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NEW IN VITRO INTEGRATED APPROACH TO PHARMACO TOXICOLOGY AND METABOLISM IN CANCER CHEMOTHERAPY

Objective

THE IMPACT OF SUCCESSFUL DEVELOPMENT OF SUCH IN VITRO MODELS WOULD BE PROVISION OF METHODS FOR : SCREENING AND PREDICTING MORE ACCURATELY THE POTENTIAL THERAPEUTIC EFFICACY OF NEW DRUGS OR DRUG COMBINATIONS; AND FOR EVALUATING AND REDUCING SIDE EFFECTS OF DRUGS AND/OR DRUG COMBINATIONS BASED ON A BETTER KNOWLEDGE OF THEIR METABOLISM AND THEIR MECHANISM OF ACTION.
Predictive in vitro models have been developed for assessing the therapeutic efficiency and the toxicity (mainly hepatoxicity), including metabolic profiles of anticancer drugs. These include: improving methods for primary culture of human cancer cells; selecting multidrug resistant human cancer cell lines; isolation, cryopreservation and culture of human hepatocytes; development of an organ slicing technique. The integrated set of in vitro models are routinely used in drug development.
SPECIFIC AIMS ARE TO DEVELOP NEW APPROACHES FOR INTEGRATING PHARMACOLOGICAL, TOXICOLOGICAL AND METABOLIC CONCEPTS FOCUSED ON CANCER CHEMOTHERAPY. TO ACHIEVE THESE AIMS, EFFORTS WILL BE DEVOTED TO :
1. AN IMPROVED BASIC UNDERSTANDING AND NEW METHODOLOGICAL DEVELOPMENT OF THE SYSTEMS TO BE USED :
IN DUBLIN (A) BY IMPROVING THE CONDITIONS FOR CELL CULTURES USED AS PREDICTORS FOR DRUG ACTIVITY;
IN MARSEILLE (B) BY IMPROVING THE RECOVERY OF HUMAN HEPATOCYTES AND BY DEVELOPING TECHNIQUES FOR CRYOPRESERVATION;
IN BRUSSELS (C) BY IMPROVING THE TECHNOLOGY OF SLICE PREPARATION AND THE CONDITIONS FOR THEIR INCUBATION.
2. THE DEVELOPMENT OF AN INTEGRATED STRATEGY :
IN A, TO DEVELOP CELL CULTURE METHODS WHICH MIGHT ALLOW PREDICTION OF TISSUE-SPECIFIC PHARMACOLOGICAL EFFECTS AND SIDE-EFFECTS OF CANCER CHEMOTHERAPEUTIC AGENTS (WITH ALSO SOME REFERENCE TO ANTIBIOTICS) AND THEIR METABOLITES, AS WELL AS COMBINATIONS OF DIFFERENT DRUGS;
IN C, TO EVALUATE THE POTENTIAL TOXICITY, MAINLY NEPHROTOXICITY (WITH REFERENCE TO HAPATOTOXICITY), OF DRUGS AND/OR THEIR METABOLITES BUT ALSO OF DRUG COMBINATIONS;
IN B, TO PREDICT MORE RAPIDLY THE METABOLIC PROFILES AND THE ROLE OF THE METABOLITES IN THE OVERALL PHARMACOLOGICAL AND TOXICOLOGICAL CELLULAR RESPONSE TO DRUGS AND DRUG COMBINATIONS.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

UNIVERSITE CATHOLIQUE DE LOUVAIN
Address
Place Montesquieu 7
1348 Louvain-la-neuve
Belgium

Participants (2)

INSERM
France
Address

Marseille
NATIONAL INSTITUTE FOR HIGHER EDUCATION
Ireland
Address

Dublin