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Author: Stephen B. Howell
Publisher: Springer Science & Business Media
ISBN: 030644027X
Category : Medical
Languages : en
Pages : 563
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Book Description
Taken together the data presented in this review, and work by many other investigators, support the notion that DNA excision repair is important in a tumor cell's resistance to platinum compounds. Inhibition of this repair system by combination chemotherapy with the excision repair inhibitors HU and Ara-C produces synergistic cell kills and increased levels and persistance of DNA interstrand crosslinks. The studies with cis-DDP and ~-DDP in combination with UV induced thymine dimers suggest that there may be competition for DNA repair enzymes between the dimer and the platinum lesion. Whether the competing lesion is an intrastrand crosslink, interstrand crosslink, or platinum monoadduct (or all of these lesions) cannot be determined. The similarity between an intrastrand crosslink and a cyclobutane dimer suggests that these lesions may compete for repair. However, the increased peak levels of interstrand crosslinks, and increased persistence of these lesions at later time points suggest that this lesion may also be a substrate for the repair system. These observations may be of clinical relevance. Recently Dr. Kathy Albain of our institution has completed a Phase III I study using a 12 hour pretreatment with HU and Ara-C in patients prior to their cis-DDP therapy. She observed a significant number of responders in this trial (54). She is currently completing a second Phase IIII study substituting IV HU for the oral formulation. We anticipate initiating other clinical trials based upon these observations.
Author: Stephen B. Howell
Publisher: Springer Science & Business Media
ISBN: 030644027X
Category : Medical
Languages : en
Pages : 563
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Book Description
Taken together the data presented in this review, and work by many other investigators, support the notion that DNA excision repair is important in a tumor cell's resistance to platinum compounds. Inhibition of this repair system by combination chemotherapy with the excision repair inhibitors HU and Ara-C produces synergistic cell kills and increased levels and persistance of DNA interstrand crosslinks. The studies with cis-DDP and ~-DDP in combination with UV induced thymine dimers suggest that there may be competition for DNA repair enzymes between the dimer and the platinum lesion. Whether the competing lesion is an intrastrand crosslink, interstrand crosslink, or platinum monoadduct (or all of these lesions) cannot be determined. The similarity between an intrastrand crosslink and a cyclobutane dimer suggests that these lesions may compete for repair. However, the increased peak levels of interstrand crosslinks, and increased persistence of these lesions at later time points suggest that this lesion may also be a substrate for the repair system. These observations may be of clinical relevance. Recently Dr. Kathy Albain of our institution has completed a Phase III I study using a 12 hour pretreatment with HU and Ara-C in patients prior to their cis-DDP therapy. She observed a significant number of responders in this trial (54). She is currently completing a second Phase IIII study substituting IV HU for the oral formulation. We anticipate initiating other clinical trials based upon these observations.
Author: T.A. Connors
Publisher: Springer
ISBN: 9783642493089
Category : Medical
Languages : en
Pages : 0
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Book Description
It was a great pleasure and honour to have been invited to attend this Seminar and to present a final impression. The association in this field between the Chester Beatty Research Institute and Dr. Rosenberg's School at East Lansing is something which I specially value and many would doubtless like to know how it came about. In the course of its work in carcinogenesis and on chemotherapy over many years, the Chester Beatty Research Institute was frequently drawn to the importance of many metals - as for example lead, iron, metalloid arsenic and the metalloid quali ties of the carcinogenic hydrocarbons. Interest started in platinum many years ago, following the possibility, c1aimed by others, that various complexes between the metal and mercaptopurine might possess significant chemotherapeutic properties. Va rious attempts to confirm such findings ended, however, in complete failure. Interest in platinum was revived by the fresh observations of Dr. Rosenberg and his collea gues, and here the outcome was entirely different. Very soon it was possible to con firm the intense growth-inhibitory properties of cis-platinum (II) diamminedi chloride and related substances. After communicating these results to Dr. Rosenberg, it was a pleasure to welcome hirn in London where he gave a Seminar which greatly engaged the interest of many of the staff. Later, several of these were to enjoy Dr. Rosenberg's hospitality at an international conference on the subject to be held in East Lansing, where many rapidly developing aspects were open for discussion.
Author: Etienne Baulieu
Publisher: Springer Science & Business Media
ISBN: 3642747604
Category : Medical
Languages : en
Pages : 228
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Book Description
With contributions by numerous experts
Author: Astrid Sigel
Publisher: Walter de Gruyter GmbH & Co KG
ISBN: 311047073X
Category : Science
Languages : en
Pages : 588
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Book Description
Volume 18, entitled Metallo-Drugs: Development and Action of Anticancer Agents of the series Metal Ions in Life Sciences centers on biological, medicinal inorganic chemistry. The serendipitous discovery of the antitumor activity of cis-diamminodichloroplatinum(II) (cisplatin) by Barnett Rosenberg in the 1960s is a landmark in metallodrug-based chemotherapy. The success of cisplatin in the clinic, followed by oxaliplatin and carboplatin, along with their drawbacks relating mainly to resistance development and severe toxicity, initiated research on polynuclear platinum complexes and on Pt(IV) complexes as prodrugs. Furthermore, the indicated shortcomings led to the exploration of other transition and main group metal ions, among them Ru(II/III), Au(I/III), Ti(IV), V(IV/V), and Ga(III) including also the essential metal ions Fe(II/III), Cu(I/II), and Zn(II). Ionic as well as covalent and non-covalent interactions between structurally very different complexes and biomolecules like nucleic acids, proteins, and carbohydrates are studied and discussed with regard to their possible anticancer actions. Hence, MILS-18 summarizes the research at the forefront of medicinal inorganic chemistry, including studies on the next-generation, tailor-made anticancer drugs. All this and more is treated in an authoritative and timely manner in the 17 stimulating chapters of this book, written by 39 internationally recognized experts from 10 nations (from the US via Europe to China and Australia). The impact of this vibrant research area is manifested by more than 2700 references, nearly 150 illustrations (more than half in color) and several comprehensive tables. Metallo-Drugs: Development and Action of Anticancer Agents is an essential resource for scientists working in the wide range from enzymology, material sciences, analytical, organic, and inorganic biochemistry all the way through to medicine including the clinic ... not forgetting that it also provides excellent information for teaching.
Author: Shahid Ul Islam
Publisher: John Wiley & Sons
ISBN: 1119640423
Category : Science
Languages : en
Pages : 432
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Book Description
This book is organized into 12 important chapters that focus on the progress made by metal-based drugs as anticancer, antibacterial, antiviral, anti-inflammatory, and anti-neurodegenerative agents, as well as highlights the application areas of newly discovered metallodrugs. It can prove beneficial for researchers, investigators and scientists whose work involves inorganic and coordination chemistry, medical science, pharmacy, biotechnology and biomedical engineering.
Author: Steef van de Velde
Publisher: Springer Science & Business Media
ISBN: 9780306452871
Category : Medical
Languages : en
Pages : 376
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Book Description
The 7th International Symposium on Platinum and other metal coordination compounds in Cancer Chemotherapy, ISPCC '95, organized by the European Cancer Centre, was held in Amsterdam, the Netherlands, March 1-4, 1995. As with previous ISPCC meetings, the goal of ISPCC '95 was to bring together c1inicians, clinical investigators, scientists, and laboratory workers from many disciplines to promote further collaboration and cooperation in the development of new platinum and other metal coordination compounds as weil as in new ways to use 'c1assical' drugs as cisplatin and carboplatin in the treatment of cancer. Important aspects addressed by experts in the field inc1uded the synthesis and activity of new platinum compounds, the biochemistry and molecular pharrnacology as weil as the c1inical pharrnacology of this c1ass of antineoplastic agents, an overview of current c1inical studies, one special minisymposium on the mechanisms of cell kill of platinum, and one on resistance against platinum compounds. Finally, the current status of development of nonplatinum metal complexes was discussed. This volume contains the contributions of the various speakers at ISPCC '95 and provides an up-to-date and comprehensive overview of this important c1ass of anticancer agents, ranging from synthesis and molecular pharrnacology on one hand to c1inical pharrnacology and cIinical investigations on the other hand. The Organizing Corrunittee and Editors wish to express their gratitude to the contributors to this volume, to the various organizations and pharrnaceutical companies for their generous sponsoring of ISPCC '95, and to the Plenum Publishing Company for their help in producing this volume.
Author: Angela Casini
Publisher: Royal Society of Chemistry
ISBN: 1788017676
Category : Science
Languages : en
Pages : 370
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Book Description
Metal-based anticancer drugs are among the most successful therapeutic agents, as evidenced by the frequent prescription of selected platinum and arsenic compounds to patients. Metal-based Anticancer Agents covers the interdisciplinary world of inorganic drug discovery and development by introducing the most prominent compound classes based on different transition metals, discussing emerging concepts and enabling methods, as well as presenting key pre-clinical and clinical aspects. Recent progress on the unique features of next-generation targeted metal-based anticancer agents, including supramolecular coordination complexes used for both therapy and drug delivery, promise a bright future beyond the benefits of pure cytotoxic activity. With contributions from global leaders in the field, this book will serve as a useful reference to established researchers as well as a practical guide to those new to metallodrugs, and postgraduate students of medicinal chemistry and metallobiology.
Author: Marino Nicolini
Publisher: Springer Science & Business Media
ISBN: 1461317177
Category : Medical
Languages : en
Pages : 813
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Book Description
Proceedings of the Fifth International Symposium, held in Abano Terme (Padova), italy, June 29-July 2, 1987
Author: Bernhard Lippert
Publisher: John Wiley & Sons
ISBN: 9783906390208
Category : Medical
Languages : en
Pages : 630
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Book Description
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.
Author: Lloyd R. Kelland
Publisher: Springer Science & Business Media
ISBN:
Category : Medical
Languages : en
Pages : 370
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Book Description
Leading international experts comprehensively review all aspects of platinum anticancer drugs and their current use in treatment, as well as examining their future therapeutic prospects. Writing from a variety of disciplines, these authorities discuss the chemistry of cisplatin in aqueous solution, the molecular interaction of platinum drugs with DNA, and such exciting new areas as DNA mismatch repair and replicative bypass, apoptosis, and the transport of platinum drugs into tumor cells. The emergent platinum drugs of the future-orally active agents, the sterically hindered ZD0473, and the polynuclear charged platinum BBR3464-are also fully considered. Timely and interdisciplinary, Platinum-Based Drugs in Cancer Therapy offers cancer therapeutics specialists an illuminating survey of every aspect of platinum drugs from mechanisms of action to toxicology, tumor resistance, and new analogs.
