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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

New criteria for analyzing the statistical relationships between biological parameters and therapeutic responses of xenografted tumor models

Georges Pompidou European Hospital, Paris, France, INSERM U612, Paris, France, Federation de Neurologie Mazarin, Groupe Hospitalier Pitie-Salpetriere, Paris, France, EA 3974, Paris, France

Abstract

B7

Preclinical studies using human tumors directly obtained from surgical samples and xenografted into immunodeficient rodents are helpful for evaluating the antitumoral activity of anti-cancer compounds. In these models, analysis of experimental data is commonly performed with two surrogate end-points of therapeutic response: the Tumor Growth Index and the Tumor Growth Delay index. To circumvent the limitations of these current parameters, two new parameters, Time To Relapse (TTR) and Tumor Growth Speed (TGS), were developed using a mathematical modeling approach based on an exponential tumor growth. TTR is similar to progression free survival used in clinical trials and TGS characterizes the pattern of tumor cell proliferation. Parameters were estimated by the maximum likelihood method and statistical analyses were performed using ANOVA.These criteria can be used each time tumors are assessed by repeated measures of their volume. As an example, we used data from a previously published study, which aimed to evaluate the relationship between histology, genetic parameters and response to different alkylating agents (Temozolomide (TMZ), BCNU, Ifosfamide and Carboplatin) in a series of 12 xenografts of human gliomas (8 oligodendroglial and 4 glioblastoma tumors (GBM)). These data were partially reanalyzed using our new criteria. The TMZ treated group presented a significantly longer TTR than the control group. TTR was also different according to tumor type, with oligodendrogliomas relapsing later than GBM. TGS were different according to the tumor type. After relapse, GBM demonstrated a faster growth rate than oligodendrogliomas. Compared to control groups, TGS were similar for tumors whose volume did not decrease after chemotherapy and faster for tumors whose volume decreased after chemotherapy. LOH 1p+/-19q, LOH 10p+/-10q, telomerase activity, PTEN mutation, and EGFR amplification were related to TMZ efficacy.Our new criteria are complementary to existing criteria. They provide more qualitative information about the pattern of response to chemotherapy and the related genetic alterations. Our approach may be useful in the preclinical development of targeted compounds and for studying tumor growth characteristics after relapse.