Session 6: Recent Advances in Pharmacotherapy (Oncology) Tuesday 10-07: 9.00–10.30 6.1.K. Adjuvant endocrine therapy in human and canine breast cancer treatment M. B. M. VAN DUURSEN 1 , E. E. J. W. SMEETS 1 , S. M. NIJMEIJER 1 , P. C. DE JONG 2 & M. VAN DEN BERG 1 1 Endocrine Toxicology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; 2 Department of Internal Medicine, St Antonius Hospital, Nieuwegein, The Netherlands Breast cancer is the most common cancer in women worldwide, both in developed and developing countries. In humans, treatment and chemoprevention of (oestrogen receptor-positive) breast cancer is based on drugs that interact with the oestrogen- signalling pathway and are used to deprive the cancer cells of oestrogens. This type of hormonal adjuvant therapy comprise of selective oestrogen receptor modulators (SERMs) that interfere with endogenous oestrogens on the ER in tumour cells or selective oestrogen enzyme modulators (SEERs) that target enzymes involved in the biosynthesis of steroid hormones. SERMs and SEERs target different cells in a breast tumour. Breast tumours are composed of not only tumour epithelial cells, but also other cell types such as fibroblasts, adipocytes, blood vessels and immune and inflammatory cells, which are impor- tant in the regulation of epithelial breast cell growth. Over the past years, it has become clear that the interaction between stromal fibroblasts and epithelial breast tumour cells is pivotal in tumour development and progression. The fibroblasts contain the aromatase enzyme and provide the ER+ epithelial tumour cells with estradiol and stimulate proliferation. The tumour cells in turn secrete growth factors and cytokines, such as interleukin- 8 (IL-8) and prostaglandin E2 (PGE2) that can induce aromatase expression in the surrounding fibroblasts. Local oestrogen production by aromatase is differentially regulated in disease- free and tumorigenic breast tissue. In disease-free mammary fibroblasts, aromatase expression is low, but in the presence of a tumor expression is elevated 3–4-fold and a promoter switch in aromatase regulation takes place. Similar to cases in humans, ~40–60% of canine mammary cancers are oestrogen receptor (ER)-positive and canine breast cancer are being considered a spontaneous model of human breast cancer (Marinelli et al. 2004). This implies that canine tissue might be useful as models for human carcinogenesis. But also, that drugs that are effective in human breast cancer may be useful in the treatment of breast tumours in dogs. In our lab, we have set up a breast cancer model that consists of a co-culture system of MCF-7 cells and primary mammary fibroblasts. We have used both human breast adipose fibroblasts (BAFs), canine BAFs and carcinoma-associ- ated fibroblasts (CAFs) from a canine breast tumour. Using this model, we can study interactions of e.g. dietary compounds with SERMs and SEERs and subsequent effects on breast tumour proliferation. In this lecture, the therapeutic use of aromatase inhibitors in human clinical practice and potential relevance for the veterinary clinic will be addressed. Further, concerns about the adverse interactions with soy-based phytoestrogens and SEERs/SERMs will be discussed. SUGGESTED READING 1. Marinelli, L. Gabai, G., Wolfswinkel, J. & Mol, J.A. (2004) Mammary steroid metabolizing enzymes in relation to hyperplasia and tumorigenesis in the dog. The Journal of Steroid Biochemistry and Molecular Biology 92(3), 167–173. 2. van Duursen, M. B., Nijmeijer, S.N., de Morree, E.S., de Jong, P.C., & van den Berg, M. (2011) Genistein induces breast cancer-associated aromatase and stimulates estrogen-depen- dent tumor cell growth in in vitro breast cancer model. Toxicology, 289(2–3), 67–73. 6.2. Population pharmacokinetics of carboplatin in dogs T. MARTIN-JIMENEZ, N. VILLARINO & A. LEGENDRE University of Tennessee, Maryville, TN, USA INTRODUCTION Precise dosing of anticancer drugs is difficult due to the proximity between effective and toxic doses. Variability among dogs in drug elimination is a major reason why the response to chemotherapy is more closely related to the concentration of drug in blood and tissues than to the administered dose. Carboplatin is an anticancer drug commonly used in the treatment of a variety of solid tumours in dogs. The objective of this study was to explore the pharmacokinetics (PK) of this drug in a population of canine oncology patients, with particular attention to the size and sources of PK variability. MATERIALS AND METHODS This prospective study included 82 cases of dogs treated at our Veterinary Teaching Hospital for a variety of malignancies. Doses were administered by a 20 min CRI at 200–300 mg m )2 (1–12.5 mg kg )1 ). Blood samples were collected on heparin- vacutainer tubes at the start of the infusion and then at several times during the following 8 h, averaging five samples per dog. Samples were analysed by HPLC using a method developed and validated in our laboratory (Villarino, 2009). Clinical and demographical covariates were recorded from each case. Data were analysed using Monolix 4.1.2 Software (Lixoft SAS, Orsay, France). RESULTS Data were best fit by a monocompartmental model with zero order input and proportional intra- and inter-individual vari- ability. Population parameter and variability estimates of Vd and Cl were 3.4 l (64% CV) and 57 ml min )1 (56% CV), respectively. Residual CV was 24.5%. Clearance was correlated with body weight (BW), body surface area (BSA) and serum creatinine, but not with age or gender. Volume was correlated with BW and Ó 2012 The Authors Journal of Veterinary Pharmacology and Therapeutics Ó 2012 Blackwell Publishing Ltd, J. vet. Pharmacol. Therap. 35 (Suppl. 3), 2–77