The cytotoxic drug cyclo-pentenyl cytosine: from manufacturing to anti-tumor activity and (cardio)toxicity

The cytotoxic drug cyclo-pentenyl cytosine: from manufacturing to

anti-tumor activity and (cardio)toxicity

schimmel, K.J.M.

Citation

Schimmel, K. J. M. (2007, September 5). The cytotoxic drug cyclo-pentenyl cytosine: from

manufacturing to anti-tumor activity and (cardio)toxicity. Retrieved from

https://hdl.handle.net/1887/12298

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the

Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/12298

Note: To cite this publication please use the final published version (if applicable).

KIRSTEN SCHIMMEL

FROM MANUFACTURING

TO ANTI-TUMOR ACTIVITY

AND ( CARDIO ) TOXICITY

THE CYTOTOXIC DRUG

The cytotoxic drug cyclopentenyl cytosine:

From manufacturing to anti-tumor activity and cardiotoxicity

© Kirsten Schimmel

ISBN: 978-90-9021981-3

Graphic design MEGLA | www.megla.nl

Printing Littera Picta

The research presented in this thesis was performed at the Department of Clinical Pharmacy and Toxicology of Leiden University Medical Centre, Leiden, The Netherlands.

The printing of this thesis was financially supported by:

AZL Onderzoeks- en Ontwikkelingskrediet Apotheek

2007 Leiden

THE CYTOTOXIC DRUG

FROM MANUFACTURING

TO ANTI-TUMOR ACTIVITY

AND (CARDIO)TOXICITY

Proefschrift ter verkrijging van

de graad van Doctor aan de Universiteit Leiden,

op gezag van de Rector Magnificus prof. mr. P.F. van der Heijden, volgens besluit van het College voor Promoties

te verdedigen op woensdag 5 september 2007 klokke 13.45 uur door

geboren te Apeldoorn op 22 september 1973

CYCLO-PENTENYL CYTOSINE:

KIRSTEN JOHANNA MARIA SCHIMMEL

Promotor

Prof. Dr. H.J. Guchelaar

Co-promotor Dr. A.J. Gelderblom

Referent

Prof. Dr. J.W.R. Nortier

Promotie-commissie Prof. Dr. A.F. Cohen Prof. Dr. P. Vermeij Dr. A.C. Verschuur

(Academisch Medisch Centrum, Universiteit van Amsterdam)

voor ...

CONTENTS

1

Aim and Outline of the thesis 9

2

Cyclopentenyl cytosine (CPEC): an overview 15

of its in vitro and in vivo activity

3

Formulation, quality control and shelf life 33

of the experimental cytostatic drug cyclopentenyl cytosine

4

Quantitative analysis of the experimental cytotoxic drug 47 cyclopentenyl cytosine (CPEC) and its metabolite in plasma

with HPLC tandem mass spectrometry

5

Limited anti-tumor-effect associated with toxicity 59 of the experimental cytotoxic drug cyclopentenyl cytosine

in NOD/scid mice with acute lymphoblastic leukemia

6

Cardiotoxicity of cytotoxic drugs 75

7

Absence of cardiotoxicity of the experimental cytotoxic 97 drug cyclopentenyl cytosine (CPEC) in rats

8

Doxorubicin and CPEC induced cardiotoxicity: 115

association with the GTPase gene Rac2, and drug transporter genes MRP1 and MRP2

9

General discussion and conclusions 133

Summary 141

Nederlandse samenvatting 144

Dankwoord 149

Curriculum Vitae 150