Cisplatin characterization

Extensive studies have been reported with cisplatin in the field of chemoembolization (59,98). Microspheres prepared by a solvent evaporation procedure were characterized in vitro and critical processing parameters in regard to drug release kinetics were identified. 

Peleg-Shulman T, Gibson D, Cohen R, Abra R, Barenholz Y. Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance. Biochim Biophys Acta 2001 1510 278-291. 

The complex [Ru(tpy)Cl3] binds to DNA, and is active as a cytostatic in L1210 leukemia cells. Its activity lies between those of cisplatin and carboplatin. Model complexes [Ru(tpy)L(H20)] + in which L = 9-ethylguanine or 9-methylhypoxanthine, have been prepared and characterized using NMR spectroscopy. " Proton NMR spectroscopy has been applied to a study of hydrogen bonding between 2, 3 -isopropylidine adenosine and [Ru(tpy)2] derivatives bearing a thymine group. 

Cisplatin was first characterized as a radiation sensitizer using hypoxic Bacillus megaterium spores (53). Radiation sensitization by cisplatin was confirmed in vegetative Escherichia coli with a maximum sensitizer enhancement ratio of 1.77 in anoxic bacteria at a cisplatin concentration of 50 uM (54). Zimbrick et al. (55) extended these studies to other platinum complexes. The earliest studies in mammalian cells used hypoxic V-79 Chinese hamster cells and showed a small radiation sensitization with 8 iM of cisplatin (56). Nias and Szumiel (57) first reported that pretreatment of Chinese hamster ovary (CHO) cells with a platinum complex could sensitize well-oxygenated cells to radiation. Wodinsky etal. (58) showed that cisplatin potentiated the effect of whole-body radiation therapy in mice inoculated intraperitoneally with P388 leukemia compared with either modality alone. Therapeutic potentiation was found in MTG-B subcutaneous tumors and intracerebral RBT when the animals were treated with cisplatin and radiation (59). 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

The distortions induced in the DNA double helix by the interstrand cross-links have been characterized by several techniques. As judged by chemical probes (diethyl pyrocarbonate, hydroxylamine, osmium tetroxide), antibodies to cisplatin-modified poly(dG-dC)-poly(dG-dC), natural (DNase I) and artificial (1,10-phenanthroline-copper complex) nucleases, the cytosine residues are accessible to the solvent, and the distortions are located at the level of the adduct [48-50]. From the electrophoretic mobility of the multimers of double-stranded oligonucleotides containing a single interstrand cross-link [50] it is deduced that the DNA double helix is unwound (79°) and its axis is bent (45°). 

As in the case of the cisplatin interstrand cross-links, several techniques have been used to characterize the distortions induced in the DNA double helix by the transplatin interstrand cross-links. From gel electrophoresis [68] it has been deduced that the DNA double helix is unwound (12°) and its axis is bent (26°) toward the major groove. Chemical probes and DNase I footprinting indicate that the distortion of the double helix spreads over four-... 

Very few structural studies have been concentrated on models of ApG adducts of cisplatin. Conformational analysis of two rotameric forms of the complex m-[Pt(NH3)2(9-MeA-A(7))(9-EtGH-A(7))]2+ has recently been described [40], One of the forms, crystallized as a PI 6 salt, can be characterized as a right-handed helicoidal model for the intrastrand ApG crosslink in double-stranded DNA. The bases in this compound assume a head-to-head orientation (Fig. 6) with the interbase dihedral angles of 81.8° and 87.5°. There are two independent complex cations in the unit cell. The left-... 

The success of cisplatin and carboplatin in treating cancer, combined with the intrinsic and acquired resistance of many tumors to traditional platinum chemotherapy, has generated considerable interest in developing next-generation platinum drugs. Since the discovery of the antitumor activity of cisplatin, researchers have reported the synthesis, characterization, and antitumor activity of thousands of platinum compounds [1] [2]. The previous two chapters in this section describe the promising activity of novel multi-nuclear Ptn and orally active PtIV complexes [3] [4],... 

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