By Bernhard Lippert
30 years after its discovery as an antitumor agent, cisplatin represents this present day some of the most profitable medicines in chemotherapy. This booklet is meant to reminisce this occasion, to take stock, and to indicate new traces of improvement during this box. Divided in 6 sections and 22 chapters, the publication offers an up to date account on issues such as
- the chemistry and biochemistry of cisplatin,
- the medical prestige of Pt anticancer drugs,
- the influence of cisplatin on inorganic and coordination chemistry,
- new advancements in drug layout, trying out and delivery.
It additionally encompasses a bankruptcy describing the ancient improvement of the invention of cisplatin. the final word query - How does cisplatin kill a phone? - is but to be replied, yet there at the moment are new hyperlinks suggesting how Pt binding to DNA may well set off a cascade of mobile reactions that at last bring about apoptosis. p53 and a chain of wear and tear reputation proteins of the HMG-domain relatives seem to be concerned. The e-book addresses the matter of mutagenicity of Pt medicines and increases the query of the prospective relevance of the minor DNA adducts, e.g. of interstrand cross-links, and the potential use of trans-(NH3)2Pt(II)-modified oligonucleotides in antisense and antigene recommendations. Our current realizing of reactions of cisplatin with DNA relies upon a variety of version reports (from remoted version nucleobases to brief DNA fragments) and alertness of a giant physique of spectroscopic and different physico-chemical options. due to those efforts there's shortly no different steel ion whose reactions with nucleic acids are greater understood than Pt. In a chain of chapters, simple experiences at the interactions of Pt electrophiles with nucleobases, oligonucleotides, DNA, amino acids, peptides and proteins are stated, which use, between others, refined NMR ideas or X-ray crystallography, to get awesome realizing of info on such reactions. Reactivity of cisplatin, as soon as certain to DNA and previously believed to be inert sufficient to stick, is an rising phenomenon. It has (not but) broadly been studied yet is possibly vitally important. Medicinal bioinorganic chemistry - the function of steel compounds in medication - has acquired an incredible advance from cisplatin, and so has bioinorganic chemistry as an entire. there's hardly ever a greater instance than cisplatin to illustrate what bioinorganic chemistry is all approximately: the wedding among vintage inorganic (coordination) chemistry and the opposite existence sciences - drugs, pharmacy, biology, biochemistry. Cisplatin has left its mark additionally on components which are normally thought of principally inorganic. the topic of mixed-valance Pt compounds is an instance: From the sound asleep good looks it made its option to the headlines of medical journals, due to a category of novel Pt antitumor brokers, the so-called "platinum pyrimidine blues". within the aftermath diplatinum (III) compounds have been famous and experiences in huge numbers, and now an organometalic chemistry of those diplatinum (III) species is starting to emerge. the ultimate component of the e-book is anxious with new advancements equivalent to novel di- and trinuclear Pt(II) medicines with DNA binding homes various from these of cisplatin, with orally energetic Pt(IV) medicinal drugs that are almost immediately in medical stories, and with makes an attempt to switch combinatorial chemistry in the sort of approach that it could possibly turn into acceptable to quick screening of Pt antitumor medicinal drugs. the potential for together with computational equipment in fixing questions of Pt-DNA interactions is seriously handled within the concluding chapter.
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Additional info for Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug
Thompson, R. J. P. Williams, S. Reslova, Struct. Bonding (Berlin) 1972, 11, 1. ‘Platinum Coordination Complexes in Cancer Chemotherapy’, Eds. T. A. Connors, J. J. Roberts, Springer, New York 1974, p. 79. 29 Part 2. Cisplatin – How Good is it? Clinical Status of Cisplatin, Carboplatin, and Other Platinum-Based Antitumor Drugs Peter J. O’Dwyer, James P. Stevenson, and Steven W. Johnson Cisplatin. Edited by Bernhard Lippert © Verlag Helvetica Chimica Acta, Postfach, CH8042 Zürich, Switzerland, 1999 Clinical Status of Cisplatin, Carboplatin, and Other Platinum-Based Antitumor Drugs Peter J.
Early trials in the 1960’s and 1970’s with non-platinum-containing regimens were negative, while studies with platinum-based therapies produced mixed results. 08) . No clear consensus regarding adjuvant therapy has emerged. The superior response rate observed when cytotoxic agents are administered pre-operatively in a variety of tumors prompted studies of induction regimens in locally advanced (Stage IIIA/B) NSCLC. A landmark CALGB study reported a four month increase in median survival and a doubling in the number of three-year survivors with two cycles of cisplatin and vinblastine administered prior to radiotherapy vs.
1,2-Diaminocyclohexane (DACH) Derivatives and their Analogues. The initial screening for platinum analogues with broader antitumor activity was conducted in murine leukemias with acquired resistance to cisplatin (reviewed by Harrap ). Compounds containing the DACH ligand as a stable carrier group were first synthesized by Connors et al. , and Burchenal et al. first demonstrated their activity in murine models . Based on these studies (reviewed in ), a number of compounds were developed for potential clinical use: DACH-(malonato)platinum(II) was insufficiently soluble , DACH-(4-carboxyphthalato)platinum(II) was not active in limited Phase-II testing , and tetraplatin (ormaplatin) caused severe and cumulative neurotoxicity in Phase-I trials .
Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug by Bernhard Lippert