- Email: [email protected]
Urokinase plasminogen activator and prognosis in breast cancer
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intrinsic membrane abnormalities which, directly or indirectly (through lipid bilayer modification), affect the expression and functioning of the glucose transporter as well as of other intrinsic plasma membrane proteins.5 Thus, it is not surprising that an increase in HbA1 has been shown in various pathological conditions unrelated to increased plasma glucose concentrations6,7 and that a relation between HbA1 and membrane red blood cell (Na-// K’)ATPase activity has also been seen in diabetic patients.8 Since sex-related differences have also been reported in membrane enzyme activities of red blood cells of normal subjects,9 it is likely that differences in glucose transport activity in diabetic patients result from genetically linked differences in membrane structure. In addition to the increased growth-stimulating property of diabetic plasma,lO this may account for the accelerated rate of vascular proliferation seen in insulin-dependent diabetes. Department of Pharmacology, University of Padua, Padua, Italy, and Institute of Internal Medicine,
University of Padua
P. FINOTTI A. PICCOLI
1. Editorial. Sex and juvenile diabetes. Br Med J 1977; 1: 594-95. 2. Stickland MH, Paton RC, Wales J. Haemoglobin A1c concentration in men and women with diabetes. Br Med J 1984; 289: 733. 3. Kitagawa T, Tanaa M, Akamatsu Y. Regulation of glucose transporter mRNA by serum, growth factor and phorbol ester in quiescent mouse fibroblasts. Biochim Biophys Acta 1989; 980: 100-08. 4. Fujii H, Miwa I, Okuda J, Tamura A, Fujii T. Glucose transport into human erythrocytes treated with phospholipase A2 or C. Biochim Biophys Acta 1986; 883: 77-82. 5. Carruthers A, Melchior DL. Effects of lipid environment on membrane transport: the human erythrocyte sugar transport protein/lipid bilayer system. Ann Rev Physiol
1988; 50: 257-71. 6. Wettres S, Arnqvist H, Von Scenck H. Abnormal concentration of stable HbA1 in non-diabetic patients. Diab Metab 1984; 10: 299-303. 7. Fournier AM, Gadia MT, Kubrusly DB, Skyler JS, Sosenko JM. Blood pressure, insulin and glycaemia in non-diabetic subjects. Am J Med 1986; 80: 861-84. 8. Finotri P, Palatini P. Reduction of eruthrocyte (Na+-K+)ATPase activity in type I (insulin-dependent) diabetic subjects and its activation by homologous plasma. Diobetologia 1986; 29: 623-29. 9. Finotti P, Verbaro R. Sex differences in erythrocyte membrane ATPase activities evidenced by exposing the cells to different hemolytic solutions. Meth Find Exp Clin Pharmacol 1989; 11: 263-67. 10. Petty RG, Pearson JD, Morgan DML, Mahler RF. Stimulation of endothelial cell growth by sera from diabetic patients with retinopathy. Lancet 1988; i: 208-11.
Deaths of heroin addicts starting on a methadone maintenance programme SiR,—The main function of our institute is the investigation of sudden and unexpected deaths in the State of Victoria. We have established that a substantial number of heroin addicts die within a few days of starting a methadone maintenance programme. We describe here our investigations of these deaths. 10 cadavers (3 female, 7 male), aged 18 to 36 at death, who were known to have been heroin addicts and on methadone maintenance, were received at the institute in the five months to November, 1989. In 5 cases examination by forensic pathologists revealed no life-threatening anatomical abnormalities. In the other 5 bronchopneumonia of varying severity was present. In all cases there was evidence of chronic persistent hepatitis. Methadone was detected in all cadavers (mean concentration in blood 0-71 mg/1, range 0-30-2-52). The concentrations are within the range reported for deaths attributed to methadone use.l Other drugs were detected in 6 cadavers: benzodiazepines in 3, morphine in 3, alcohol in 2, and propoxyphene in 1. In 4 subjects the presence of additional drugs possibly contributed to their death-these were the morphinepositive subjects and 1 whose blood alcohol was 0 13 g/dl. Methadone had been begun in all 10 subjects between 2 and 6 days before death. The mean prescribed dose at the time of death was about 60 mg. Others have advised caution about starting doses greater than 30 mg.2,3 We have no evidence that the subjects received any additional methadone from other sources. Methadone is prescribed only on a daily basis, and the patient usually takes the drug in the presence of the dispensing pharmacist. There are about 900 heroin addicts on the methadone programme in Victoria. We are not aware of other reports of deaths attributed to methadone occurring in association with the start of methadone
Although the presence of chronic persistent hepatitis in intravenous drug addicts is unremarkable, liver disease can reduce the clearance of methadone.4 Therefore these subjects could have had a reduced clearance allowing methadone to reach higher than expected blood concentrations. We recommend that consideration be given not only to the screening of subjects for entry into a methadone maintenance programme (including testing of liver function and urine testing for the presence of drugs) but also to the use of lower starting doses. We recognise the difficulties inherent in methadone maintenance programmes, but these steps may decrease the likelihood of such deaths. treatment.
Victorian Institute of Forensic South Melbourne, Victoria 3205, Australia
Pathology,
OLAF H. DRUMMER MARIE SYRJANEN KENNETH OPESKIN STEPHEN CORDNER
1. Segal RJ, Catherman RL. Methadone: a cause of death. J Forensic Sci 1974; 19: 64-74. 2. Milner G. Methadone. Med J Aust 1976, 2: 551-53. 3. Gardner R. Methadone misuse and death by overdosage. Br J Addict 1970; 65: 113-18. 4. Sawe J. High-dose morphine and methadone in cancer patients: clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokin 1986; 11: 87-106.
Urokinase
plasminogen activator and prognosis in breast cancer
SIR,-Evidence from animal tumours suggests that proteolytic enzymes are implicated in cancer invasion and metastasis.l,2 One of these proteases is the urokinase form of plasminogen activator (UK-PA). Dr Janicke and colleagues (Oct 28, p 1049) show that UK-PA antigen values are significantly higher in breast carcinomas than in benign tumours and that these high levels correlate significantly with early disease recurrence. With an enzyme activity assay, we have reported similar findings for UK-PA-ie, breast carcinomas had significantly higher UK-PA activity than had benign samples3 and, furthermore, that patients with high levels of UK-PA had a shorter disease-free interval than patients with low levels.4 We now report further findings of UK-PA activity with respect to overall patient survival. After a median follow-up of 35 months, patients with high UK-PA activity (over 0-5 IU per mg protein) had a significantly greater risk of early death than those with low levels (univariate analysis with proportional hazards general linear model procedure: relative risk 3-92, 95% confidence intervals [CI] 1-45-10-2, p=0-0056, n=119). In multivariate analysis, UK-PA as a prognostic factor was independent of tumour size, axillary node status, and oestrogen receptor status (relative risk 27-1, 95% CI
1 -13-648, p=0041). We conlude therefore that UK-PA, whether assayed by immunoassay or catalytic assay, is a new prognostic marker in breast cancer. Another protease, cathepsin D has also been reported to be
such
a
marker in breast cancer .5,6 We suggest that other proteases
implicated in cancer spread should also be investigated as prognostic markers in breast cancers. Indeed, certain proteases might be prognostic markers for solid tumours in general. Departments of Nuclear Medicine and Medical Oncology, and Education and Research Centre, St Vincent’s Hospital, Dublin 4, Ireland; St Luke’s Hospital, Dublin; and Department of Surgery, University College, Dublin
MICHAEL J. DUFFY DAVID REILLY
CATHRIONA O’SULLIVAN NIALL O’HIGGINS JAMES J. FENNELLY
1. Duffy MJ. Do proteases play a role m cancer invasion and metastasis? Eur JCancer Clin Oncol 1987; 23: 583-89. 2. Zucker S. A critical appraisal of the role of proteolytic enzymes in cancer invasion emphasis on tumor surface proteinases. Cancer Invest 1988; 6: 219-31. 3. O’Grady P, Lijnen HR, Duffy MJ. Multiple forms of plasminogen activator in human breast tumours. Cancer Res 1985; 45: 6216-18. 4. Duffy MJ, O’Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen HJ. Urokinase-plasmmogen activator, a marker for aggressive breast carcinomas Cancer 1988; 62: 531-33. 5. Thorpe SM, Rochefort H, Garcia M, et al. Association between high concentrations of 52% cathepsin D and poor prognosis in primary breast cancer. Cancer Res 1989; 49: 6008-14. 6. Spyratos F, Maudelonde T, Brouilett J-P, et al. Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet 1989; ii: 1115-18.
intrinsic membrane abnormalities which, directly or indirectly (through lipid bilayer modification), affect the expression and functioning of the glucose transporter as well as of other intrinsic plasma membrane proteins.5 Thus, it is not surprising that an increase in HbA1 has been shown in various pathological conditions unrelated to increased plasma glucose concentrations6,7 and that a relation between HbA1 and membrane red blood cell (Na-// K’)ATPase activity has also been seen in diabetic patients.8 Since sex-related differences have also been reported in membrane enzyme activities of red blood cells of normal subjects,9 it is likely that differences in glucose transport activity in diabetic patients result from genetically linked differences in membrane structure. In addition to the increased growth-stimulating property of diabetic plasma,lO this may account for the accelerated rate of vascular proliferation seen in insulin-dependent diabetes. Department of Pharmacology, University of Padua, Padua, Italy, and Institute of Internal Medicine,
University of Padua
P. FINOTTI A. PICCOLI
1. Editorial. Sex and juvenile diabetes. Br Med J 1977; 1: 594-95. 2. Stickland MH, Paton RC, Wales J. Haemoglobin A1c concentration in men and women with diabetes. Br Med J 1984; 289: 733. 3. Kitagawa T, Tanaa M, Akamatsu Y. Regulation of glucose transporter mRNA by serum, growth factor and phorbol ester in quiescent mouse fibroblasts. Biochim Biophys Acta 1989; 980: 100-08. 4. Fujii H, Miwa I, Okuda J, Tamura A, Fujii T. Glucose transport into human erythrocytes treated with phospholipase A2 or C. Biochim Biophys Acta 1986; 883: 77-82. 5. Carruthers A, Melchior DL. Effects of lipid environment on membrane transport: the human erythrocyte sugar transport protein/lipid bilayer system. Ann Rev Physiol
1988; 50: 257-71. 6. Wettres S, Arnqvist H, Von Scenck H. Abnormal concentration of stable HbA1 in non-diabetic patients. Diab Metab 1984; 10: 299-303. 7. Fournier AM, Gadia MT, Kubrusly DB, Skyler JS, Sosenko JM. Blood pressure, insulin and glycaemia in non-diabetic subjects. Am J Med 1986; 80: 861-84. 8. Finotri P, Palatini P. Reduction of eruthrocyte (Na+-K+)ATPase activity in type I (insulin-dependent) diabetic subjects and its activation by homologous plasma. Diobetologia 1986; 29: 623-29. 9. Finotti P, Verbaro R. Sex differences in erythrocyte membrane ATPase activities evidenced by exposing the cells to different hemolytic solutions. Meth Find Exp Clin Pharmacol 1989; 11: 263-67. 10. Petty RG, Pearson JD, Morgan DML, Mahler RF. Stimulation of endothelial cell growth by sera from diabetic patients with retinopathy. Lancet 1988; i: 208-11.
Deaths of heroin addicts starting on a methadone maintenance programme SiR,—The main function of our institute is the investigation of sudden and unexpected deaths in the State of Victoria. We have established that a substantial number of heroin addicts die within a few days of starting a methadone maintenance programme. We describe here our investigations of these deaths. 10 cadavers (3 female, 7 male), aged 18 to 36 at death, who were known to have been heroin addicts and on methadone maintenance, were received at the institute in the five months to November, 1989. In 5 cases examination by forensic pathologists revealed no life-threatening anatomical abnormalities. In the other 5 bronchopneumonia of varying severity was present. In all cases there was evidence of chronic persistent hepatitis. Methadone was detected in all cadavers (mean concentration in blood 0-71 mg/1, range 0-30-2-52). The concentrations are within the range reported for deaths attributed to methadone use.l Other drugs were detected in 6 cadavers: benzodiazepines in 3, morphine in 3, alcohol in 2, and propoxyphene in 1. In 4 subjects the presence of additional drugs possibly contributed to their death-these were the morphinepositive subjects and 1 whose blood alcohol was 0 13 g/dl. Methadone had been begun in all 10 subjects between 2 and 6 days before death. The mean prescribed dose at the time of death was about 60 mg. Others have advised caution about starting doses greater than 30 mg.2,3 We have no evidence that the subjects received any additional methadone from other sources. Methadone is prescribed only on a daily basis, and the patient usually takes the drug in the presence of the dispensing pharmacist. There are about 900 heroin addicts on the methadone programme in Victoria. We are not aware of other reports of deaths attributed to methadone occurring in association with the start of methadone
Although the presence of chronic persistent hepatitis in intravenous drug addicts is unremarkable, liver disease can reduce the clearance of methadone.4 Therefore these subjects could have had a reduced clearance allowing methadone to reach higher than expected blood concentrations. We recommend that consideration be given not only to the screening of subjects for entry into a methadone maintenance programme (including testing of liver function and urine testing for the presence of drugs) but also to the use of lower starting doses. We recognise the difficulties inherent in methadone maintenance programmes, but these steps may decrease the likelihood of such deaths. treatment.
Victorian Institute of Forensic South Melbourne, Victoria 3205, Australia
Pathology,
OLAF H. DRUMMER MARIE SYRJANEN KENNETH OPESKIN STEPHEN CORDNER
1. Segal RJ, Catherman RL. Methadone: a cause of death. J Forensic Sci 1974; 19: 64-74. 2. Milner G. Methadone. Med J Aust 1976, 2: 551-53. 3. Gardner R. Methadone misuse and death by overdosage. Br J Addict 1970; 65: 113-18. 4. Sawe J. High-dose morphine and methadone in cancer patients: clinical pharmacokinetic considerations of oral treatment. Clin Pharmacokin 1986; 11: 87-106.
Urokinase
plasminogen activator and prognosis in breast cancer
SIR,-Evidence from animal tumours suggests that proteolytic enzymes are implicated in cancer invasion and metastasis.l,2 One of these proteases is the urokinase form of plasminogen activator (UK-PA). Dr Janicke and colleagues (Oct 28, p 1049) show that UK-PA antigen values are significantly higher in breast carcinomas than in benign tumours and that these high levels correlate significantly with early disease recurrence. With an enzyme activity assay, we have reported similar findings for UK-PA-ie, breast carcinomas had significantly higher UK-PA activity than had benign samples3 and, furthermore, that patients with high levels of UK-PA had a shorter disease-free interval than patients with low levels.4 We now report further findings of UK-PA activity with respect to overall patient survival. After a median follow-up of 35 months, patients with high UK-PA activity (over 0-5 IU per mg protein) had a significantly greater risk of early death than those with low levels (univariate analysis with proportional hazards general linear model procedure: relative risk 3-92, 95% confidence intervals [CI] 1-45-10-2, p=0-0056, n=119). In multivariate analysis, UK-PA as a prognostic factor was independent of tumour size, axillary node status, and oestrogen receptor status (relative risk 27-1, 95% CI
1 -13-648, p=0041). We conlude therefore that UK-PA, whether assayed by immunoassay or catalytic assay, is a new prognostic marker in breast cancer. Another protease, cathepsin D has also been reported to be
such
a
marker in breast cancer .5,6 We suggest that other proteases
implicated in cancer spread should also be investigated as prognostic markers in breast cancers. Indeed, certain proteases might be prognostic markers for solid tumours in general. Departments of Nuclear Medicine and Medical Oncology, and Education and Research Centre, St Vincent’s Hospital, Dublin 4, Ireland; St Luke’s Hospital, Dublin; and Department of Surgery, University College, Dublin
MICHAEL J. DUFFY DAVID REILLY
CATHRIONA O’SULLIVAN NIALL O’HIGGINS JAMES J. FENNELLY
1. Duffy MJ. Do proteases play a role m cancer invasion and metastasis? Eur JCancer Clin Oncol 1987; 23: 583-89. 2. Zucker S. A critical appraisal of the role of proteolytic enzymes in cancer invasion emphasis on tumor surface proteinases. Cancer Invest 1988; 6: 219-31. 3. O’Grady P, Lijnen HR, Duffy MJ. Multiple forms of plasminogen activator in human breast tumours. Cancer Res 1985; 45: 6216-18. 4. Duffy MJ, O’Grady P, Devaney D, O’Siorain L, Fennelly JJ, Lijnen HJ. Urokinase-plasmmogen activator, a marker for aggressive breast carcinomas Cancer 1988; 62: 531-33. 5. Thorpe SM, Rochefort H, Garcia M, et al. Association between high concentrations of 52% cathepsin D and poor prognosis in primary breast cancer. Cancer Res 1989; 49: 6008-14. 6. Spyratos F, Maudelonde T, Brouilett J-P, et al. Cathepsin D: an independent prognostic factor for metastasis of breast cancer. Lancet 1989; ii: 1115-18.