BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

TABLE OF CONTENTS
CHAPTER 1. INTRODUCTION .....................................................................................1
1.1 Drug Penetration in Solid Tumors .......................................................................1
1.1.1 Features of tumor microenvironment ...............................................................1
1.1.2 Determinants for drug penetration in solid tumors ...........................................2
1.1.3 Strategies to improve drug penetration in solid tumors ....................................4
1.2 Angiogenesis and Anti-angiogenic Therapy ........................................................5
1.2.1 Angiogenesis in solid tumors ...........................................................................5
1.2.2 Role of vascular endothelial growth factor in tumor growth and
angiogenesis .....................................................................................................6
1.2.3 Anti-angiogenesis therapy and tumor vasculature normalization ....................6
1.2.4 BEV in preclinical studies ................................................................................7
1.2.5 BEV in patients .................................................................................................7
1.3 Rh30 Rhabdomyosarcoma as a Tumor Model ....................................................9
1.3.1 Rhabdomyosarcoma .........................................................................................9
1.3.2 Characteristics of Rh30 cell line .....................................................................10
1.4 Methods to Evaluate Drug Penetration in Solid Tumors ...................................11
1.4.1 Homogenization and quantitative imaging .....................................................11
1.4.2 Microdialysis ..................................................................................................12
1.5 The Effects of Anti-angiogenic Agents on the Pharmacokinetics of
Cytotoxic Drugs ................................................................................................13
1.5.1 The effects of anti-angiogenic agents on cytotoxic drugs disposition in
solid tumors ....................................................................................................13
1.5.2 The effects of BEV on cytotoxic drugs disposition in solid tumors ...............16
1.6 Pharmacokinetic Models of TPT in Preclinical Studies ....................................17
1.7 Summary ............................................................................................................18
1.8 Specific Aims .....................................................................................................19
CHAPTER 2. THE EFFECT OF BEVACIZUMAB ON THE
PHARMACOKINETICS OF TOPOTECAN IN A RH30
RHABDOMYOSARCOMA XENOGRAFT .................................................................20
2.1 Introduction ........................................................................................................20
2.2 Materials and Methods .......................................................................................21
2.2.1 Materials and chemicals .................................................................................21
2.2.1 Cell culture .....................................................................................................21
2.2.3 Animals ...........................................................................................................21
2.2.4 Tumor model and treatment ...........................................................................22
2.2.5 In vivo tumor microdialysis ............................................................................23
2.2.6 High-performance liquid chromatography analysis for PK studies ...............27
2.2.7 Pharmacokinetic model evaluation .................................................................27
2.2.8 Population pharmacokinetic analysis .............................................................29
2.2.9 Covariate analysis ...........................................................................................29
2.2.10 Statistical analyses ..........................................................................................30
2.3 Results ................................................................................................................30
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