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6 NEW TECHNOLOGIES
Pages 191-216

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From page 191...
... The S phase starts when DNA synthesis starts and ends when the DNA content of the nucleus has cloubled. Thereafter, the cells move into the G2 phase of the cycle, where new protein and RNA synthesis occurs and the cells increase in size.
From page 192...
... \ Growth Factors / autocrine \ Go/ paracrine In /,f, endocrine M phase (nuclear division) Cell Cycle \ \ S phase (start of DNA synthesis)
From page 194...
... Autocrine control occurs when cells secrete growth peptides that induce their own growth by binding to their own receptors. Intracrine growth, which has so far been observed in model systems, occurs when the growth factors are prevented from being exported by mutations that inhibit cleavage of the pre-pro forms of the peptides.
From page 195...
... Indeed, exogenous EGF administered to rats after renal ischemic injury enhances renal tubular cell regeneration and accelerates the recovery of renal function (Humes et al., 1989; Tsau et al., 1989~. The synthesis or processing of preproEGF mRNA is also altered by exposure to nephrotoxic agents, such as cisplatin (Safirstein et al., 1989~.
From page 196...
... Transforming Growth Factor Beta Transforming growth factor beta hi or-~' constitutes a family of ubiquitous growth peptides that are intimately involved in extracellular matrix forn~ation, cellular proliferation and differentiation, wound-healing, cartilage and bone formation, and possibly oncogenesis. Evidence is growing that TGF-B operates in an autocrine or paracrine fashion to bring about a multiplicity of cellular actions.
From page 197...
... to its ability to stimulate Na+/H+ pump activity in proximal tubular cells. Early-Response Genes In cellular proliferation and hypertrophy, an orderly pattern of gene expression (Cowley et al., 1989)
From page 198...
... During the repair phase of ischemic acute renal failure, c-myc expression in the renal cortex increases by a factor of 10 (Hurries and Daniel, 1 990~. Nucleic Acid Synthesis and Hypertrophy Although attention has been given to the cell cycle and DNA synthesis, other mechanisms are operative when cells hypertrophy.
From page 199...
... With a reduction in renal mass, growth stimulation and increase in Na+/H+ pump activity are closely related (Fine, 1986~. It also appears that Na+ influx is necessary for the initiation of DNA synthesis stimulated by peptide growth factors.
From page 200...
... the carcinogenic process in 200 SV40-immortalized human uroepithelial cells (Jacob et al, 1991~. Quantitative Fluorescence Image Analysis Quantitative fluorescence image analysis (QFIA)
From page 201...
... The numbers and DNA content of bladder-wash cells obtained from rats treated with carcinogens and chemopreventive retinoids was found to be an accurate predictor of risk of developing bladder cancers (Hemstreet et al., 1992; Hurst et al., 1991~. There are newer directions of QFIA research to learn whether commonly seen atypical cells are the result of an inflammatory or irritative process or are truly progressing toward malignancy.
From page 202...
... In addition, other studies have shown that using QFIA with Gactin (a precursor molecule of the cytosIceleton) yields an early marker of carcinogenesis that can guide chemoprevention studies and, in conjunction with tumor markers of aneuploidy and the presence of cells that react with antibodies against tumor-specific antigens, can be helpful in the diagnosis and management of bladder cancer in worker cohorts exposed to bladder carcinogens (Rao et al., 1990; Hen~street al., 1992~.
From page 203...
... Prostate-specific antigen (PSA) , a glycoprotein that is produced by the epithelial cells of the prostate and acts as a protease to liquefy the seminal coagulum (Wang et al.7 19793, has been used in screening for prostatic cancer, for its staging, and as a marker of response to treatment.
From page 204...
... Studies have compared prostatic cancers found in radical cystoprostatectomy specimens (latent form) with prostaticcancers detected in current prostaticcancer screening programs.
From page 205...
... Some studies indicate that most patients who are found to have prostatic cancer on the basis of increased PSA are those who should be effectively treated with radical surgical intervention. However, screening and treatment of this group must take several factors into consideration, including the cost of the evaluation, the morbidity associated with the tests themselves, and the morbidity of those who will not be cured, in contrast with those with .
From page 206...
... In contrast, when PIN II or III is identified the prostate is commonly rebiopsied; these lesions have been associated with increased PSA. Which of the premalignant lesions will develop into prostatic cancer is of current interest, and such markers as oncogenes, growth factors, and cytoslceletal mariners are being evaluated (see Table 4-5~.
From page 207...
... CANCER OF THE KIDNEY This section discusses examples in urinary toxicology of the examination and use of biologic markers to cletermine the choice of relevant test species and aid in the interpretation of the results of toxicity studies. Renal Tumors in Male Rats Mediated by Alpha2u-globulin A structurally diverse group of organic chemicals has been shown to cause a renal syndrome in male rats that is manifested acutely by the accumulation of marlcer protein in renal proximal-tubule cells visible under the light microscope as hyaline droplets (Hard et al., 1 993; Health Effects Institute, 1985,1988; USEPA, 1991a,b)
From page 208...
... assay F detects PSA that has not formed a complex, but has difficulty recognizing PSA that has formed a complex with proteinase inibitors such as alphal-antichymotrypsin. Source: Lilja, H., A.T.IC.
From page 209...
... , but it has not been detected in the liver of normal female rats or in other species, including humans (MacInnes et al., 1986; Sippel et al., 1975~. In addition to stimulating the synthesis of large amounts of alpha2u-globulin in the male rat, testosterone suppresses the clegradation of alpha2u-globulin (Feigelson and ICurtz, 1977; MacInnes et al., 1986; Motwani et al., 1984; Roy and Chatterjee, 1983; Roy and Nenhaus, 1967; Roy et al., 1983; Sippel et al., 1975~.
From page 210...
... The features of acute nephropathy include accumulation of hyaline droplets in the proximal tubules; necrosis and regeneration, particularly in the P2 segment of the proximal tubule; linear mineralization in the papilla; and granular cast formation, primarily at the junction of the inner and outer stripes of the outer medulla (Alden et al., 1984, Balder et al., 1984; Hard and Whysner, 1994; HEI, 1988; Swenbergetal., 1989~. Studies that have involved the aclministration of chemicals capable of inducing alpha2u-gIobulin accumulation in immature rats, aged rats, castrated male rats, male NCI Black Reiter (NBR)
From page 211...
... . In contrast, there is no background incidence of hyaline droplets containing alpha2u-globulin in female rats, which synthesize less than one-hundrec~th as much alpha2u-globulin as male rats (Vandoren et al., 1983~; this small amount of protein probably floes not accumulate as histologically evident hyaline droplets.
From page 212...
... If followed over the entire life span of the rat, those incidences increase to 0.2 and 0.4% of male rats and 0.4 and 0.6% of female rats (Solleveld et al., 1984~. (See also National Toxicology Program (NTP)
From page 213...
... The alpha2u-globulin found in male rats is structurally related to a group of transport proteins, many of which are synthesized in humans. The proteins in this group of about 20 low-molecularweight proteins, the alpha2u-giobulin superfamily of proteins called lipocalins, are similar in molecular weight, certain sequence homology, and tertiary structure (where it is known)
From page 214...
... A nongenotoxic chemical that causes renal tumors in male rats but not in female rats or in other species is probably acting through the alpha2u-globulin mechanis~n if there is evidence of hyaline
From page 215...
... Therefore, the renal tumors observed in male rats after tetrachloroethylene exposure would be considered as contributing to the overall weight of evidence in identifying potential cancer hazards to humans, although the tumors would not be used to derive a quantitative risk estimate because of the feasibility of their resulting in part from the alpha2u-globulin nephropathy. d-Li~nonene is the example of a tested chemical that meets all the criteria for the alpha2u-gIobulin process of renal-tumor induction.
From page 216...
... The uncertainties associated with its use have emphasized the need for the cooperation of various disciplines including 216 biostatistics and epidemiology, the basic sciences, and clinical specialties to review the utility of specific biologic markers before their integration into clinical practice. Extensive studies have attempted to extrapolate (lata concerning alpha2uglobulin from animal studies to human conditions, such as nephrotoxicity and renal cancer.


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