Ovarian tumors

It is not appropriate to generali2e the carcinogenicity of this class of compounds. Nitrofura2one appears to increase the incidence of benign mammary tumors in rats. The tumorigenic activity of fura2ohdone is expressed by an increase in the incidence of spontaneous tumors in both mice and rats. Bioassays of nitrofurantoin in several species of mice and rats failed to reveal any evidence of direct tumorigenic activity. Ovarian tumors have been reported in B C F mice, but these are beheved due to an indirect expression of toxicity (14,15). 

The three major pathologic categories of ovarian tumors include sex-cord stromal, germ cell, and epithelial. About 85% to 90% of ovarian cancers are of epithelial origin. 

Epithelial ovarian tumors are composed of cells that cover the surface of the ovary, such as serous, mucinous, endometrioid, clear cell, and poorly differentiated adenocarcinomas. 

Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999 ... 

Wang W, Guo T, Rudnick PA, et al. Membrane proteome analysis of micro-dissected ovarian tumor tissues using capillary isoelectric focusing/reversed-phase liquid chromatography-tandem MS. Anal. Chem. 2007 79 1002-1009. 

Hyaluronic acid (from vitreous humor, umbilical cord, synovial fluid, ovarian tumor, Group A hemolytic streptococcus and skin)... 

The incidence of ovarian tumors in mice, guinea pigs, and rabbits increased after 3 years of chronic irradiation at doses as low as 1.1 mGy daily (Lorenz et al. 1954). Unlike other tumors, the induction of ovarian tumors depended on a minimum total dose and seemed to be independent of a daily dose (Lorenz et al. 1954). Radiation-induced neoplastic transformation of hamster cells may be associated initially with changes in expression of the genes modifying cytoskeletal elements (Woloschak et al. 1990b). 

KI2. Koivunen, E., Huhtala, M. L., and Stenman, U. H., Human ovarian tumor-associated trypsin. J. Biol. Chem. 264, 14095-14099 (1989). 

This digestion, isolation, and storage approach has been successfully applied to a wide range of tumor and normal tissues. Tumor tissues include both primary and metastatic tumors of the more common types, such as colon, lung, and ovarian tumors, melanomas, and sarcomas, and rare tumors, such as schwannoma. Normal cell populations include lung, ovary, colon, heart, liver, kidney, and blood. 

As might be expected from a screen in which the target tumor was a soft tissue sarcoma, those tumors were among the most sensitive to the compound, along with ovarian tumors, mesotheliomas, melanomas, and lung carcinomas. Tumors least sensitive to this compound included pancreatic carcinomas, neuroblastomas, and especially, renal cell carcinomas. As a rule, for the seven classes of compounds identified in the screen, soft tissue sarcomas, ovarian carcinomas, and mesotheliomas were the most sensitive tumor types. 

A class of DUBs only identified since 2002 is the OTU (ovarian tumor protein) DUB class. The OTU domain was originally identified in an ovarian tumor protein from Drosophila mdanogaster, and over 100 proteins from organisms ranging from bacteria to humans are annotated as having an OTU domain. The members of this protein superfamily were annotated as cysteine proteases, but no specific function had been demonstrated for any of these proteins. The first hint of a role for OTU proteins in the ubiquitin pathway was afforded by the observation that an OTU-domain-containing protein, HSPC263, reacted with ubiquitin vinyl sulfone (an active-site-directed irreversible inhibitor of DUBs) [41]. 

GgO- igsp) Pituitary tumors, adenomas, endocrine ovarian tumors... 

Toxicological studies have suggested that the species specificity for induction of ovarian tumors (produced in mice but not rats) occurs because the blood level of the ovotoxic VCH metabolite VCH-1,2-epoxide is dramatically higher in VCH-treated female mice compared with rats. VCH has been shown to be metabolized by the liver of mice to the ovotoxic metabolite (VCH-1,2-epoxide), which circulates in blood and is delivered to the ovary, where it destroys small oocytes. This destruction of small oocytes is considered to be an early event in carcinogenesis. Species difference in epoxidation of VCH by hepatic micro-somes correlates well with the differences observed in the blood concentration of VCH-1,2-epoxide and VCH ovarian toxicity. Further in vitro studies have found that the rate of VCH epoxidation in humans by human hepatic microsomes was 13- and 2-fold lower than epoxidation by mouse and rat systems respec-tively. Therefore, if the rate of hepatic VCH epoxidation is the main factor that determines the ovotoxicity of VCH, rats may be a more appropriate animal model for humans. 

Premenopausal use There is no indication for premenopausal use of raloxifene. Hepatic function impairment Raloxifene was studied, as a single dose, in Child-Pugh class A patients with cirrhosis and serum total bilirubin ranging from 0.6 to 2 mg/dL. Plasma raloxifene concentrations were approximately 2.5 times higher than in controls and correlated with total bilirubin concentrations. Safety and efficacy have not been evaluated further in patients with severe hepatic insufficiency. Carcinogenesis In long term carcinogenicity studies in animals there was an increased incidence of ovarian tumors, testicular interstitial cell tumors, and prostatic adenocarcinomas. 

Kavallaris M, Kuo DY, Burkhart CA, et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest 1997 100(5) 1282-1293. 

Milas L, Hunter NR, Kurdoglu B, et al. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol 1995 35 297-303. 

The implementation of animal test protocols in the 1980s has been accompanied by the development of a host of alternative methods to study adverse effects of chemicals on reproductive and developmental parameters. For example, rat whole embryo culture stems from the seventies (16), as does the rat limb bud organ culture (17) and rat limb bud and brain micromass was developed in the eighties (18). An elegant nonvertebrate alternative model used regeneration of polyps of Hydra atUnuata from dissociated cells (19). Animal-free in vitro alternatives include those employing the proliferation of a human embryonic palatal mesenchymal cell line (20), the attachment of a mouse ovarian tumor cell line (21), and the differentiation of a neuroblastoma cell line (22) and a embryonal carcinoma cell line (23). Various overviews of methods have been published over the years (24). The predictability of... 

Thompson ER, Herbert SC, Forrest SM et al. Whole genome SNP arrays using DNA derived from formalin-fixed, paraffin-embedded ovarian tumor tissue. Hum Mutat 2005 26 384-389. 

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