Cisplatin : chemistry and biochemistry of a leading anticancer drug

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. booktextfm.pdf......Page 1 booktext.pdf......Page 12 booktext_001.pdf......Page 38 booktext_002.pdf......Page 78 booktext_003.pdf......Page 117 booktext_004.pdf......Page 141 booktext_005.pdf......Page 164 booktext_006.pdf......Page 186 booktext_007.pdf......Page 211 booktext_008.pdf......Page 226 booktext_009.pdf......Page 249 booktext_010.pdf......Page 294 booktext_011.pdf......Page 320 booktext_012.pdf......Page 339 booktext_013.pdf......Page 363 booktext_014.pdf......Page 377 booktext_015.pdf......Page 403 booktext_016.pdf......Page 427 booktext_017.pdf......Page 452 booktext_018.pdf......Page 473 booktext_019.pdf......Page 492 booktext_020.pdf......Page 517 booktext_021.pdf......Page 531 booktextind.pdf......Page 551 "Since Rosenberg's serendipitous discovery of its antitumor activity, cisplatin has become one of the greatest success stories of cancer chemotherapy. This book compiles in six Parts the various aspects of chemistry, biochemistry, biology, pharmacology, and medicine relevant to cisplatin, describing new links that suggest how cisplatin may trigger a cascade of cellular events that result ultimately in apoptosis."--BOOK JACKET. "This volume provides all scientists, from coordination chemists to oncologists, with a unique resource detailing the state-of-the-art and future research perspectives, together with the fascinating story, of cisplatin."--Jacket "Since Rosenberg's serendipitous discovery of its antitumor activity, cisplatin has become one of the greatest success stories of cancer chemotherapy. This book compiles in six Parts the various aspects of chemistry, biochemistry, biology, pharmacology, and medicine relevant to cisplatin, describing new links that suggest how cisplatin may trigger a cascade of cellular events that result ultimately in apoptosis." "This volume provides all scientists, from coordination chemists to oncologists, with a unique resource detailing the state-of-the-art and future research perspectives, together with the fascinating story, of cisplatin."--BOOK JACKET 30 years after its discovery by Rosenberg as an antitumor agent, cisplatin represents one of the most successful drugs in cancer chemotherapy. This book presents the developments in this field. It provides an account on topics such as: the chemistry and biochemistry of cisplatin; the clinical status of Pt anticancer drugs; and others. This text describes the history of cisplatin, offering an account of the clinical status of Pt antitumor agents. It deals with the biochemistry of cisplatin, providing modern views of the mode action, and focuses on the chemistry relevant to interactions of Pt(II) species with biomolecules.