Cancer model

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

We have linked the gastric cancer model of Sugimura to the examination of the occurrence of human gastric cancer and to consideration of the underlying mechanisms ... 

Siler, U., L. Barella, V. Spitzer et al. 2004. Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model. Faseb J 18(9) 1019-1021. 

Kim, Y., Chongviriyaphan, N., Liu, C., Russell, R.M., and Wang, X.D. 2006. Combined antioxidant (beta-carotene, alpha-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model. 

To evaluate PARP inhibition in a realistic setting, olaparib (7) was tested in a BrcflI / p53 / mouse breast cancer model. Treatment with olaparib caused tumor growth inhibition without generating signs of toxicity [14]. Interestingly, upon cessation of treatment and tumor... 

Kota J, Chivukula RR, O Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137 1005-1017... 

In addition to their possible prooxidant activity (see above) polyphenols and flavonoids may influence cancer cells via their antioxidant properties. Recently, Jang et al. [219] studied cancer chemopreventive activity of resveratrol, a natural polyphenolic compound derived from grapes (Chapter 29). These authors showed that resveratrol inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. Flavonoids silymarin and silibinin also exhibited antitumor-promoting effects at the stage I tumor promotion in mouse skin [220] and manifested antiproliferative effects in rat prostate cancer cells [221]. 

Other compounds, such as ZK-703 and ZK-253, are currently under preclinical testing, and preliminary data show a pure antiestrogen activity in xenograft breast cancer models (Hoffmann et al. 2004). 

Risk Assessment. This model successfully described the disposition of chloroform in rats, mice and humans following various exposure scenarios and developed dose surrogates more closely related to toxicity response. With regard to target tissue dosimetry, the Corley model predicts the relative order of susceptibility to chloroform toxicity consequent to binding to macromolecules (MMB) to be mouse > rat > human. Linking the pharmacokinetic parameters of this model to the pharmacodynamic cancer model of Reitz et al. (1990) provides a biologically based risk assessment model for chloroform. 

While the work of Chen et al. (2001) broadly defined the expression of genes associated with metastatic potential in the lung cancer model, others have more narrowly focused upon relationships for specific genes. For example, Pinheiro et al. (2001) examined gene expression profiles from patients... 

Farmer P Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment ILSl/HESl research programme on alternative cancer models results of Syrian hamster embryo cell transformation assay. International Life Sciences Institute/Health and Environmental Science Institute. Toxicol Pathol 2002 30 536-8. 

An endogenous SI RTl modulator and several targets have been described that hint at potential therapeutic benefits from pharmacological SIRTl inhibition in a number of cancer models. The gene product of deleted in breast cancer 1 (DBCl) interacts with and inhibits SIRTl [95, 96]. Dovmregulation of DBCl expression in normal... 

DuPage M, Dooley AL, Jacks T (2009) Conditional mouse lung cancer models using... 

Oxaliplatin (trans-L-diaminocyclohexane oxalate platinum II) was selected for development based on preclinical antitumor activity in murine leukemia lines and in colon cancer models (151,152). The clinical development of oxaliplatin has been primarily in colorectal cancer alone and in combination with 5-fluorouracil. 

Fujiwara T, Cai DW, Georges RN, Mukhopadhyay T, Grimm EA, Roth JA. Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. 7 Natl Cancer Inst 1994 86 1458-1462. 

Phosphorus-31 MRS continues to be a powerful tool to study cancer models in rodent xenografts. Because such studies are conducted at high magnetic fields with dedicated surface or volume coils, SNR and... 

The efficacy of a macromolecular anticancer conjugate against an in vivo cancer model will be influenced by the conjugate s ability to cross com-partmental barriers within the organism as mentioned in Sect. 2.2. Therefore, initial in vivo testing of a polymeric anticancer conjugate will often employ the same compartment of the animal, e.g., peritoneum, for both the cancer cell and... 

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