Part I: Liver function in oncology: biochemistry and beyond.

The liver has a key role in the metabolism (ie, inactivation or activation) of many commonly used anticancer agents-cytotoxics or new biological agents. Therefore, assessment of liver function is a fundamental part of initial work-up and management of patients with cancer. An understanding of the meaning of conventional serum biochemical testing of liver function and status, what variables they are measuring, and usefulness for chemotherapy dosing is essential. Emerging awareness of the drawbacks of conventional serum biochemical testing and further understanding of the intricacies of liver function is leading to the development of alternative strategies for appropriate chemotherapy regimens and dosing. We present an overview of assessment of liver function and chemotherapy dosing. We consider the use of serum liver biochemical testing to predict liver function, potential causes of biochemical abnormalities in patients with cancer, and chemotherapy drugs that are associated with hepatotoxicity. Part II will overview the current knowledge surrounding chemotherapy dosing in the setting of liver dysfunction; as well as alternative tests of hepatic metabolic function that are beginning to be used as strategies for appropriate individualised chemotherapy administration.

Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130.

BACKGROUND AND AIMS: We have developed a mouse model of gastric cancer that resembles human intestinal-type adenocarcinoma. The aim of this study was to determine the identity and temporal changes in mediators of IL-6 signaling regulating tumor development. METHODS: gp130(757F/F) Mice that lack the SHP2-binding site on the IL-6 family receptor gp130 and have increased STAT 3 activity and wild-type littermates were used. Cohorts were assessed by quantitative histology and immunohistochemistry for gastric cell phenotype and proliferation markers from 4 to 40 weeks of tumor development. Northern blotting and in situ hybridization were used to quantify expression of the tumor suppressor TFF1 and the mitogens gastrin and Reg I. Expression of epidermal growth factor receptor (EGFr) and its ligands was measured by RT-PCR analysis. Age-matched differences in gene expression profiles were tested by ANOVA. RESULTS: Hyperplastic antral tumors with inflammation and ulceration were evident in gp130(757F/F) mice at 4 weeks of age and reached maximum size by 20 weeks. Tumor progression was marked by gastritis, atrophy, intestinal metaplasia, dysplasia, and submucosal invasion after 30 weeks. Both TFF1 and gastrin expression were progressively inhibited during tumorigenesis, whereas Reg I was stimulated. The EGFr and its ligands transforming growth factor (TGF)-alpha and heparin-binding EGF had increased expression corresponding to maximal tumor growth. CONCLUSIONS: gp130(757F/F) Mice rapidly develop distal stomach tumors, with loss of SHP2/Erk/AP-1 transcriptional regulation exemplified by decreased TFF1 expression and increased STAT1/3 regulated genes such as Reg I. Tumor development occurs in a hypogastrinemic environment. Balanced IL-6 signaling is required for maintaining gastric homeostasis.