- Email: [email protected]
From dendritic cells to tumour vaccines
Ottawa Conference of Medical Education. Toronto: University of Toronto Bookstore Custom Publishing, 1994: 412-15. 6 Swanson DB. A measurement framework for performance-based tests. In: Hart IR, Harden RM, eds. Further developments in assessing clinical competence. Montreal: Can-Heal, 1987: 13-45. 7 Newble D, Jaeger K. The effect of assessments and examinations on the learning of medical students. Med Educ 1983; 17: 165-71. 8 Jolly BC, Newble DI, Chinner T. The learning effect of repeating content over time in a clinical skills based examination. Teach Learn Med 1993; 5: 66-71.
Mastocytosis:
for better and
worse
Of all the endocrine and metabolic itches,’ mastocytosis is the most logical, mysterious, and intimidating. Logical, because it is no surprise that the release of excessive amounts of histamine and other mast-cell mediators should cause itching, flushing, diarrhoea, and a related panoply of symptoms and signs.2 Mysterious, because that panoply can be so variable: to know mastocytosis is to enter a stream of information that cuts across many fields. Intimidating, because the diagnosis can be difficult to make3, the course hard to predict,4 and the treatment challenging. Systemic forms can occur without obvious cutaneous involvement, and cutaneous mastocytosis can occur with or without systemic involvement, and even without a rash.6,7 Mastocytosis is one of those diseases that physicians fail to think of when they should, or consider only to be proven wrong: ten patients with recurrent unexplained flushing referred to the National Institutes of Health over a nine-year period, mostly with the diagnosis of or mastocytosis idiopathic anaphylaxis, did not earn either diagnosis after intensive evaluation.3 Perhaps they had idiopathic recalcitrant facial flushing syndrome.9 But there histamine release may be intermittent. are caveats: tests for histamine, its metabolites, and other Diagnostic mast-cell products such as tryptase" are not yet always readily available. Small wonder that the failure to establish a diagnosis of mastocytosis leaves some of us persistently uneasy with the idiopathic retreat. Think of the possible fearful outcomes: gradual personality changes; 20 years of episodic headache, flushing, lacrimation, hypotension, and syncope;" or 40 years of mastocytotic diarrhoea without a diagnosis.12 And socalled indolent mastocytosis can occasionally become aggressive, as in mast-cell leukaemia. How occasional is occasionally and how does one watch for it? A Dutch group" with a longstanding interest in mastocytosis and skilled in its chemical evaluation has now followed 16 adult patients with indolent systemic mastocytosis for a median 90 months (range 13-135). Sequential measurements of urinary N’-methylhistamine (MH) and N’-methylimidazoleacetic acid (MIMA) reveal that adult-onset indolent mastocytosis is not always progressive: chemical and clinical evidence of disease can stay the same or decline substantially. None of the 16 developed a myeloproliferative disorder. In two patients, both MH and MIMA excretion decreased, as did their enlarged spleens. In several patients, the changes in MH and MIMA were not concordant. Overall, assay of MH seemed to be a better monitor of the course of indolent mastocytosis than did MIMA, partly because of dietary influences on MIMA concentrations. Until now, the general opinion has been that most children with mastcell disease get better whereas most adults get worse. The Dutch evidence that adult mastocytosis is not always
progressive is welcome-except, perhaps, for one disconcerting implication. Those of us who took some comfort in the notion that worsening over time would ultimately help establish a diagnosis in unclear cases will just have to worry that much longer.
Jeffrey
D Bernhard Dermatology, University of Massachusetts
Division of
Medical Center,
Worcester, MA, USA 1
2 3 4 5 6
7
8
9 10
11 12
13
Bernhard JD. Endocrine itches. In: Bernhard JD, ed. Itch: mechanisms and management of pruritus. New York: McGraw-Hill, 1994: 251-60. Longley J, Duffy TP, Kohn S. The mast cell and mast cell disease. J Am Acad Dermatol 1995; 32: 545-61. Duffy TP. Getting the story right. N Engl J Med 1993; 328: 1333-36. Metcalfe DD. Classification and diagnosis of mastocytosis: current state. J Invest Dermatol 1991; 96: 2s-4s. Austen KF. Systemic mastocytosis. N Engl J Med 1992; 326: 639-40. Kendall ME, Fields JP, King LE. Cutaneous mastocytosis without clinically obvious skin lesions. J Am Acad Dermatol 1984; 10: 903-05. Legrain V, Taïeb A, Bioulac-Sage P, Maleville J. Mastocytose cutanée diffuse sans lésion permanente. Ann Dermatol Venereal 1994; 121: 561-64. Friedman BS, Germano P, Miletti J, Metcalfe DD. A clinicopathologic study of ten patients with recurrent unexplained flushing. J Allergy Clin Immunol 1994; 93: 53-60. Tur E, Ryatt KS, Maibach HI. Idiopathic recalcitrant facial flushing syndrome. Dermatologica 1990; 181: 5-7. Schwartz LB, Metcalf DD, Miller JS, et al. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 1987; 316: 1622-26. Kuter I, Harris NL. Systemic mastocytosis. N Engl J Med 1992; 326: 472-81. Mahood JM, Harrington CI, Slater DN, Corbett CL. Forty years of diarrhoea in a patient with urticaria pigmentosa. Acta Derm Venereal 1982; 62: 264-65. Kors JW, Van Doormaal JJ, Breukelman H, Van Voorst Vade PC, De Monchy JGR. Long-term follow-up of indolent mastocytosis in adults. J Intern Med 1996; 239: 157-64.
From dendritic cells to tumour vaccines One of the chemotherapist’s greatest successes has been the treatment of the lymphomas, yet low-grade for all their chemosensitivity, remain incurable. This continued dismal outlook has prompted oncologists to look for other means of treatment. Immunotherapy is attractive because B-cell lymphomas carry on their surfaces a tumour-specific target. The antibody-combining site of the surface immunoglobulin has a unique molecular structure. This structure, when seen as an antigen, is known as the idiotype. Monoclonal antibodies directed against idiotypes have had some success in treating low-grade lymphomas,1,2 but they are cumbersome and expensive to produce and are unlikely to become a serious treatment option. Active immunisation with idiotypic vaccines overcomes many of the objections to passive serotherapy, and in mice can suppress for the lifetime of the animal. In patients, a lymphoma clinical trial of idiotypic vaccines successfully induced anti-idiotypic immune responses in 20 of 34 cases and in some instances led to tumour regression.4 Unfortunately, idiotype is a weak antigen, and the tumour has already grown with the tolerance of the patient’s immune system. Attempts to increase the immunogenicity of vaccines have employed foreign carrier
lymphomas,
proteins, adjuvants, cytokines, and genetically engineered viruses. 5-7 All these approaches seek to stimulate the processing of antigen and the presentation of antigenic peptides to T cells. Of all the dedicated antigenpresenting cells, the bone-marrow-derived dendritic cell is 705
the most effective.8 These are large cells with elongated stellate processes that are present in most tissues including skin, lymph nodes, spleen, liver, blood, and bone marrow. They express high levels of major histocompatibility complex class I and class II molecules, together with the adhesins ICAM-1 and LFA-3, and the immunostimulatory proteins CD40, CD80, and CD86.9 Dendritic precursor cells can be isolated from peripheral blood by leucapheresis followed by differential centrifugation through Percoll gradients.’° Such cells, allowed to mature in culture in the presence of idiotype, have been used as vaccines first in mice and more recently in patients. In mice, a single immunisation produced
protective immunity against tumour challenge." Levy’s’2 group at Stanford have now used autologous dendritic cells pulsed with idiotypic protein to vaccinate four patients with previously treated follicular lymphoma. Although none produced anti-idiotypic antibody, all produced lymphocytes which, in vitro, were able to proliferate specifically in response to idiotypic protein. One patient showed a specific T-lymphocytotoxic effect against an idiotype-expressing heterohybridoma formed by fusion of the patient’s lymphoma cells with a murine myeloma cell line. In this patient a clinical complete remission was achieved. In another patient, whose disease was detectable only by molecular analysis of blood and bone marrow, resolution was also complete. In a third "’---patient a minor response was seen. These experiments lend support to the concept that useful immune responses against weak antigens such as tumour proteins may be achievable with dendritic cell vaccines. In lymphomas their utility is limited by the need to create a new vaccine for each patient. This process is extremely time consuming, although newer molecular techniques" may lead to acceleration. Tumour antigens represented on most examples of a tumour type-eg, melanomas14 adenocarcinomas15-may be even dendritic cell approach.
MAGE-11
on
or
more
MUC-1 on suitable for the
T J Hamblin Department of Haematology and Oncology, Royal Bournemouth Hospital, Bournemouth, UK 1
2
3
4
5
6
7
8 9
Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B cell lymphoma with monoclonal anti-idiotype therapy. N Engl J Med 1982; 306: 517-22. Hamblin TJ, Cattan AR, Glennie MJ, et al. Initial experience in treating human lymphoma with a chimeric univalent derivative of monoclonal anti-idiotype antibody. Blood 1987; 69: 790-97. George AJ, Folkard SG, Hamblin TJ, Stevenson FK. Idiotypic vaccination as a treatment for B cell lymphoma. J Immunol 1988; 141: 2168-74. Hsu FJ, Kwak KL, Campbell M, et al. Clinical trials of idiotypic specific vaccine in B cell lymphomas. Ann N Y Acad Sci 1993; 690: 385-87. Tao MH, Levy R. Idiotype/granulocyte-macrophage colony stimulating factor fusion protein as a vaccine for B cell lymphoma. Nature 1993; 362: 755-58. Chen TT, Tao MH, Levy R. Idiotype-cytokine fusion proteins as cancer vaccines: relative efficiency of IL-2, IL-4, and granulocytemacrophage colony stimulating factor. J Immunol 1994; 153: 4775-87. McCabe BJ, Irvine KR, Nishimura MI, et al. Minimal determinant expressed by a recombinant vaccinia virus elicits therapeutic antitumour cytolytic T lymphocyte responses. Cancer Res 1995; 55: 1741-47. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9: 271-96. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen cultured human dendritic cells is maintained by granulocyte/ macrophage colony stimulating factor plus interleukin-4 and
706
by
tumour necrosis factor alpha. J Exp Med 1994; 179: 1109-18. Takamizawa M, Fagnoni F, Mehta DA, Rivas A, Engleman EG. Cellular and molecular basis of human gamma delta T activation: role of accessory molecules in alloactivation. J Clin Invest 1995; 95: 296-303. Flamand V, Sornasse T, Thielemans K, et al. Murine dendritic cells pulsed in vitro with tumour antigen induce tumour resistance in vivo. Eur J Immunol 1994; 42: 605-10. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Med 1996; 2: 52-58. Hawkins RE, Zhu D, Ovecka M, et al. Idiotypic vaccination against human B-cell lymphoma: rescue of variable region gene sequences from biopsy material for assembly as single chain Fv personal vaccines. Blood 1994; 83: 3279-88. Marchand M, Brasseur F, van der Bruggen P, Coulie P, Boon T. Perspectives for immunisation of HLA-A1 patients carrying a malignant melanoma expressing gene MAGE-1. Dermatology 1993; 186: 278-80. Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res 1994; 54: 2856-60.
downregulated by
10
11
12
13
14
15
Zinc in the
healing wound
Zinc was identified as an essential trace metal by Raulin’ in 1869, yet it remains an enigma to medical science. It is the second most abundant trace metal in the human body and is present in all living cells and body secretions. Despite extensive research in recent years, scientists and clinicians are still unclear about the regulation of zinc uptake and excretion. Zinc concentrations in an adult range from 95 to 130 I-Lg/100 mL of serum, and as much as 20% of total body content is found in the skin, mainly in the form of zinc metalloenzymes.2 For more than 3000 years, zinc in the form of zinc oxide or calamine has been used in the treatment of skin wounds. Zinc in castor oil still has a special place in the treatment of nappy (diaper) rash. However, only during the past 40 years have serious clinical evaluations of topical or systemic zinc supplementation been conducted in patients with bed sores, venous ulcers, incisional wounds, and pilonidal cysts.3°4 After more than 100 published reports, the precise role of supplementary zinc therapy remains unclear. Early studies claiming that oral zinc accelerated wound healing by as much as 43%3 have not been confirmed, and zincated bandages were not shown to be beneficial in many subsequent trials.5,6 (In individuals with dietary zinc deficiency or hereditary hypozincaemia, zinc therapy is indicated in wound healing.) Nevertheless a vast range of zincated bandages, dressings, emollients, and creams are available commercially, although we still do not know how much additional zinc a wound needs to enhance healing, or to what extent zinc is absorbed and used from the commercial products. Scientific progress in understanding the importance of zinc in the health and wellbeing of skin has been hampered by the low concentrations present in some skin samples (<10 I-Lg/g wet tissue weight) and the lack of sufficiently sensitive analytical techniques. With the introduction of atomic absorption spectrophotometry, more accurate information about zinc metabolism can be obtained. We now know that zinc is a constituent of more than 70 metalloenzymes-notably, carbonic anhydrase, DNA
and RNA polymerases, reverse transcriptase, proteases, and enzymes that have a central role in the
Mastocytosis:
for better and
worse
Of all the endocrine and metabolic itches,’ mastocytosis is the most logical, mysterious, and intimidating. Logical, because it is no surprise that the release of excessive amounts of histamine and other mast-cell mediators should cause itching, flushing, diarrhoea, and a related panoply of symptoms and signs.2 Mysterious, because that panoply can be so variable: to know mastocytosis is to enter a stream of information that cuts across many fields. Intimidating, because the diagnosis can be difficult to make3, the course hard to predict,4 and the treatment challenging. Systemic forms can occur without obvious cutaneous involvement, and cutaneous mastocytosis can occur with or without systemic involvement, and even without a rash.6,7 Mastocytosis is one of those diseases that physicians fail to think of when they should, or consider only to be proven wrong: ten patients with recurrent unexplained flushing referred to the National Institutes of Health over a nine-year period, mostly with the diagnosis of or mastocytosis idiopathic anaphylaxis, did not earn either diagnosis after intensive evaluation.3 Perhaps they had idiopathic recalcitrant facial flushing syndrome.9 But there histamine release may be intermittent. are caveats: tests for histamine, its metabolites, and other Diagnostic mast-cell products such as tryptase" are not yet always readily available. Small wonder that the failure to establish a diagnosis of mastocytosis leaves some of us persistently uneasy with the idiopathic retreat. Think of the possible fearful outcomes: gradual personality changes; 20 years of episodic headache, flushing, lacrimation, hypotension, and syncope;" or 40 years of mastocytotic diarrhoea without a diagnosis.12 And socalled indolent mastocytosis can occasionally become aggressive, as in mast-cell leukaemia. How occasional is occasionally and how does one watch for it? A Dutch group" with a longstanding interest in mastocytosis and skilled in its chemical evaluation has now followed 16 adult patients with indolent systemic mastocytosis for a median 90 months (range 13-135). Sequential measurements of urinary N’-methylhistamine (MH) and N’-methylimidazoleacetic acid (MIMA) reveal that adult-onset indolent mastocytosis is not always progressive: chemical and clinical evidence of disease can stay the same or decline substantially. None of the 16 developed a myeloproliferative disorder. In two patients, both MH and MIMA excretion decreased, as did their enlarged spleens. In several patients, the changes in MH and MIMA were not concordant. Overall, assay of MH seemed to be a better monitor of the course of indolent mastocytosis than did MIMA, partly because of dietary influences on MIMA concentrations. Until now, the general opinion has been that most children with mastcell disease get better whereas most adults get worse. The Dutch evidence that adult mastocytosis is not always
progressive is welcome-except, perhaps, for one disconcerting implication. Those of us who took some comfort in the notion that worsening over time would ultimately help establish a diagnosis in unclear cases will just have to worry that much longer.
Jeffrey
D Bernhard Dermatology, University of Massachusetts
Division of
Medical Center,
Worcester, MA, USA 1
2 3 4 5 6
7
8
9 10
11 12
13
Bernhard JD. Endocrine itches. In: Bernhard JD, ed. Itch: mechanisms and management of pruritus. New York: McGraw-Hill, 1994: 251-60. Longley J, Duffy TP, Kohn S. The mast cell and mast cell disease. J Am Acad Dermatol 1995; 32: 545-61. Duffy TP. Getting the story right. N Engl J Med 1993; 328: 1333-36. Metcalfe DD. Classification and diagnosis of mastocytosis: current state. J Invest Dermatol 1991; 96: 2s-4s. Austen KF. Systemic mastocytosis. N Engl J Med 1992; 326: 639-40. Kendall ME, Fields JP, King LE. Cutaneous mastocytosis without clinically obvious skin lesions. J Am Acad Dermatol 1984; 10: 903-05. Legrain V, Taïeb A, Bioulac-Sage P, Maleville J. Mastocytose cutanée diffuse sans lésion permanente. Ann Dermatol Venereal 1994; 121: 561-64. Friedman BS, Germano P, Miletti J, Metcalfe DD. A clinicopathologic study of ten patients with recurrent unexplained flushing. J Allergy Clin Immunol 1994; 93: 53-60. Tur E, Ryatt KS, Maibach HI. Idiopathic recalcitrant facial flushing syndrome. Dermatologica 1990; 181: 5-7. Schwartz LB, Metcalf DD, Miller JS, et al. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 1987; 316: 1622-26. Kuter I, Harris NL. Systemic mastocytosis. N Engl J Med 1992; 326: 472-81. Mahood JM, Harrington CI, Slater DN, Corbett CL. Forty years of diarrhoea in a patient with urticaria pigmentosa. Acta Derm Venereal 1982; 62: 264-65. Kors JW, Van Doormaal JJ, Breukelman H, Van Voorst Vade PC, De Monchy JGR. Long-term follow-up of indolent mastocytosis in adults. J Intern Med 1996; 239: 157-64.
From dendritic cells to tumour vaccines One of the chemotherapist’s greatest successes has been the treatment of the lymphomas, yet low-grade for all their chemosensitivity, remain incurable. This continued dismal outlook has prompted oncologists to look for other means of treatment. Immunotherapy is attractive because B-cell lymphomas carry on their surfaces a tumour-specific target. The antibody-combining site of the surface immunoglobulin has a unique molecular structure. This structure, when seen as an antigen, is known as the idiotype. Monoclonal antibodies directed against idiotypes have had some success in treating low-grade lymphomas,1,2 but they are cumbersome and expensive to produce and are unlikely to become a serious treatment option. Active immunisation with idiotypic vaccines overcomes many of the objections to passive serotherapy, and in mice can suppress for the lifetime of the animal. In patients, a lymphoma clinical trial of idiotypic vaccines successfully induced anti-idiotypic immune responses in 20 of 34 cases and in some instances led to tumour regression.4 Unfortunately, idiotype is a weak antigen, and the tumour has already grown with the tolerance of the patient’s immune system. Attempts to increase the immunogenicity of vaccines have employed foreign carrier
lymphomas,
proteins, adjuvants, cytokines, and genetically engineered viruses. 5-7 All these approaches seek to stimulate the processing of antigen and the presentation of antigenic peptides to T cells. Of all the dedicated antigenpresenting cells, the bone-marrow-derived dendritic cell is 705
the most effective.8 These are large cells with elongated stellate processes that are present in most tissues including skin, lymph nodes, spleen, liver, blood, and bone marrow. They express high levels of major histocompatibility complex class I and class II molecules, together with the adhesins ICAM-1 and LFA-3, and the immunostimulatory proteins CD40, CD80, and CD86.9 Dendritic precursor cells can be isolated from peripheral blood by leucapheresis followed by differential centrifugation through Percoll gradients.’° Such cells, allowed to mature in culture in the presence of idiotype, have been used as vaccines first in mice and more recently in patients. In mice, a single immunisation produced
protective immunity against tumour challenge." Levy’s’2 group at Stanford have now used autologous dendritic cells pulsed with idiotypic protein to vaccinate four patients with previously treated follicular lymphoma. Although none produced anti-idiotypic antibody, all produced lymphocytes which, in vitro, were able to proliferate specifically in response to idiotypic protein. One patient showed a specific T-lymphocytotoxic effect against an idiotype-expressing heterohybridoma formed by fusion of the patient’s lymphoma cells with a murine myeloma cell line. In this patient a clinical complete remission was achieved. In another patient, whose disease was detectable only by molecular analysis of blood and bone marrow, resolution was also complete. In a third "’---patient a minor response was seen. These experiments lend support to the concept that useful immune responses against weak antigens such as tumour proteins may be achievable with dendritic cell vaccines. In lymphomas their utility is limited by the need to create a new vaccine for each patient. This process is extremely time consuming, although newer molecular techniques" may lead to acceleration. Tumour antigens represented on most examples of a tumour type-eg, melanomas14 adenocarcinomas15-may be even dendritic cell approach.
MAGE-11
on
or
more
MUC-1 on suitable for the
T J Hamblin Department of Haematology and Oncology, Royal Bournemouth Hospital, Bournemouth, UK 1
2
3
4
5
6
7
8 9
Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B cell lymphoma with monoclonal anti-idiotype therapy. N Engl J Med 1982; 306: 517-22. Hamblin TJ, Cattan AR, Glennie MJ, et al. Initial experience in treating human lymphoma with a chimeric univalent derivative of monoclonal anti-idiotype antibody. Blood 1987; 69: 790-97. George AJ, Folkard SG, Hamblin TJ, Stevenson FK. Idiotypic vaccination as a treatment for B cell lymphoma. J Immunol 1988; 141: 2168-74. Hsu FJ, Kwak KL, Campbell M, et al. Clinical trials of idiotypic specific vaccine in B cell lymphomas. Ann N Y Acad Sci 1993; 690: 385-87. Tao MH, Levy R. Idiotype/granulocyte-macrophage colony stimulating factor fusion protein as a vaccine for B cell lymphoma. Nature 1993; 362: 755-58. Chen TT, Tao MH, Levy R. Idiotype-cytokine fusion proteins as cancer vaccines: relative efficiency of IL-2, IL-4, and granulocytemacrophage colony stimulating factor. J Immunol 1994; 153: 4775-87. McCabe BJ, Irvine KR, Nishimura MI, et al. Minimal determinant expressed by a recombinant vaccinia virus elicits therapeutic antitumour cytolytic T lymphocyte responses. Cancer Res 1995; 55: 1741-47. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9: 271-96. Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen cultured human dendritic cells is maintained by granulocyte/ macrophage colony stimulating factor plus interleukin-4 and
706
by
tumour necrosis factor alpha. J Exp Med 1994; 179: 1109-18. Takamizawa M, Fagnoni F, Mehta DA, Rivas A, Engleman EG. Cellular and molecular basis of human gamma delta T activation: role of accessory molecules in alloactivation. J Clin Invest 1995; 95: 296-303. Flamand V, Sornasse T, Thielemans K, et al. Murine dendritic cells pulsed in vitro with tumour antigen induce tumour resistance in vivo. Eur J Immunol 1994; 42: 605-10. Hsu FJ, Benike C, Fagnoni F, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Med 1996; 2: 52-58. Hawkins RE, Zhu D, Ovecka M, et al. Idiotypic vaccination against human B-cell lymphoma: rescue of variable region gene sequences from biopsy material for assembly as single chain Fv personal vaccines. Blood 1994; 83: 3279-88. Marchand M, Brasseur F, van der Bruggen P, Coulie P, Boon T. Perspectives for immunisation of HLA-A1 patients carrying a malignant melanoma expressing gene MAGE-1. Dermatology 1993; 186: 278-80. Kotera Y, Fontenot JD, Pecher G, Metzgar RS, Finn OJ. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients. Cancer Res 1994; 54: 2856-60.
downregulated by
10
11
12
13
14
15
Zinc in the
healing wound
Zinc was identified as an essential trace metal by Raulin’ in 1869, yet it remains an enigma to medical science. It is the second most abundant trace metal in the human body and is present in all living cells and body secretions. Despite extensive research in recent years, scientists and clinicians are still unclear about the regulation of zinc uptake and excretion. Zinc concentrations in an adult range from 95 to 130 I-Lg/100 mL of serum, and as much as 20% of total body content is found in the skin, mainly in the form of zinc metalloenzymes.2 For more than 3000 years, zinc in the form of zinc oxide or calamine has been used in the treatment of skin wounds. Zinc in castor oil still has a special place in the treatment of nappy (diaper) rash. However, only during the past 40 years have serious clinical evaluations of topical or systemic zinc supplementation been conducted in patients with bed sores, venous ulcers, incisional wounds, and pilonidal cysts.3°4 After more than 100 published reports, the precise role of supplementary zinc therapy remains unclear. Early studies claiming that oral zinc accelerated wound healing by as much as 43%3 have not been confirmed, and zincated bandages were not shown to be beneficial in many subsequent trials.5,6 (In individuals with dietary zinc deficiency or hereditary hypozincaemia, zinc therapy is indicated in wound healing.) Nevertheless a vast range of zincated bandages, dressings, emollients, and creams are available commercially, although we still do not know how much additional zinc a wound needs to enhance healing, or to what extent zinc is absorbed and used from the commercial products. Scientific progress in understanding the importance of zinc in the health and wellbeing of skin has been hampered by the low concentrations present in some skin samples (<10 I-Lg/g wet tissue weight) and the lack of sufficiently sensitive analytical techniques. With the introduction of atomic absorption spectrophotometry, more accurate information about zinc metabolism can be obtained. We now know that zinc is a constituent of more than 70 metalloenzymes-notably, carbonic anhydrase, DNA
and RNA polymerases, reverse transcriptase, proteases, and enzymes that have a central role in the