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Claire HAUVILLE Produits Marins Et Cancers : Les Substances En Cours D'essais Cliniques

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Claire HAUVILLE Produits Marins Et Cancers : Les Substances En Cours D'essais Cliniques UNIVERSITE DE NANTES FACULTE DE PHARMACIE ANNEE 2008 N°48 THESE pour le DIPLOME D’ETAT DE DOCTEUR EN PHARMACIE par Claire HAUVILLE --------------------------------------- Présentée et soutenue publiquement le 20 octobre 2008 Produits marins et cancers : les substances en cours d’essais cliniques. Présidente : Mme Nicole GRIMAUD Maître de Conférences de Pharmacologie Membres du Jury : M. Jean-François BIARD Professeur de Pharmacognosie Mme Martine FOREAU-COUDERT Pharmacien à Sautron 1 Sommaire. Introduction. ........................................................................................................... 7 Partie 1 : Les molécules en essais cliniques de phase II et III……………………………….. 10 I. Les molécules en phase II. ................................................................................................ 10 I.1 Dehydrodidemnine B (Aplidine®) (DDB). ................................................................ 10 1.1.1 Origine et date de découverte. ............................................................................ 11 1.1.2 Structure. ............................................................................................................. 12 1.1.3 Métabolisme in vitro. .......................................................................................... 12 1.1.4 Mode de production actuel……………………………………………………...13 1.1.5 Activité et mécanisme d’action. .......................................................................... 13 A. Activité. ............................................................................................................... 13 B. Mécanisme d’action. ............................................................................................ 14 1.1.6 Toxicité et effets indésirables. ............................................................................. 15 A. Les toxicités musculaires. .................................................................................... 15 B. Les effets indésirables. ........................................................................................ 15 1.1.7 Les études in vitro et in vivo. ............................................................................... 15 B. Les études in vitro. ............................................................................................... 15 A. Les études in vivo. ............................................................................................... 16 1.1.8 Les essais cliniques. ............................................................................................ 16 A. Le cancer de la prostate. ...................................................................................... 16 B. Les tumeurs solides. ............................................................................................ 16 1.1.9 Etat actuel et perspectives. .................................................................................. 17 I.2 La dolastatine 10 : D10. .............................................................................................. 18 1.2.1 Origine et date de découverte. ............................................................................. 18 1.2.2 Structure. ............................................................................................................. 19 1.2.3 Essais de toxicité. ................................................................................................ 19 A. Essais de toxicité pré clinique. ............................................................................ 19 B. Essais de toxicité de phase I. ............................................................................... 20 C. Essais de toxicité de phase II. .............................................................................. 21 1.2.4 Mode de production actuel. ................................................................................. 21 1.2.5 Activité et mécanisme d’action. .......................................................................... 22 1.2.6 Les essais cliniques. ............................................................................................ 22 A. Cancer de la prostate. .......................................................................................... 22 B. Cancer colorectal. ................................................................................................ 23 C. Mélanome. ........................................................................................................... 23 D. Cancer respiratoire. ............................................................................................. 24 E. Cancer hépatobiliaire. .......................................................................................... 24 1.2.7 Etat actuel et perspectives. .................................................................................. 25 I.3 La cématodine (LU 103793), analogue de D15. ......................................................... 26 1.3.1 Origine et découverte. ......................................................................................... 26 2 1.3.2 Structure, formule et mode de production. .......................................................... 27 1.3.3 Activité et mécanisme d’action. .......................................................................... 27 1.3.4 Etude de la toxicité. ............................................................................................. 27 1.3.5 Etudes de phase I sur la pharmacocinétique, la toxicité et les modalités d’administration de la molécule. .................................................................................. 28 1.3.6 Les essais cliniques. ............................................................................................ 30 A. Cancer respiratoire. ............................................................................................. 30 B. Mélanome. ........................................................................................................... 30 C. Cancer du poumon non à petites cellules. ........................................................... 31 1.3.7 Etat actuel et perspectives. .................................................................................. 31 I.4 La synthadotine (ILX 651, tasidotine), analogue de D15. .......................................... 32 1.4.1 Origine et structure. ............................................................................................. 32 1.4.2 Propriétés pharmacocinétiques, métabolisation et toxicité. ................................ 32 1.4.3 Mode de production. ........................................................................................... 35 1.4.4 Activité et mécanisme d’action. .......................................................................... 35 1.4.5 Les essais cliniques. ............................................................................................ 36 1.4.6 Etat actuel et perspectives. .................................................................................. 36 I.5 La bryostatine 1. .......................................................................................................... 37 1.5.1 Origine et date de découverte. ............................................................................. 38 1.5.2 Mode de production. ........................................................................................... 38 1.5.3 Mécanisme d’action. ........................................................................................... 41 1.5.4 Toxicité de la molécule. ...................................................................................... 41 1.5.5 Les essais cliniques. ............................................................................................ 42 A. Mélanome métastasique. ..................................................................................... 42 B. Lymphome non Hodgkinien. ............................................................................... 43 C. Cancers colorectaux. ............................................................................................ 43 D. Carcinome rénal. ................................................................................................. 44 1.5.6 La bryostatine 1 en association. .......................................................................... 45 1.5.7 Etat actuel et perspectives. .................................................................................. 48 I.6 Le kahalalide F : KF. .................................................................................................. 49 1.6.1 La découverte de KF. .......................................................................................... 49 1.6.2 Structure et formule. ............................................................................................ 50 1.6.3 Stabilité chimique et mode de production. .......................................................... 50 1.6.4 Firme propriétaire. ............................................................................................... 51 1.6.5 Activité et mécanisme d’action. .......................................................................... 51 1.6.6 La toxicité et les effets indésirables. ................................................................... 52 1.6.7 Les essais cliniques. ........................................................................................... 53 A. Pré clinique. ........................................................................................................
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