagocytic function of reticuloendothelial ceils are capable of modifying drug metabolism (15R). The actual consequences of these findings in clinical situations remain to be determined. Indeed, antipyrine (16 c ) and theophylline (17 c ) disposition are clearly influenced in humans. The potential importance of this phenomenon in the field of combined cancer chemo-immunotherapy is obvious (15R).
EFFECTS RELATED COMPOUNDS
TO
INDIVIDUAL
Most immunomodulating agents except levamisole, the specific side effects of which are reviewed in another chapter of
Although low doses, e.g. 300 mg, of azimexone are well tolerated, higher doses (900 mg) may induce toxic hemolytic anemia (22c). Bestatine
Serrou et al. (23 C) have reported one case of skin rash in a phase I patient after ingesting a six-months supply o f bestatin in a single dose. These authors concluded, however, that in normal use bestatin is safe, a view so far confirmed by others (24r). Diethyldithio carbamat e (DTC)
Patients complained of burning sensations in the epigastric area and in the limbs, which persisted for a few minutes, following excessively rapid injection of DTC via the intravenous route. Clinical and biological tolerance was otherwise good (25r). Glucan
The intralesional administration of glucan in 11 patients with cutaneous and subcutaneous metastatic tumors was associated with painful local reactions. Fever was observed in five out of six patients receiving doses above 100 mg; it rose to a maximum 39~ in 6 - 1 2 hours after injection and returned to normal within 48 hours. Two of these patients complained of headaches and asthenia (26c). Similar findings were reported by Mansell et al. (27c). Isoprinosine
Isoprinosine is an antiviral agent with immunostimulating capacity. A number of clinical trials have shown the good tolerance of isoprinosine in healthy volunteers as well as in patients with cancer or viral infections (28 R, 29R); the only untoward effects seen were occasional nausea and a transient rise in serum and urinary uric acid with no sequelae. Segond et al. (30c), in the course of an open trial in 14 patients with rheumatoid arthritis, observed nausea with abdominal
368 discomfort in one case, isolated eosinophilia in two cases and l y m p h a d e n i t i s in one case, the latter persisting over a six-month followup period. Po lyinosinic-polycytid ylic acid This double-stranded R N A has been associated with a low t o x i c i t y level so far, nausea, v o m i t i n g and fever having been described (31 R, 32C).
J. Descotes and J.Cl. Evreux
Thymosine and thymic hormones A d m i n i s t r a t i o n o f t h y m o s i n e or t h y m i c factors has usually been associated with few side effects or none. However, Costanzi et al. (33 c ) n o t e d a generalized urticarial rash o n the seventh day o f t h y m o s i n e t r e a t m e n t at a dose o f 50 m g / m 2 ; the rash subsided w i t h o u t therapy over 24 hours. T w o additional patients complained o f a mild febrile reaction and one o f painful local reaction.
REFERENCES 1. Arrigoni-Martelh, E. (1981): Developments in drugs enhancing the immune responses. Meth. Find. exp. clin. PharmacoL, 3, 247. 2. Mathe, G., Schwarzenberg, L., Halle-Panenko, O. and Simmler, M.C. (1976): Experimental and clinical immuno-pharmacology data applicable to cancer immunotherapy. Ann. N.Y. Acad. ScL, 277, 467. 3. Thorne, R.D. (1978): Interpretation and management of levamisole-associated side-effects. In: Immune Modulation and Control of Neoplasia by Adjuvant Therapy, p. 157. Editor: M.A. Chirigos. Raven press, New York. 4. Macfarlane, D.G. and Bacon, P.A. (1978): Side effects of drugs. Levamisoleqnduced vasculitis due to circulating immune complexes. Brit. med. J., 1,407. 5. Scheinberg, M.A., Gomez Bezerra, J.B., Almeida, F.A. and Silveira, L.A. (1978): Cutaneous necrotizing vasculitis induced by levamisole. Brit. med. Z, 1,408. 6. Siklos, P. (1977): Levamisoleqnduced arthritis. Brit. reed. J., 2, 773. 7. Patt, Y.Z., Hersh, E.M., Schafer, L.A. et al. (1978): Clinical and immunological evaluation of the use of thymosin plus BCG • DTIC in adjuvant treatment of stage 3B melanoma. In: Immune Modulation and Control of Neoplasia by Adjuvant Therapy, p. 357. Editor: M.A. Chirigos, Raven Press, New York. 8. Secher, L., Permin, H., Skov, P.S. et al. (1977): Levamisole-induced hypersensitivity. Lancet, 11, 932. 9. Parkinson, D.R., Cano, P.O., Jerry, L.M. et al. (1977): Complication of cancer immunotherapy with levamisole. Lancet, I, 1129. 10. Christiansen, F.T., Ng, K.C., Zilko, P.J. and Dawkins, R.L. (1977): Levamisole-induced hypersensitivity. Lancet, I, 1111. 11. Mansell, P.W.A., Rowden, G. and Hammer, C. (1978): Clinical experience with the use of glucan. In: Immune Modulation and Control Neoplasia by Adjuvant Therapy, p. 255. Editor: M.A. Chirigos. Raven press, New York. 12. Dinarello, C.A., Elin, R.J., Chedid, L. and
Wolff, S.M. (1978): The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues. J. infect. Dis., 138, 760. 13. Bocci, V. (1980): Possible causes of fever after interferon administration. Biomedicine, 32, 16. 14. Pollard, R.B. (1982): Interferons and interferon inducers. Drugs, 23, 37. 15. Mullen, P.W. (1977): Cancer immunotherapy and drug disposition. Brit. J. clin. PharmacoL, 4, 695. 16. Kramer, P. and MeClain, C.J. (1981): Depression of aminopyrine metabolism by influenza vaccination. New Engl. Z Med., 305, 1262. 17. Renton, K.W., Gray, J.D. and Hall, R.I. (1980): Decreased elimination of theophylline after influenza vaccination. Canad. med. Ass. J., 123, 288. 18. Renton, K.W. (1981): Effects of infection and immune stimulation on theophyliine metabolism. Sere. PerinatoL, 5, 378. 19. Renton, K.W. (1979): The deleterious effect of Bordetella pertussis vaccine and poly (rI. r.C) on the metabolism and disposition of phenytoin. J. Pharmacol. exp. Ther., 208, 267. 20. Renton, K.W. and Mannering, G.J. (1976): Depression of the hepatic cytochrome P 450 mono-oxygenase system by administration of tilorone. Drug Metab. Dispos., 4, 223. 21. Giampetri, A., Puccetti, P. and Contessa, A.R. (1981): Depression of hepatic biotransformations by chemical immuno-adjuvants, or. lmmunopharmacol., 3, 251. 22. Bicker, U. (1981): The immunopharmacology of azimexone. In: Advances in Immunopharmacology, p. 457. Editors: J. Hadden, L. Chedid, P. Mullen and F. Spreafico. Pergamon press, New York. 23. Serrou, B., Cupissol, D., Caraux, J. et al. (1980): New immunomodulating agents with immunorestorative potential in cancer patients. In: Cancer Immunology and Parasite Immunology, p. 153. Editors: L. Israel, P. Lagrange and J.C. Salomon. INSERM, Paris. 24. Umezawa, H. (1982): Recent studies on anti-
Immunomodulating agents biotics and small molecular immunomodulators with potential usefulness in treating lung cancer. lnt. J. din. Pharm. Ther. Toxicol., 20, 19. 25. Renoux, G. and Renoux, M. (1981): Immunologic activity of DTC: potential for cancer therapy. In: Augmenting Agents in Cancer Therapy, p. 427. Editor: E.M. Hersh. Raven Press, New York. 26. Israel, L. and Edelstein, R. (1978): Treatment of cutaneous and subcutaneous metastatic tumors with intralesional glucan. In: lmmune
Modulation and Control of Neoplasia by Adjuvant Therapy, p. 249. Editor: M.A. Chirigos. Raven press, New York. 27. Mansell, P.W.A., Rowden, G. and Hammer, C. (1978): Clinical experiences with the use of glucan. In: lmmune Modulation and Control of Neoplasia; by, Adjuvant Therapy, p. 255. Editor: M.A. Chirigos. Raven Press, New York. 28. Chang, T.W. and Heel, R.C. (1981): Rebavirin and inosiplex: a review of their present status in viral diseases. Drugs, 22, 111. 29. Hadden, J.W. and Giner-Sorolla, A. (1981):
369 Isoprinosine and NPT 15392: modulators of lymphocyte and macrophage development and function. In: Augmenting Agents in Cancer Therapy, p. 497. Editor: E.M. Hersch, Raven Press, New York. 30. Segond, P. and Salliere, D., Clerc, D. et al. (1982): Essai de traitement de la polyarthrite rheumatofde par l'isoprimosine. Rev. Rhumat., 49, 45. 31. Pollard, R.B. (1982): Interferon inducers. Drugs, 23, 37. 32. Crane, L.R., Levy, H.B. and Lerner, A.M. (1982): Topical polyinoxinic-polycydiglic and complex in the treatment of recurrent genital herpes. Antimicrob. Agents Chemother., 21, 481. 33. Constanzi, J.J., Harris, N. and Goldstein, A. (1978): Thymosin in patients with disseminated solid tumors: phase I and II results. In:
Immune modulation and Control of Neoplasia by Adjuvant Therapy, p. 373. Editor: M.A. Chirigos. Raven press, New York.