Cisplatin: Chemistry and Biochemistry of a Leading by Bernhard Lippert PDF

By Bernhard Lippert

ISBN-10: 3906390209

ISBN-13: 9783906390208

30 years after its discovery as an antitumor agent, cisplatin represents at the present time probably the most winning medications 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 ebook presents an up to date account on issues such as
- the chemistry and biochemistry of cisplatin,
- the scientific prestige of Pt anticancer drugs,
- the effect of cisplatin on inorganic and coordination chemistry,
- new advancements in drug layout, trying out and delivery.
It additionally incorporates a bankruptcy describing the ancient improvement of the invention of cisplatin. the final word query - How does cisplatin kill a mobile? - is but to be spoke back, yet there are actually new hyperlinks suggesting how Pt binding to DNA may possibly set off a cascade of mobile reactions that at last bring about apoptosis. p53 and a sequence of wear and tear acceptance proteins of the HMG-domain kinfolk seem to be concerned. The ebook addresses the matter of mutagenicity of Pt medicines and increases the query of the potential 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 thoughts. Our current realizing of reactions of cisplatin with DNA is predicated upon a variety of version reports (from remoted version nucleobases to brief DNA fragments) and alertness of a big physique of spectroscopic and different physico-chemical thoughts. 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, uncomplicated experiences at the interactions of Pt electrophiles with nucleobases, oligonucleotides, DNA, amino acids, peptides and proteins are mentioned, which use, between others, refined NMR suggestions or X-ray crystallography, to get awesome knowing of info on such reactions. Reactivity of cisplatin, as soon as guaranteed to DNA and previously believed to be inert sufficient to stick, is an rising phenomenon. It has (not but) generally been studied yet is probably very important. Medicinal bioinorganic chemistry - the function of steel compounds in drugs - has obtained an important strengthen 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 lifestyles sciences - drugs, pharmacy, biology, biochemistry. Cisplatin has left its mark additionally on components which are ordinarily thought of principally inorganic. the topic of mixed-valance Pt compounds is an instance: From the slumbering good looks it made its approach to the headlines of clinical 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 reports in huge numbers, and now an organometalic chemistry of those diplatinum (III) species is starting to emerge. the ultimate component to the publication is anxious with new advancements comparable to novel di- and trinuclear Pt(II) medicines with DNA binding houses various from these of cisplatin, with orally energetic Pt(IV) medicines that are almost immediately in medical stories, and with makes an attempt to switch combinatorial chemistry in this kind of approach that it might probably develop into appropriate to speedy screening of Pt antitumor medicinal drugs. the potential for together with computational tools in fixing questions of Pt-DNA interactions is severely handled within the concluding chapter.

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35 major adducts formed are d(GpG)Pt and d(ApG)Pt intrastrand crosslinks. Saris et al. [19] showed that at equimolar concentrations in cultured cells, oxaliplatin forms fewer intrastrand crosslinks than cisplatin. Oxaliplatin is active in several cisplatin-resistant tumor cell lines [20]. Moreover, comparative analysis of the results from the NCI human tumor screen suggests that oxaliplatin and other DACH-ligand-containing platinum drugs form a distinct family of agents with a pattern of tumor sensitivity that differs from that of cisplatin [21][22].

Similarly, if the optimal dose cures the large tumors, then a much smaller dose should cure the smaller tumors. This, too, is contrary to our experiments. Something other than direct chemical cell kill must be operating to achieve cures. Dead Sarcoma-180 cells injected into mice do not cause tumors, neither do they induce an immune reaction to reimplanted live tumor cells. Here one must be cautious since only small numbers of live implanted cells (~ 40) can eventually lead to large tumors and death.

However, the success of combination chemotherapy regimens in other tumor types led investigators to pursue combination chemotherapy. Phase II combination studies of cisplatin paired with vindesine (VP) [72] and etoposide (EP) [73], or incorporated into triplets with mitomycin C and vinblastine (MVP) [74], and cyclophosphamide and doxorubicin (CAP) [75] revealed increments in response rates (30–53%). Results of larger randomized studies conducted by the ECOG investigating these and other combinations underscored the shortcomings of smaller single-institution studies: MVP was associated with the highest response rate (31%), yet no combination conferred a clear survival advantage [76][77].

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Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug by Bernhard Lippert


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