- Email: [email protected]
Sunlight, DNA Repair, and Skin Cancer
1362
The possibility of an increased risk of cardiovascular death associated with TUR is very
worrying. To what might this result be attributed? The technique of TUR has to be learnt with practice; whilst the expert can remove 60 g of prostate an hour, beginners may manage only 10-20 g an hour. Resection time should not exceed 1 hour. Usually 35-50 g is resected in 30-50 min by skilled urologists,’ but retrospective studies from single centres have shown that in 45-50% of operations less than 10 g is removed,26 which
be
of the main reasons after TUR. The why reoperation longer and more complex the resection, the greater the incidence of perioperative and postoperative complications 3,11 and it seems likely that there would also be greater risk of subsequent problems. The report of the international study1 gives no information about size of TUR resection or length or type of anaesthetic. The metabolic consequences of TUR, in particular of extravasation, are well recognised" but their long-term effects are unknown. During the period from which the study data were obtained, different irrigation solutions (eg, water, glycine, and sorbitol) would have been used in different centres, and even now there is no unanimous choice. There are almost no data about cardiac performance during simple, prolonged, or complicated TUR. A study in 1970 found that, in an unselected group of 30 men, cardiac output fell by an average of 17% during and after the operation, and blood volume fell in half the patients but was only gross enough in 3 to cause a fall in central venous pressure.12 In a much smaller study of 9 men with overt cardiac disease, left atrial pressure rose to a dangerous level without a concomitant rise in right atrial pressure.13 Similarly, there is no information about activation of coagulation factors or platelets during the procedure. What should be done next? Calls for controlled, randomised trials would be naive and inappropriate. Much more basic information on the medical state of the patients is required first. Although patients may appear fit, many will be hypertensive and not on regular treatment, and many will have ischaemic heart disease which may be symptomless. Information on cardiac function during both simple and complicated procedures is essential, and needs to be correlated with careful measurements of electrolyte disturbances, type of irrigation fluids, and length of anaesthesia. Any progress in this area will require identification of one or more perioperative events that correlate with an increasing relative risk of cardiovascular mortality. The urologists’ boat is being rocked and there is no room for complacency. is
must
one
more common
11. Rao PN. Fluid absorption during urological endoscopy. Br J Urol 1987; 60: 93-99. 12. Mebust WK, Brady TW, Valk WL. Observations on cardiac output, blood volume, central venous pressure, fluid and electrolyte changes in patients undergoing transurethral prostatectomy. J Urol 1970; 103: 632-37. 13. De Angelis J, Chang P, Kaplan JH, et al. Hemodynamic changes during prostatectomy in cardiac patients. Crit Care Med 1982; 10: 38-40.
Sunlight,
DNA Repair, and Skin Cancer
THE ability of certain physical and chemical agents in the environment to cause cancer is widely attributed to their capacity to interact with and modify genetic material. For example, radiation from the ultraviolet end of the sun’s emission spectrum is absorbed by pyrimidines and purines, whose unsaturated chemical
permit formation of intrastrand, usually thymine, dimers. These bulky lesions distort the duplex structure of DNA, blocking both replication and transcription, and are potentially mutagenic or bonds
lethal if left uncorrected. However, since genetic continuity and genomic stability are prerequisites for maintenance of cellular life, almost all prokaryotic and eukaryotic organisms have evolved mechanisms to repair such damage. Studies of the uncommon autosomal recessive disorder xeroderma pigmentosum have provided evidence for an association between mutagenesis with cancer formation and poor DNA repair. Clinical features of the disease are essentially those of exaggerated sunlight-induced acute and chronic skin damage, including increased susceptibility to sunburning, premature ageing, and a severalthousand-fold increased risk of skin cancer.1 At the cellular level, sunlight sensitivity is shown by hypersensitivity of cultured cells to the deleterious effects of short-wavelength ultraviolet radiation and of various chemical carcinogens. Such cells consistently show reduced repair of ultraviolet-induced cellular
DNA damage, a multistep enzymatic process of strand incision adjacent to the lesion, dimer excision, resynthesis, and rejoining. In patients with classic xeroderma pigmentosum, the defect appears to occur at the incisional step, since prokaryotic ultraviolet-radiation-specific endonuclease introduced into "permeabilised" cells alleviates the deficiency.Genetic studies have documented nine subgroups (complementation groups A-1) of the disease, each with a different type of mutation, suggesting that at least nine different gene products are necessary for the incisional step. The different mutations corresponding to each complementation group lead to different capacities for residual excision repair (expressed as unscheduled DNA synthesis) that correlate broadly with clinical severity. At one extreme, group A patients (unscheduled DNA synthesis < 5 % of normal) have pronounced sunburn susceptibility, early skin cancers, and in most cases
neurological deficiency. By contrast, patients in the very rare group E (unscheduled DNA synthesis 40-60%) are only mildly affected, with skin
1. Kraemer
KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular and neurological abnormalities in 830 published cases. Arch Dermatol 1987, 123: 241-50.
2. Hanawalt
PC, Cooper PK, Ganesan A, Smith CA. DNA repair in bacteria and mammalian cells. Ann Rev Biochem 1979; 48: 783-836.
1363
malignancy, mostly basal cell carcinoma, not appearing before about 15 years of age. The molecular defect in xeroderma pigmentosum is unknown, but Chu and Chang3 have lately shown that a nuclear factor capable of binding specifically to DNA damaged by ultraviolet radiation, and therefore possibly instrumental in DNA repair, is absent in complementation group E. A sixty-five base-pair DNA fragment (f65) with eight consecutive thymine constructed as a target for ultraviolet dimer induction. After incubation of pyrimidine nuclear extracts from HeLa cells with ultravioletirradiated f65 probe DNA, gel electrophoresis showed two major bands of protein-DNA complexes, designated B1and B2. Formation of such complexes was unaffected by the presence of unlabelled f65 DNA or of DNA from salmon sperm but inhibited by ultraviolet-irradiated DNA, suggesting preferential
residues
was
binding damaged DNA, probably cyclobutane pyrimidine dimers. The affinity of the Bl factor was ten times greater for ultraviolet-damaged than for intact DNA, whereas that of the B2 factor was a to
to
hundred times greater. Several thousand of each of these molecules, designated damaged DNA binding factors DDBF1 and DDBF2, appear to be present in every HeLa cell. When the eight xeroderma pigmentosum complementation groups A to H were surveyed for binding activity, DDBF1 and DDBF2 were not detected in complementation group E, whereas cells from all the other groups contained both bands. Moreover, the absence of specific binding activity in group E could be corrected by addition of nuclear extract from any other group, indicating that the cause of the group E defect was not a binding inhibitory factor. An autosomal recessive disorder such as xeroderma pigmentosum with a genetic defect at both alleles of a single locus is unlikely to result in the absence of two distinct proteins. Possible explanations include processing of a single polypeptide to yield both factors or inability of a second factor to bind to damaged DNA unless complexed with the protein absent in group E, similar to the DNA repair system of Escherichia coli.4 The mild clinical features of group E patients also suggest that even very low levels of DDBFl and DDBF2, undetectable in these experiments, might permit moderately effective DNA repair, or that other mechanisms may allow partial
repair instead. The
exact implications of these and the of the defect in the other nature investigations complementation groups remain to be determined. Other new work on related clinical disorders has contributed to our understanding of the important processes of cellular DNA repair and their role in limiting cell mutagenesis and carcinogenesis. Defective DNA repair, particularly of actively 3 Chu G, Chang E Xeroderma pigmentosum group E cells lack a nuclear factor that binds to damaged DNA Science 1988; 242: 564-67. 4 Kacinski B, Rupp W E coli uvrB protein binds to DNA in the presence of uvrA
protein Nature 1981, 294: 480-81.
and hypermutability following ultraviolet irradiation6are also features of the rare autosomal recessive Cockayne’s syndrome (photosensitivity, dwarfism, and retinal and neurological degeneration), but on this occasion the risk of cancer is not increased.Studies of immune function may
transcribing genes,5
provide an explanation. Bridges8 originally speculated that reduced DNA repair capacity in xeroderma pigmentosum may not account for increased cancer susceptibility unless immune surveillance is defective. Defective adaptive immune responses, including cutaneous reactions to DNCB and recall antigens9-12 and lymphocyte proliferation in response to phytohaemagglutinin,9-12 have been reported, although not in all patients,13 and more recently a striking deficiency in natural killer cell function has also been described.14 However, both T lymphocyte and natural killer cell mediated responses are normal in Cockayne’s syndrome. 15 Increased skin cancer risk in xeroderma pigmentosum may therefore result both from defective repair of ultraviolet-induced DNA damage, with consequent somatic mutation, and from impaired natural killer cell surveillance. Since each of these functions appears to be an essential protective mechanism against the growing threat of skin cancer, 16 continuing research in this area is a matter of
increasing public concern.
ROUTINE H2-RECEPTOR ANTAGONISTS BEFORE ELECTIVE SURGERY? ASPIRATION pneumonia after regurgitation of gastric acid is an important cause of anaesthetic morbidity and mortality. This condition is a particular hazard of obstetric anaesthesia, but also occurs in non-obstetric practice. Patients at special risk include those with gross obesity, hiatus hernia, or gastroduodenal obstruction.1 There is also an increased risk in patients who require emergency surgery. In such high-risk groups, it is customary to take precautions 5
Mayne LV, Mullenders LHF, van Zeeland AA. Cockayne’s syndrome. a UV sensitive disorder with a defect in the repair of transcribing DNA but normal overall excision
repair. In Friedberg E, Hanawalt P, eds. Mechanisms and consequences of DNA damage processing New York A. R. Liss 1988; 349-53. 6. Arlett CF. Mutagenesis in repair-deficient human cell strains. In: Alacevic M, ed. Progress in environmental mutagenesis. Amsterdam: Elsevier/North Holland, 1980: 161-74.
Cockayne’s syndrome and trichothiodystrophy: defective repair without cancer. Cancer Rev 1987; 7: 82-103. 8. Bridges BA. How important are somatic cell mutations and immune control in skin cancer? Reflections on xeroderma pigmentosum. Carcinogenesis 1981, 2: 471-72 9. Dupuy JM, Lafforet D. A defect of cellular immunity in xeroderma pigmentosum. Clin Immunol immunopathol 1974; 3: 52-58. 10 Salamon T, Stojakovic M, Bogdanovic B. Delayed hypersensitivity in xeroderma pigmentosum. Arch Dermatol Forsch 1975; 251: 277-80. 11. Morison WL, Bucana C, Hasem N, et al. Impaired immune function in patients with xeroderma pigmentosum Cancer Res 1985, 45: 3929-31 12. Wysenbeek AJ, Weiss H, Duczyminer-Kahana M, Grunwald MH, Pick AI Immunologic alterations in xeroderma pigmentosum patients. Cancer 1986; 58: 219-21 13 Berkel AI, Kiran O. Immunological studies in children with xeroderma pigmentosum. Turk J Paed 1974, 16: 43-52 14. Norns PG, Limb GA, Hamblin AS, Hawk JLM. Natural killer cell activity is impaired in xeroderma pigmentosum. N Engl J Med 1988; 319: 1668-69. 15 Noms PG, Limb A, Hamblin A, Cole Arlett CF, Hawk JLM. Lymphocyte mutation, natural killer cell activity and lymphocyte proliferative responses in xeroderma pigmentosum and Cockayne’s syndrome. Proceedings of the 10th International 7. Lehmann AR.
Congress on Photobiology (in press). 16 Russell Jones R. Ozone depletion and cancer risk. Lancet 1988, ii 443-46 1. Coombs DW. Aspiration pneumonia prophylaxis Anesth Analg 1983, 62: 1055-58
The possibility of an increased risk of cardiovascular death associated with TUR is very
worrying. To what might this result be attributed? The technique of TUR has to be learnt with practice; whilst the expert can remove 60 g of prostate an hour, beginners may manage only 10-20 g an hour. Resection time should not exceed 1 hour. Usually 35-50 g is resected in 30-50 min by skilled urologists,’ but retrospective studies from single centres have shown that in 45-50% of operations less than 10 g is removed,26 which
be
of the main reasons after TUR. The why reoperation longer and more complex the resection, the greater the incidence of perioperative and postoperative complications 3,11 and it seems likely that there would also be greater risk of subsequent problems. The report of the international study1 gives no information about size of TUR resection or length or type of anaesthetic. The metabolic consequences of TUR, in particular of extravasation, are well recognised" but their long-term effects are unknown. During the period from which the study data were obtained, different irrigation solutions (eg, water, glycine, and sorbitol) would have been used in different centres, and even now there is no unanimous choice. There are almost no data about cardiac performance during simple, prolonged, or complicated TUR. A study in 1970 found that, in an unselected group of 30 men, cardiac output fell by an average of 17% during and after the operation, and blood volume fell in half the patients but was only gross enough in 3 to cause a fall in central venous pressure.12 In a much smaller study of 9 men with overt cardiac disease, left atrial pressure rose to a dangerous level without a concomitant rise in right atrial pressure.13 Similarly, there is no information about activation of coagulation factors or platelets during the procedure. What should be done next? Calls for controlled, randomised trials would be naive and inappropriate. Much more basic information on the medical state of the patients is required first. Although patients may appear fit, many will be hypertensive and not on regular treatment, and many will have ischaemic heart disease which may be symptomless. Information on cardiac function during both simple and complicated procedures is essential, and needs to be correlated with careful measurements of electrolyte disturbances, type of irrigation fluids, and length of anaesthesia. Any progress in this area will require identification of one or more perioperative events that correlate with an increasing relative risk of cardiovascular mortality. The urologists’ boat is being rocked and there is no room for complacency. is
must
one
more common
11. Rao PN. Fluid absorption during urological endoscopy. Br J Urol 1987; 60: 93-99. 12. Mebust WK, Brady TW, Valk WL. Observations on cardiac output, blood volume, central venous pressure, fluid and electrolyte changes in patients undergoing transurethral prostatectomy. J Urol 1970; 103: 632-37. 13. De Angelis J, Chang P, Kaplan JH, et al. Hemodynamic changes during prostatectomy in cardiac patients. Crit Care Med 1982; 10: 38-40.
Sunlight,
DNA Repair, and Skin Cancer
THE ability of certain physical and chemical agents in the environment to cause cancer is widely attributed to their capacity to interact with and modify genetic material. For example, radiation from the ultraviolet end of the sun’s emission spectrum is absorbed by pyrimidines and purines, whose unsaturated chemical
permit formation of intrastrand, usually thymine, dimers. These bulky lesions distort the duplex structure of DNA, blocking both replication and transcription, and are potentially mutagenic or bonds
lethal if left uncorrected. However, since genetic continuity and genomic stability are prerequisites for maintenance of cellular life, almost all prokaryotic and eukaryotic organisms have evolved mechanisms to repair such damage. Studies of the uncommon autosomal recessive disorder xeroderma pigmentosum have provided evidence for an association between mutagenesis with cancer formation and poor DNA repair. Clinical features of the disease are essentially those of exaggerated sunlight-induced acute and chronic skin damage, including increased susceptibility to sunburning, premature ageing, and a severalthousand-fold increased risk of skin cancer.1 At the cellular level, sunlight sensitivity is shown by hypersensitivity of cultured cells to the deleterious effects of short-wavelength ultraviolet radiation and of various chemical carcinogens. Such cells consistently show reduced repair of ultraviolet-induced cellular
DNA damage, a multistep enzymatic process of strand incision adjacent to the lesion, dimer excision, resynthesis, and rejoining. In patients with classic xeroderma pigmentosum, the defect appears to occur at the incisional step, since prokaryotic ultraviolet-radiation-specific endonuclease introduced into "permeabilised" cells alleviates the deficiency.Genetic studies have documented nine subgroups (complementation groups A-1) of the disease, each with a different type of mutation, suggesting that at least nine different gene products are necessary for the incisional step. The different mutations corresponding to each complementation group lead to different capacities for residual excision repair (expressed as unscheduled DNA synthesis) that correlate broadly with clinical severity. At one extreme, group A patients (unscheduled DNA synthesis < 5 % of normal) have pronounced sunburn susceptibility, early skin cancers, and in most cases
neurological deficiency. By contrast, patients in the very rare group E (unscheduled DNA synthesis 40-60%) are only mildly affected, with skin
1. Kraemer
KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular and neurological abnormalities in 830 published cases. Arch Dermatol 1987, 123: 241-50.
2. Hanawalt
PC, Cooper PK, Ganesan A, Smith CA. DNA repair in bacteria and mammalian cells. Ann Rev Biochem 1979; 48: 783-836.
1363
malignancy, mostly basal cell carcinoma, not appearing before about 15 years of age. The molecular defect in xeroderma pigmentosum is unknown, but Chu and Chang3 have lately shown that a nuclear factor capable of binding specifically to DNA damaged by ultraviolet radiation, and therefore possibly instrumental in DNA repair, is absent in complementation group E. A sixty-five base-pair DNA fragment (f65) with eight consecutive thymine constructed as a target for ultraviolet dimer induction. After incubation of pyrimidine nuclear extracts from HeLa cells with ultravioletirradiated f65 probe DNA, gel electrophoresis showed two major bands of protein-DNA complexes, designated B1and B2. Formation of such complexes was unaffected by the presence of unlabelled f65 DNA or of DNA from salmon sperm but inhibited by ultraviolet-irradiated DNA, suggesting preferential
residues
was
binding damaged DNA, probably cyclobutane pyrimidine dimers. The affinity of the Bl factor was ten times greater for ultraviolet-damaged than for intact DNA, whereas that of the B2 factor was a to
to
hundred times greater. Several thousand of each of these molecules, designated damaged DNA binding factors DDBF1 and DDBF2, appear to be present in every HeLa cell. When the eight xeroderma pigmentosum complementation groups A to H were surveyed for binding activity, DDBF1 and DDBF2 were not detected in complementation group E, whereas cells from all the other groups contained both bands. Moreover, the absence of specific binding activity in group E could be corrected by addition of nuclear extract from any other group, indicating that the cause of the group E defect was not a binding inhibitory factor. An autosomal recessive disorder such as xeroderma pigmentosum with a genetic defect at both alleles of a single locus is unlikely to result in the absence of two distinct proteins. Possible explanations include processing of a single polypeptide to yield both factors or inability of a second factor to bind to damaged DNA unless complexed with the protein absent in group E, similar to the DNA repair system of Escherichia coli.4 The mild clinical features of group E patients also suggest that even very low levels of DDBFl and DDBF2, undetectable in these experiments, might permit moderately effective DNA repair, or that other mechanisms may allow partial
repair instead. The
exact implications of these and the of the defect in the other nature investigations complementation groups remain to be determined. Other new work on related clinical disorders has contributed to our understanding of the important processes of cellular DNA repair and their role in limiting cell mutagenesis and carcinogenesis. Defective DNA repair, particularly of actively 3 Chu G, Chang E Xeroderma pigmentosum group E cells lack a nuclear factor that binds to damaged DNA Science 1988; 242: 564-67. 4 Kacinski B, Rupp W E coli uvrB protein binds to DNA in the presence of uvrA
protein Nature 1981, 294: 480-81.
and hypermutability following ultraviolet irradiation6are also features of the rare autosomal recessive Cockayne’s syndrome (photosensitivity, dwarfism, and retinal and neurological degeneration), but on this occasion the risk of cancer is not increased.Studies of immune function may
transcribing genes,5
provide an explanation. Bridges8 originally speculated that reduced DNA repair capacity in xeroderma pigmentosum may not account for increased cancer susceptibility unless immune surveillance is defective. Defective adaptive immune responses, including cutaneous reactions to DNCB and recall antigens9-12 and lymphocyte proliferation in response to phytohaemagglutinin,9-12 have been reported, although not in all patients,13 and more recently a striking deficiency in natural killer cell function has also been described.14 However, both T lymphocyte and natural killer cell mediated responses are normal in Cockayne’s syndrome. 15 Increased skin cancer risk in xeroderma pigmentosum may therefore result both from defective repair of ultraviolet-induced DNA damage, with consequent somatic mutation, and from impaired natural killer cell surveillance. Since each of these functions appears to be an essential protective mechanism against the growing threat of skin cancer, 16 continuing research in this area is a matter of
increasing public concern.
ROUTINE H2-RECEPTOR ANTAGONISTS BEFORE ELECTIVE SURGERY? ASPIRATION pneumonia after regurgitation of gastric acid is an important cause of anaesthetic morbidity and mortality. This condition is a particular hazard of obstetric anaesthesia, but also occurs in non-obstetric practice. Patients at special risk include those with gross obesity, hiatus hernia, or gastroduodenal obstruction.1 There is also an increased risk in patients who require emergency surgery. In such high-risk groups, it is customary to take precautions 5
Mayne LV, Mullenders LHF, van Zeeland AA. Cockayne’s syndrome. a UV sensitive disorder with a defect in the repair of transcribing DNA but normal overall excision
repair. In Friedberg E, Hanawalt P, eds. Mechanisms and consequences of DNA damage processing New York A. R. Liss 1988; 349-53. 6. Arlett CF. Mutagenesis in repair-deficient human cell strains. In: Alacevic M, ed. Progress in environmental mutagenesis. Amsterdam: Elsevier/North Holland, 1980: 161-74.
Cockayne’s syndrome and trichothiodystrophy: defective repair without cancer. Cancer Rev 1987; 7: 82-103. 8. Bridges BA. How important are somatic cell mutations and immune control in skin cancer? Reflections on xeroderma pigmentosum. Carcinogenesis 1981, 2: 471-72 9. Dupuy JM, Lafforet D. A defect of cellular immunity in xeroderma pigmentosum. Clin Immunol immunopathol 1974; 3: 52-58. 10 Salamon T, Stojakovic M, Bogdanovic B. Delayed hypersensitivity in xeroderma pigmentosum. Arch Dermatol Forsch 1975; 251: 277-80. 11. Morison WL, Bucana C, Hasem N, et al. Impaired immune function in patients with xeroderma pigmentosum Cancer Res 1985, 45: 3929-31 12. Wysenbeek AJ, Weiss H, Duczyminer-Kahana M, Grunwald MH, Pick AI Immunologic alterations in xeroderma pigmentosum patients. Cancer 1986; 58: 219-21 13 Berkel AI, Kiran O. Immunological studies in children with xeroderma pigmentosum. Turk J Paed 1974, 16: 43-52 14. Norns PG, Limb GA, Hamblin AS, Hawk JLM. Natural killer cell activity is impaired in xeroderma pigmentosum. N Engl J Med 1988; 319: 1668-69. 15 Noms PG, Limb A, Hamblin A, Cole Arlett CF, Hawk JLM. Lymphocyte mutation, natural killer cell activity and lymphocyte proliferative responses in xeroderma pigmentosum and Cockayne’s syndrome. Proceedings of the 10th International 7. Lehmann AR.
Congress on Photobiology (in press). 16 Russell Jones R. Ozone depletion and cancer risk. Lancet 1988, ii 443-46 1. Coombs DW. Aspiration pneumonia prophylaxis Anesth Analg 1983, 62: 1055-58