Biologic Markers in Urinary Toxicology (1995) / Chapter Skim
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4 BIOLOGIC MARKERS OF EFFECT
4 BIOLOGIC MARKERS OF EFFECT
Pages 81-152
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From page 81... ...
Measurement of these mariners is preferably minimally invasive, accurate, and suitable for screening populations at risk. A number of techniques have been developed to assess renal function, but these techniques generally lack the sensitivity and specificity necessary for detecting preclinical disease or are not applicable to large populations.
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From page 82... ...
URINARY CLEARAIICE MEASUREMENTS Direct Measurement of urinary clearances is not convenient for use in large populations at risk, but it continues to constitute a basic approach to evaluating renal function. Indeed, the introduction of the clearance concept into renal physiology by Moller et al.
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From page 83... ...
load minus filtered loacl, whereas reabsorption is calculated as filtered load minus excreted load. These techniques require determination of the glomerular filtration rate (GFR)
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From page 84... ...
is excreted by tubular secretion, and the rate of its recovery in urine is therefore controlled by indepenclent variables, such as renal plasma flow, the integrity of tubular transport mechanisms, and a linear dependence of the rate of transport on plasma concentration of the dye at the dose used. Measurement of fractional excretion of a standard dose of PSP over 15 or 30 min can yield little information on specific aspects of renal function.
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From page 85... ...
Simple urinalysis remains perhaps the most useful screening test for the detection of renal injury in large populations. Changes in urinary excretion of numerous solutes have been suggested as markers of exposure and effect.
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From page 86... ...
However, some forms of renal injury are associated with defects in acid excretion. Such so-called tubular acidosis can be induced by some xenobiotics, by solvents and metals, and by obstruction of the urinary tract.
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From page 87... ...
Negatively charged molecules of intermediate size, such as albumin, are impeded at the endothelial-cell surface and the proximal layers of the glomerular basement membrane. Uncharged or positively charged molecules, such as myeloperoxidase, permeate the glomerular basement membrane and are retarded at the slit diaphragm of epithelial cells.
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From page 88... ...
Although the test is sensitive to small quantities of negatively charged proteins, such as albumin, it is insensitive to positively charged proteins, such as some immunoglobutin light chains, and to Tamm-Horsfall protein. Lowmolecular-weight proteins (which are less negatively charged than albumin)
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From page 89... ...
Recluction in the fixed anionic charge of the glomerular filtration barrier enables greater leakage of serum albumin across the glomerular basement membrane. Nephrotic syndrome induced by puromycin aminonucleoside is associated with reduction of giomerular anionic sites (Michael et al., 1970~.
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From page 90... ...
In 1985, a consensus conference agreed to define microalbuminuria as a urinary excretion
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From page 91... ...
Nevertheless, with an increase in filtered load, urinary excretion generally increases well before the tubular maximum for absorption is reached (WaIdmann et al., 1972~. Because low-molecular-weight proteins are reabsorbed solely and virtually completely in the proximal tubule, their .
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From page 92... ...
Cadmium worI |
From page 93... ...
and the predominant protein in hyatine casts (Fletcher et al., 1970; McQueen, 1962; Rutecki et al., 1971~. In humans, the daily urinary excretion of THP ranges from 20 to 200 mg with an average of about 2 might, or 93
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From page 94... ...
THP is an 85-lcD, 616-amino-acid mature protein with a 24-amino-acid leader sequence (Fletcher et al., 1970; Hession et al., 1987; ICumar and Muchmore, 1990~. It is homologous with the human low-density lipoprotein receptor, epidermal growth factor (EGF)
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From page 95... ...
Changes in renal THP have also been extensively found in patients with giomerular nephritis, the nephrotic syndrome, and in renal-allograft recipients. Although THP is the major protein in normal human urine, measures of its excretion have unknown utility as indexes of renal function or markers of ~ .
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From page 96... ...
Some recent innovations hold promise, but further technologic advances and clinical studies will be required before they can be applied in routine screening of urine samples. The use of monoclonal antibodies and immunohistochemical staining should malce it possible to distinguish among epithelial cells arising from individual nephron segments or structures of the lower urinary tract.
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From page 97... ...
Techniques of in situ hybridization have been widely disseminated in recent years for analyzing changes in gene expression that accompany tissue damage. Those methods of molecular biology have been applied successfully to the investigation of mechanisms of renal injury in tissue samples and should prove similarly useful in detecting abnormal gene expression or synthetic capacity among cells in urinary sediments.
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From page 98... ...
· Major histocompatibility antigens. · Growth factors and cytoicines: platelet-derived growth factor, epidermal growth factor, transforming growth factor (TGF)
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From page 99... ...
Although marrow-derived mononuclear cells are a major and wellstudied source of those molecules, many can also be produced by cells intrinsic to the l |
From page 100... ...
Urinary Enzymes The modern era of using urinary enzymes in the investigation and diagnosis of renal injury or disease was initiated by Rosall
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From page 101... ...
Theoretical and Diagnostic Importance The theoretical basis for recommending the use of urinary enzymes in assessing renal injury is well reasoned. Enzymes are uniquely distributed along the course of the nephron; at least 10 separate segments have been defined (Gucler and Ross, 1984~.
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From page 102... ...
might also contribute enzymatic activity to urine. Well over 100 urinary enzymes have been investigated for diagnostic use in various states of renal injury, although only a few have gained notable acceptance for routine clinical use.
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From page 103... ...
Because of diurnal variation, especially for NAG and AAP, the use of a concentration expression demands that similar collection intervals during the day be used if comparisons are to be useful. Another source of difficulty in the use of urinary enzymes arises from lack of information on several factors: What is the influence of aging on the excretion of urinary enzymes?
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From page 104... ...
For instance, many benign prostatic glands are larger than primary prostatic cancers, and many low-volume, high-grade prostatic cancers metastasize Worming et al., 1989, 1992; Wheeless et al., 1991, 1993~. Tumors commonly have abnormal 104 cell divisions that result in abnormal numbers of chromosomes, and therefore abnormal amounts of DNA, but it is difficult to estimate these with precision in hyperdiploid tumors when there are overlapping populations of cells.
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From page 105... ...
Superimposed on the diagram of the cell cycle are indications of where different proliferation markers are positive. PCNA and plO5 are positive in all cells that are not in GO, including the G1 transition phase.
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From page 106... ...
Clearly, the one feature of DNA ploidy analysis that consistently correlates with cancer survival involves cellproliferative rates. Biologic markers to assess populations of cells in each stage of the cell cycle accurately should prove beneficial in evaluating the efficacy of chemotherapy and predicting tumor aggressiveness.
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From page 107... ...
Dipstick Testing The sensitivity of dipstick and microscopic analysis for the detection of microhematuria is controversial, and the results afforded by the two methods have not always correlated. It has been estimated that a single-dipstick method for detecting blood in urine has a sensitivity of about 37% for detecting bladder cancer.
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From page 108... ...
108 Markers in Occupationally Exposed Cohorts Several cohorts are being monitored nationally and internationally for bladder cancer with marIcers of varied effectiveness (Davies et al., 1988; hi Sant' Agnese, 1988; di S ant' Agnese and de Mesy Jensen, 1987; Doctor et al., 1986; Eaton et al., 1988~. The mariners include elements of conventional urinary cytology, the addition of DNA ploidy (to determine the presence of an excessive number of chromosome sets)
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From page 109... ...
Its introduction has highlighted a number of important issues with regard to biologic markers of effect, including health-care costs, its effective use, its sensitivity and specificity, and the relationship between cryptic and active disease. Current research into the molecular and cellular biology of the prostate and of growth regulation are expected to result in new tests with higher specificity and sensitivity that should permit individual risk assessment and differentiation of indolent and active disease.
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From page 110... ...
Scram Prostate-Specif~c Antigen Biologic markers of disease have been detected primarily in the serum and are nonspecific for malignancy, reflecting quantitative alterations in normal cellular constituents. Until recently, acid phosphatase, an enzyme normally expressecl in prostatic epithelial cells, was the principal serum biologic marker.
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From page 111... ...
Research on cytolceratins has focused on delineating the integrity of the basement membrane adjacent to the prostatic epithelial cells in normal tissue, benign lesions, premaTignant lesions, PIN, and malignant lesions. Studies with monoclonal antibodies, such as MH-903 (Shah et al., 1991)
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From page 112... ...
It is not known whether the biologically active form develops along a separate oncogenic pathway or occurs as an additional mutation in the low-grade form of the disease. In addition to oncogenes and growth factors, cancer research has focused on the tumor-suppressor genes.
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From page 113... ...
They reported that half of all clinically manifest tumors show neuroendocrine differentiation, and suggested that the cells are of greater prognostic value than conventional histopathologic grading systems. Cultured stromal and epithelial cells from prostatic cancer contain a protein-like nerve growth factor (NGF)
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From page 114... ...
Of great interest was the finding that 11 patients with IC had high urinary concentrations of neutrophi! chemotactic factors; but these were not found in patients with diseases other than IC or in interstitial-cystitis patients treated with the anti-inflammatory agent dimethyl sulfoxide (DMSO)
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From page 115... ...
A recent study of mariners of cellular activation in urothelial cells showed that urothelial ce lI s from interstitial -cystitis patients expressed increased HLA-DR but not increased ICAM- 1 or IL- 1 a (Lie bert et al., 1993~. Urothelial cells in culture respond to cytolcine stimulation in the same way as most epithelial cells that is, ICAM- 1 and HLA-DR increase simultaneously.
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From page 116... ...
Such a marlcer should be produced in the kidney and secreted into urine in a readily detectable form. Substantial changes in urinary concentration of the marIcer should correlate well with patho physiologic or histopathologic manifestations of renal injury.
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From page 117... ...
Of particular use in that regard would be a nonisotopic technique for analyzing iodothalamate or Cr-EDTA, both marIcers of glomerular filtration rate. There is no "ideal" marker, i.e., a single marlcer able to provide all the information necessary to identify people at risk.
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From page 119... ...
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From page 121... ...
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From page 125... ...
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From page 126... ...
D au ._ V)
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From page 127... ...
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From page 129... ...
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From page 131... ...
x x x x x x .o -= ~ · in x a; ce ~ ~a., .Y ~ 0N ~ ~ ~ ~ _ ~ _ ~ an ~ O ~·= ~ ~~ ~ ~' ~- ~- ^ N J ~Cal Fix ~¢ ~ .
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From page 133... ...
literature documenting possible intrarenal sources of some biologic markers of cell injury that might have clinical value. Glomerular sites of synthesis of individual molecules have been relatively easy to identify because glomeruli are readily separated from other kidney tissue components for extractions, tissue culture, and other analytic procedures.
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From page 134... ...
Biologic Markers in Urinal Toxicology TABLE 4-3 Potential Biologic Marlcers of Renal Cancer Marlcer References Clinical and pathologic markers Nuclear grade T umor size Tumor stage Morphometric markers Nuclear abnormalities Quantitative morphometry Proliferative markers BrDU DNA ploidy ICi-67 PCNA Ploidy S-phase 134 Fuhrman et al., 1982; Medeiros et al., 1988; Madeiros and Weiss, 1990; Selli et al., 1983 Fuhrman et al., 1982; Medeiros et al., 1988; Madeiros and Weiss, 1990; Selli et al., 1983 Fuhrman et al., 1982; Libertino et al., 1987; McNichols et al., 1981; Medeiros et al., 1988; Robson et al., 1969; Skinner et al., 1971; Waters and Richie, 1979 Tosi et al., 1986 Tarnowslci et al., 1993; Unger et al., 1993; vanden Houte et al., 1991 Rewetal., 1991 Baisch et al., 1985, 1990; Bringuier et al., 1993; el-Naggar, et al., 1994; Grignon et al., 1989; ICloppel et al., 1986; ICumar and ICumar et al., 1993; Lanigan et al., 1993; Leyh et al., 1992; Ljungberg et al., 1956; Oosterwijk et al., 1988; Rainwater et al., 1987,1991; van Leeuwen et al., 1987; Veloso et al., 1992; Yoshida et al., 1986 Baretton, etal., 1991; Chowetal., 1993; de Riese et al., 1993; Kaiser et al., 1991 Delahunt et al., 1993; Hiaish et al., 1993; Lipponen et al., 1994; Tanioka et al., 1993 al-Abadi and Nagel 1988; Baretton et al., 1991; Ellis et al., 1992; ICieseweter et al., 1987; Larsson et al., 1993; Masters et al., 1992; Rew et al., 1991; Tanioka et al., 1993; Yuetal., 1991, 1993
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From page 135... ...
Biologic Markers of Effect Table 4-3, continued Marlcer References Growth factors EGF and EGF receptor Endothelin-2 (ET-2) fgf tgf-alpha and tgf-beta tnf IFN IGF p 170-glycoprotein p-glycoprotein Oncogenes cl 4-2 c-etsl erb (c-erbB-2)
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From page 136... ...
Biolegie Markers in Urinal Toxicology l Table 4-3, continued Marl |
From page 137... ...
Biologic Markers of ENeet Table 4-3, continued Marlcer References . Chromosome 3 Chromosome 5 Chromosome 7 Chromosome 16 Chromosome 17 Chromosome Y Chromosome 12 Chromosome 14 Chromosome 18 Chromosome 20 Chromosome 21 Anglard et al., 1991; Boldog et al., 1991; Brauch et al., 1990; Dietrick and Droz, 1992; Erlandsson et al., l 99O, 1991 a,b; Fournet et al., 1992; Fuzesi and Cober 1992; Glenn et al., 1991; Hoogstraten et al., 1982; ICohno et al., 1993; ICovacs et al., 1989a, 1991 a; Ljungberg et al., 1991; Presti et al., 1991,1993; Sugao et al., 1992; Szymanslci et al., 1993; Teyssier and Ferre, 1990; van der Hout et al., 1993; Yamal |
From page 138... ...
Biologie Markers in Urinar'Toxieology Table 4-3, continued Earlier References Cytol |
From page 139... ...
Bio~ogie Markers o'EfIee! Table 4-3, continued Marlcer References IGF-I IL-6 Pollaketal.,1989 Blay et al., 1992 139
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From page 140... ...
. TABLE 4-4 Potential Biolo ic Parlors of Bladder Cancer Earlier References Clinical and pathologic markers Dysplasia Host inflammatory response Morphologic variants of cancer Tumor volume Tumor stage Tumor grade, WHO Morphometric markers Chromatin abnormalities Nuclear abnormalities Nucleolar abnormalities Proliferative markers BrDU ICi-67 plO5 PCNA Ploidy S-phase fraction Berman et al., 1991 Levin et al., 1991; Nouri et al., 1991; Tomita etal., 1990 Christopher et al., 1991; Fossa, 1992 Herr, 1992; Lee et al., 1993 Escudero Barrilero et al., 1991 Jordan et al., 1987 Van Velthoven et al., 1994 Lipponen and Eslcelinen, 1990; Lipponen et al., 1991 a, l 992; Nielsen et al., 1988; Sanchez-Fernandez de Sevilla et al., 1992; van der Poel et al., 1991 Cairns et al., 1989; Hitmair et al., 1994; Neilsen et al., 1988 Cohen et al., 1993 Hattori et al., 1988; Waldman et al., 1993 Mulder et al., 1992 Horowitz et al., 1990 Malmstrom et al., 1992; Waldman et al., 1993 Lipponen et al., l991b; Wheeless et al., 1993 Ploidy analysis and genetic markers Trapman, 1992 Chromosome 1 Chromosome 3 Chromosome 5 ~0 Borland et al., 1992; Hopman et al., 1991 Mao et al., 1919; Iaingelhutz et al., 1992 Borland et al., 1992
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From page 141... ...
Bio~o~ie Markers of Effee' TABLE 4-4, continued Marker References Chromosome 7 Chromosome 9 Chromosome 11 Chromosome 17 DNA ploidy erb-B2 Loss of heterozygosity myc neu (pl85)
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From page 142... ...
Biologic Markers in Urinary Toxicology TABLE 4-4, continued Marlcer References Growth factors e-cadherin EGF and EGF receptor fgf P-glyprotein Plasminogen activator tgf-beta and tgf-alpha tnf Differentiation amf Cytol~eratin ECP EMA F-actin G-actin PNA, WGA Blood-group antigens ABH 142 Bringuier et al., 1993 Fuse et al., 1992, Harney et al., 1991 a,b; Ishil~ura et al., 1991; ICageyama et al., 1991; Messing et al., 1987; Neal et al., 1989, 1990; Rao et al., 1993; Smith et al., 1989; Theodorescu et al., 1991; Wood et al., 1992 Ravery et al., 1992; Welles et al., 1990 ICageyama et al., 1991; Moriyama et al., 1991a Hasui et al., 1992; Hiti et al., 1990; See, 1992 Hiti et al., 1990; ICawamata et al., 1992 Hitti et al., 1990 Javadpour and Guirguis, 1992; Nabi et al., 1992 Basta et al., 1988; el-Mohamady et al., 1991; Helmy et al., 1991; IConchuba et al., 1992; Schaafsma et al., 1990; Sumi et al., 1990 Lose and Frandsen, 1989 Ring et al., 1990 Rao etal., 1991, 1993 Raoetal.,1993 Orntoft et al., 1988 Das and Glashan, 1988; Das et al., 1986; Limas, 1990; Malmstrom et al., 1991; Orntoft et al., 1988; Sanders et al., 1991; Tichy et al., 1991; Yamada et al., 1991
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From page 143... ...
Bio~ogie Markers of Effee! TABLE 4-4, continued Marlcer References Due ABC 3 HLA Lewis-X Lewis antigens Tumor-associated antigens 1001 12F6 19A211 2A6 2E1 3-48-2, 48-1,3-50-3 3-71 - 1,94-3 3C6 3G2-C6 4-72-2 486P 3/12 6D1 7C12 8-30-3,771 -,2-94-2 9A7 AN43 BB369 Declcen et al., 1992 Cordon-Cardo et al., 1991; Eryigit and ICirkali, 1990; Levin et al., 1991, 1992; Nouri et al., l 990; Tomita et al., 1990 Limas, 1991; Matsusalco et al., 1991 Fradet et al., l 990a; Langlcilde et al., 1991 a,b; Limas, 1991; Matsusako et al., 1991 Hijazi et al., 1989 Hijazi et al., 1989 Cordon-Cardo et al., 1992; Fradet et al., l 990a Messing et al., 1984 Messing et al., 1984 Summerhayes et al., 1985 Summerhayes et al., 1985 Summerhayes et al., 1985 Lin et al., 1988; Young et al., 1985 Summerhayes et al., 1985 Arndt et al., 1987; Huland et al., 1990, 1991 Hi jazi et al., 1989 Hijazi et al., 1989 Summerhayes et al., 1985 Messing et al., 1984 Liebert et al., 1989 Liebert et al., 1989 143
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From page 144... ...
Biologie Markers in Urinan, ToxiBology TABLE 4-4, continued Marker References BIUH4, BIUH6, BIUH9 BL 2-lOD1 BLCA-8 C3 CA50 CEA DD23 G4,E7 GF 26.7.3 HBA4, HBE3 HBE10 HBF2 HBG9 HBH8 1143 M344 Mano 4/4 OM5 P7A5-4 PBS-31, PBS-85, RBA-1, HBP-1 SIC 4H-12 T16 T23 144 Guo, 1992 Longin et al., 1989 Lose and Frandsen, 1989; Wallcer et al. 1989 Young et al., 1985 Morote et al., 1990 Boileau et al., 1987; Morote et al., 1990; Piana et al., 1991 Bonner et al., 1995; Grossman et al., 1992 Chopin et al., l 985 Baricordi et al., 1985 Masuko et al., 1984 Masuko et al., 1984 Masuko et al., 1984 Masulco et al., 1984 Masuko et al., 1984 Fradet et al., 1984, 1986 Bonner et al., 1993; Cordon-Cardo et al., l 992; Fradet et al., 1987; Rao et al., 1993 Arndt et al., 1987 Fradetetal.,1984, 1986, 1990b Ben-Aissa et al., 1985 Masuko et al., 1989 Ben-Aissa et al., 1985 Bretton et al., 1989; Fradet et al., 1984, 198671990b Fradet et al., 1984, 1986
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From page 145... ...
Biologic Markers of Effect .
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From page 146... ...
Biologie Markers in Urinal Toxieolog' TABLE 4-5 Potential Biologic Markers of Prostatic Cancer Marl |
From page 147... ...
Bio~ogie Markers of Effee' TABLE 4-5, continued Marlcer References fgf IGF, NGF, POGF, ICGF tgf tnf Oncogenes erb (c-erbB-2)
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From page 148... ...
Biologic Markers in Urinan'Tox ~ TABLE 4-5, continued Marker References alpha-HCG Argentaffin beta-Endorphins beta-HCG BOM Bombesin (GRP) Calcitonin CGRP Chromogranin Corticotropin Enkephalin Glucagon G luco co rti co i d s HIAA Lipofuscin Neuron-specific enolase Parathormone Prolactin Eble and Epstein, 1990 Turbat-Herrera et al., 1988; Weaver et al., 1992 Eble and Epstein, 1990; Nemoto et al., 1990 Eble and Epstein, 1990; Maddy et al., 1989; Nabi et al., 1992; Sesterhenn et al., 1991; Sukumar et al., 1991; Tawfic et al., 1993; Webster et al., 1959 Helpap, 1980; Purnell et al., 1984 Maddy et al., 1989 Bauer, 1988; Eble and Epstein, 1990; Eskelinen et al., 1991; Fox et al., 1993; Fuse et al., 1991; Heim et al., 1977; Helpap, 1980; Maddy et al., 1989; Purnell et al., 1984; Sarkar et al., 1992 Fuse et al., 1991 Bostwick et al., 1993; Maddy et al., 1989 Fox et al., 1993 Eble and Epstein, 1990 Eble and Epstein, 1990; Maddy et al., 1989; Purnell et al., 1984 Clar-Blanch et al., 1992 Radjaipour et al., 1994 Weaver et al., 1992 Maddy et al., 1989; Shalitin et al., 1991 Fuse et al., 1991; Purnell et al., 1984 Maddy et al., 1989
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From page 149... ...
1983; Watanabe et al., 1988 di Sant' Agnese and de Mesy Jensen, 1987; Velaere et al., 1988; Scrivner et al., 1991 Buck et al., l 992; Guenette et al., 1994; Hasnain et al., 1992 di S ant' Agnese and de Mesy Jensen, 1987; Milani et al., 1986; Morote et al., 1990; Papapetrou et al., 1980 Boag and Young, 1992; Jarrett et al., 1964; Partin et al., 1993; Perlman and Epstein, 1990; Shulkes et al., 1991 Capella et al., 1981 Fekete et al., 1989 Grasso, 1952 ICleer et al., 1993 Pretlow et al., 1994 Wuetal., 1994 Bostwick, 1990 Grasso, 1952 149
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From page 150... ...
Biologic Markers in Urinal ToxieolosY TABLE 4-5, continued Marl |
From page 151... ...
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From page 152... ...
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