Cis-platin

X 16.101 cis-Platin is an anticancer drug with a structure jQ that can be viewed on the Web site, (a) What is the formula and systematic name for the compound cis-jf Platin (b) Draw any isomers that are possible for this compound. Label any isomers that are optically active, (c) What is the coordination geometry of the platinum atom ... 

Bioassays of a considerable number of drugs embodying a combination of porphyrin and cis-platin moieties in the same molecule have led to compound (43) in vitro and in vivo studies on this compound showed a phototoxicity which was additive to the cytotoxic effect of the platinum moiety.190-193... 

Fig. 21. Molecular structures of new aromatic [M(ATSM)] analogs (a) M — Zn(II) and (b) M = Cu(II), (c) cytotoxicity tests in MCF-7 cells for the Zn(II) complex (group 2) and Cu(II) complex (group 3) and comparison with control and with cis-platin over a range of concentrations, (d) cell uptake profile monitored over 90 min, (e) confocal fluorescence imaging of Zn(II) complex in MCF-7 cells, at 100 pM cone, in DMEM, 1% DMSO (112,113).

A 35-year-old female is being treated for cervical cancer with cis-platin. Of the following, how is ci splat in classified ... 

In this review, we present an introduction to the theory, and exemplify the wide range of problems that can be addressed with some illustrative results from our work in the field of ah initio drug design. The problems addressed are those of activation and DNA binding of the antitumor drug cis-platin (PtCl2(NH3)2), and basic spectrometric data from a family of drugs known as psoralens. 

The crystal structure of the sodium salt of 30 (NAMI) is shown in Fig. 9, where Na(I) bridges two molecules of 30 via oxygens of S-bound DMSO and water. This complex may be readily reduced in vivo (E1/2, -0.001 V) (166), whereas the bis-imidazole complex 28 has a lower redox potential and is more difficult to reduce. The reduction potential of 28 is strongly pH dependent (AE = —118 mV/pH unit near pH 7), reduction being more favorable at acidic pH values (167). This complex hydrolyses at a similar rate to cisplatin (ty ca. 3 h at 310 K) and, like cis-platin, aquation appears to be necessary for DNA binding (168). 

Vogelzang, N.J. et al.. Phase III study of pemetrexed in combination with cisplatm versus cis-platin alone in patients with malignant pleural mesothelioma, /. Clin. Oncol, 21, 2636-2644, 2003. 

As a logical step in studies of the antiproliferative action of pool components in tumor cells we studied the antitumor activity of peptides in combination with standard antitumor chemotherapeutic agents (vincristin, metatrexate, cis-platin, epirubicin) [48]. 

Combination studies with PKCa antisense and standard chemotherapeutic agents (cis-platin, mitomycin-C, vinblastine, estracyt and adriamycin) in nude mice that had been transplanted with a variety of human tumors (breast, prostate, large cell lung and small cell lung carcinomas, and melanomas) were found to be additive or superadditive (Geiger et al, 1998). 

Short term treatment with TPA sensitized human 2008 ovarian carcinoma cells to cis-platin. This sensitization disappeared completely by seven hours after treatment, indicating that not inhibition, but activation of PKC sensitizes 2008 cells to the antiproliferative activity of cis-platin (Isonishi et al., 1990). Pretreatment of HeLa cells with TPA or PdBu caused a 9-fold increase in cellular sensitivity to cis-platin and 2.5-fold to melphalan, but had now effect on the antiproliferative activity of bleomycin, adriamycin, vincristine, or mitomycin C. The sensitization of HeLa cells by TPA was associated with a 6-fold stimulation of PKC activation and a concentration- and time-dependent increase in cellular platinum content. (Basu et al. 1990). PKC activity was found to be decreased significantly in cis-platin-resistant human small cell lung H69/CP cancer cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cis-platin. A modest decrease in PKC activity was also observed in etoposide-resistant H69 cells but not in taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells (Basu et al., 1996), indicating that reduced PKC activity leads to decreased sensitivity in this system. 

The influence of PKC on cellular sensitivity or resistance to cis-platin, adriamycin or irradiation may arise from the status of phosphoiylation of raf-1, bcl-2, IkB IkB kinase P, and many others (Grant and Jarvis, 1996 Schbnwasser et al., 1998 Lallena et al., 1999). It has been shown that PKCa phosphorylates raf-1 (Kolch et al, 1993) and bcl-2, leading to resistance (Ruvolo et al, 1998). Raf-1 also interacts with the apoptosis-preventing bcl-2 (Blagosklonny et al, 1997). Phorbol ester treatment of quiescent Swiss 3T3 cells led to cell proliferation, a response thought to be mediated by PKC. In... 

Sanchez-Perez I, Perona R (1999) Lack of c-Jun activity increases survival to cis-platin. FEBS Lett 453 151-158... 

McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cis-platin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl JMed 1996 334 1-6. 

Intravenous silymarin has been demonstrated to lower mortality from Amanita mushroom poisonings, but this formulation is available only in Europe. Animal studies have demonstrated hepatic protection against alcohol, acetaminophen, and mushroom toxins and protection against hepatic fibrosis with bile duct occlusion. There is also evidence of silybin protecting against cis-platin-induced nephrotoxicity in rats. It is not yet clear whether milk thistle extract offers any renal protection to humans. 

Very recently, Lippard has introduced a new model which reinterprets the NMR results of Reedijk and Chotard and which is esthetically more satisfactory. Lippard and his colleagues measured the uptake of both trans- and cis-platin in CV-1 monkey cells infected with SV-40 virus particles. Initially tra/w-platin was taken up more rapidly than cis-platin but DNA concentrations of tawis-platin reached a maximum after eight hours and then dropped rapidly. cis-Platin continued to rise throughout the whole 24 hour period of the experiments and DNA concentrations of cis-platin were very much higher than trans concentrations after 24 hours. The results were interpreted as removal of the bound frans-platin by the repair proteins whereas the bound cis-platin was not removed by the repair mechanism. 

The minor perturbation of the DNA structure caused by cis-platin may well not be detected in a cell which has a deficiency in the repair mechanism, whereas a normal cell might have a more selective repair mechanism. Whether this is the mechanism of action of the platinum anticancer drugs still has to be established, but it is the first model which satisfactorily accounts for all the known chemical and structural restraints. In addition, it suggests further modeling experiments with the more effective second generation drugs. 

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