By Bernhard Lippert
30 years after its discovery as an antitumor agent, cisplatin represents this present day some of the most profitable medicinal drugs in chemotherapy. This e-book is meant to reminisce this occasion, to take stock, and to show new traces of improvement during this box. Divided in 6 sections and 22 chapters, the publication offers an updated account on themes such as
- the chemistry and biochemistry of cisplatin,
- the scientific prestige of Pt anticancer drugs,
- the impression of cisplatin on inorganic and coordination chemistry,
- new advancements in drug layout, checking out and delivery.
It additionally features a bankruptcy describing the historic 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 perhaps set off a cascade of mobile reactions that finally bring about apoptosis. p53 and a chain of wear and tear reputation proteins of the HMG-domain relations seem to be concerned. The ebook addresses the matter of mutagenicity of Pt medicinal drugs and increases the query of the prospective relevance of the minor DNA adducts, e.g. of interstrand cross-links, and the prospective use of trans-(NH3)2Pt(II)-modified oligonucleotides in antisense and antigene techniques. Our current realizing of reactions of cisplatin with DNA relies upon a number of version reviews (from remoted version nucleobases to brief DNA fragments) and alertness of a big physique of spectroscopic and different physico-chemical recommendations. because of those efforts there's almost immediately no different steel ion whose reactions with nucleic acids are greater understood than Pt. In a sequence 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, subtle NMR concepts or X-ray crystallography, to get amazing realizing of information on such reactions. Reactivity of cisplatin, as soon as sure to DNA and previously believed to be inert sufficient to stick, is an rising phenomenon. It has (not but) extensively been studied yet is very likely vitally important. Medicinal bioinorganic chemistry - the function of steel compounds in medication - has obtained an immense increase from cisplatin, and so has bioinorganic chemistry as an entire. there's not often 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 - medication, pharmacy, biology, biochemistry. Cisplatin has left its mark additionally on components which are ordinarily thought of mostly inorganic. the topic of mixed-valance Pt compounds is an instance: From the dozing attractiveness it made its solution 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 well-known and reports in huge numbers, and now an organometalic chemistry of those diplatinum (III) species is commencing to emerge. the ultimate component to the booklet is worried with new advancements reminiscent of novel di- and trinuclear Pt(II) medicinal drugs with DNA binding houses varied from these of cisplatin, with orally lively Pt(IV) medications that are almost immediately in medical reviews, and with makes an attempt to switch combinatorial chemistry in the sort of means that it might probably turn into appropriate to quick screening of Pt antitumor medicinal drugs. the possibility of together with computational tools 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
The induction of the new, virus-associated antigens was monitored both by an indirect immunofluorescence test for the coat proteins of the virus appearing at the cell surface, and by the visualization of virus-like particles in the treated cells by electron microscopy. Thus the platinum drug, at least in this case, causes the hypothesized derepression in a cancer cell line, and has enhanced the antigenicity of the cells. While the enhanced antigenicity hypothesis is consistent with a large body of information, and does bridge the gap between molecular events involving the platinum drug interaction with cellular DNA and the host immunologic intervention, it still leaves unexplained the detailed mechanisms of derepression of latent viral genomes, its role in cell transformation and the nature of the immune response.
In order to compare the efficacy of paclitaxel against standard chemotherapy, a clinical trial was performed by the Gynecologic Oncology Group (GOG) to compare the combination of cisplatin and paclitaxel vs. cisplatin and cyclophosphamide. The results indicated that 73% of the patients receiving cisplatin/paclitaxel responded to treatment, whereas 60% of the patients receiving cisplatin/cyclophosphamide responded . Median survival was also significantly higher in the cisplatin/paclitaxel arm (38 month vs.
Subsequent randomized studies confirmed these results [130–132], and Phase-II data suggested that three cycles of induction therapy induced more complete responses that one or two . Thus, while substantial survival improvements were not observed, induction chemotherapy with PF followed by surgery or radiotherapy has become standard therapy for patients with Stage III/IV carcinomas of the larynx and hypopharynx. CISPLATIN – HOW GOOD IS IT? 49 Investigators have also attempted to exploit the synergistic interaction between platinum agents and radiotherapy through concurrent chemoradiotherapy protocols.