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Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug

Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug

Bernhard Lippert (Editor)

ISBN: 978-3-906-39042-0

Nov 2006

576 pages

Select type: O-Book


30 years after its discovery as an antitumor agent, cisplatin represents today one of the most successful drugs in chemotherapy. This book is intended to reminisce this event, to take inventory, and to point out new lines of development in this field. Divided in 6 sections and 22 chapters, the book provides an up-to-date account on topics such as
- the chemistry and biochemistry of cisplatin,
- the clinical status of Pt anticancer drugs,
- the impact of cisplatin on inorganic and coordination chemistry,
- new developments in drug design, testing and delivery.
It also includes a chapter describing the historical development of the discovery of cisplatin. The ultimate question - How does cisplatin kill a cell? - is yet to be answered, but there are now new links suggesting how Pt binding to DNA may trigger a cascade of cellular reactions that eventually result in apoptosis. p53 and a series of damage recognition proteins of the HMG-domain family appear to be involved. The book addresses the problem of mutagenicity of Pt drugs and raises the question of the possible relevance of the minor DNA adducts, e.g. of interstrand cross-links, and the possible use of trans-(NH3)2Pt(II)-modified oligonucleotides in antisense and antigene strategies. Our present understanding of reactions of cisplatin with DNA is based upon numerous model studies (from isolated model nucleobases to short DNA fragments) and application of a large body of spectroscopic and other physico-chemical techniques. Thanks to these efforts there is presently no other metal ion whose reactions with nucleic acids are better understood than Pt. In a series of chapters, basic studies on the interactions of Pt electrophiles with nucleobases, oligonucleotides, DNA, amino acids, peptides and proteins are reported, which use, among others, sophisticated NMR techniques or X-ray crystallography, to get remarkable understanding of details on such reactions. Reactivity of cisplatin, once bound to DNA and formerly believed to be inert enough to stay, is an emerging phenomenon. It has (not yet) widely been studied but is potentially extremely important. Medicinal bioinorganic chemistry - the role of metal compounds in medicine - has received an enormous boost from cisplatin, and so has bioinorganic chemistry as a whole. There is hardly a better example than cisplatin to demonstrate what bioinorganic chemistry is all about: The marriage between classic inorganic (coordination) chemistry and the other life sciences - medicine, pharmacy, biology, biochemistry. Cisplatin has left its mark also on areas that are generally considered largely inorganic. The subject of mixed-valance Pt compounds is an example: From the sleeping beauty it made its way to the headlines of scientific journals, thanks to a class of novel Pt antitumor agents, the so-called "platinum pyrimidine blues". In the aftermath diplatinum (III) compounds were recognized and studies in large numbers, and now an organometalic chemistry of these diplatinum (III) species is beginning to emerge. The final section of the book is concerned with new developments such as novel di- and trinuclear Pt(II) drugs with DNA binding properties different from those of cisplatin, with orally active Pt(IV) drugs which are presently in clinical studies, and with attempts to modify combinatorial chemistry in such a way that it may become applicable to fast screening of Pt antitumor drugs. The potential of including computational methods in solving questions of Pt-DNA interactions is critically dealt with in the concluding chapter.
Platinum Complexes for the Treatment of Cancer: Why the Search goes on
Clinical Status of Cisplatin and other Pt Antitumor Drugs
The Response of Cellular Proteins to Cisplatin -
Damaged DNA
The Mechanism of Action of Cisplatin: From Adducts to Apoptosis
Replication of Platinated DNA and its Mutagenic Consequences
Interstand Cross-Links in Cisplatin- or Transplatin-Modified DNA
Platinum Complexes: Hydrolysis and Binding to N7 and N1 of Purines
Reactivity and Inertness of Pt-Nucleobase Complexes
Kinetics and Selectivity of DNA Platination
Structure and Dynamics of Pt Anticancer Drug Adducts from Nucleotides to Oligonucleotides as Revealed by NMR Methods
Pt and 15N NMR Spectroscopic Studies of Cisplatin Reactions with Biomolecules
Structural Aspects of Pt-Purine Interactions: From Models to DNA
Platinum-Sulfur Interactions involved in Antitumor Drugs, Rescue Agents and Biomolecules
Diammine- and Diamineplatinum Complexes with Non-Sulfur-Containing Amino Acids and Peptides
Platinum Blues: On the Way toward Unraveling a Mystery
Heteronuclear Pt(II) Complexes with Pyrimidine Nucleobases
Diplatinum(III) Complexes: Chemical Species more widely spread than suspected
Inorganic and Organometallic Chemistry of Cisplatin-Derived PT(III) Complexes
Structure-Activity Relationships within Di- and Trinuclear Platinum Phase I Clinical Anticancer Agents
The Development of Orally-active Platinum Drugs
Methods for Screening the Potential Antitumor Activity of Platinum Compounds in Combinatorial Libraries
Computational Studies on Platinum Antitumor Complexes and their Adducts with Nucleid Acids Constituents