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PubMedDate not supplied

A combination of platinum and tamoxifen in advanced ovarian cancer failing platinum-based chemotherapy: results of a Phase II study.

The treatment of recurrent or progressive ovarian cancer has limited therapeutic potential. The clinical outcome of second-line therapy largely depends on the potential chemo-sensitivity of the tumor expressed during up-front chemotherapy, as well as on the treatment-free interval from the last course of cytotoxic therapy. However, the identification of agents such as tamoxifen (TAM) at nontoxic doses, able to act synergistically with standard chemotherapy, may be useful to overcome resistance. Fifty patients with recurrent or progressive ovarian cancer following platinum (P)-based chemotherapy (28 platinum-resistant and 22 platinum-sensitive) entered a Phase II trial to evaluate the efficacy and toxicity of P re-challenge with the addition of TAM as a chemotherapy response modulator. The choice of the P compound (100 mg/m2 cisplatin or 400 mg/m2 carboplatin, q3 weeks) was made on the basis of the prior total cisplatin dose and the presence of neurotoxicity. TAM was administered at the doses of 80 mg/day for 30 days followed by 40 mg/day for the remaining period of treatment. Toxicity consisted mainly of mild to moderate nausea and vomiting (76%), peripheral neuropathy (43%), nephrotoxicity (4%), anemia (16%), leukopenia (58%) and thrombocytopenia (16%). The overall response to the P-TAM combination was 50% (complete response 30%; partial response 20%) with a median duration of 8.5 months (3-42). Sixty-four percent of the P-sensitive and 39% of the P-resistant patients responded (59% and 33%, respectively, for those bearing measurable disease). The overall median survival was 23 (3-48) and 19 months for the patients with measurable disease (20 months for the P-resistant group). This phase II trial confirmed the activity for a re-challenge employing a P compound and TAM in clinically defined P-resistant ovarian cancer patients. The mild toxicity profile and the relatively low cost of the treatment render further investigations on the P-TAM regimen worthwhile.

Adenocarcinoma, Clear Cell↗
PubMed1991

The role of murine tumour models and their acquired platinum-resistant counterparts in the evaluation of novel platinum antitumour agents: a cautionary note.

Two murine tumour models, the L1210 leukaemia and the ADJ/PC6 plasmacytoma, have featured prominently in the preclinical development of platinum drugs. Mindful of the unequivocal need to discover new platinum-based drugs exhibiting activity in cisplatin/carboplatin refractory and relapsed cancers, and to devise clinically-predictive screening models, we have generated resistance in vivo in the ADJ/PC6 plasmacytoma to cisplatin (19- to 21-fold), to carboplatin (25-fold), iproplatin (greater than 14-fold) and tetraplatin (10-fold). The chemo-sensitivity profiles of these tumours have been compared with L1210 leukaemia lines resistant to either cisplatin (10-fold) or tetraplatin (34-fold). In cross-resistance studies, the L1210 and ADJ/PC6 resistant variants provided conflicting predictions of structures likely to circumvent cisplatin-acquired resistance. In particular, the L1210/cisplatin resistant model exhibited cross-resistance to carboplatin and iproplatin, whereas the diaminocyclohexane (DACH)-containing complex, tetraplatin, was even more active in the cisplatin resistant tumour than in the 'wild-type' tumour. The ADJ/PC6/cisplatin resistant tumour, however, was cross-resistant, not only to carboplatin and iproplatin, but also to tetraplatin. These data provide an important caveat on the adoption of single acquired resistant animal tumour models for platinum drug development.

Animals↗
PubMed2004

Paclitaxel and carboplatin as second-line therapy in women with platinum-sensitive ovarian carcinoma treated with platinum and paclitaxel as first-line therapy.

The study was performed to assess response rate, progression-free interval (PFI), and side effects of the combination paclitaxel and carboplatin as second-line therapy among women with platinum-sensitive epithelial ovarian carcinoma (EOC). Thirty women who achieved partial surgical response at second-look surgery (n = 8) or who had recurrence (n = 22) more than 6 months after treatment with platinum-based chemotherapy were treated with paclitaxel (135 mg/m2 for 3 hours) and carboplatin (area under the concentration-time curve 5) every 3 weeks. Response rate, PFI, and side effects of treatment were recorded. One hundred sixty-seven cycles of treatment (median = 6, range = 2-11) were administered. Among 22 patients with measurable or assessable disease, 14 had complete response and 3 had partial response. Five patients had progressive disease. The overall response rate was 77%. The median PFI was 10 months (range = 1-29). Among 22 patients in whom recurrence or progression developed after second-line therapy, the median interval was 9 months (range = 1-26). The incidence of grade III or IV neutropenia, leukopenia, and thrombocytopenia was 48%, 27%, and 3%, respectively. One patient discontinued treatment secondary to persistent thrombocytopenia. Eight patients died secondary to their disease. It was concluded that the combination paclitaxel and carboplatin has a high success rate, long duration of response, and is well tolerated as a second-line therapy among patients with platinum-sensitive EOC.

Adult↗
PubMed2002

Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells.

Molecular bases for targeting bile acid-cisplatin derivatives Bamet-R2 [cis-diammine-chloro-cholylglycinate-platinum(II)] and Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)] toward liver cells were investigated. Carriers for bile acids [human Na(+)-taurocholate cotransporting polypeptide (NTCP)], organic anions [organic anion transporting polypeptide (OATP)], and organic cations [organic cation transporter (OCT)] were expressed in Xenopus laevis oocytes (XO) and Chinese hamster ovary (CHO) cells. Drug uptake was measured by flameless atomic absorption of platinum. Rat Oatp1- or rat Ntcp-transfected CHO cells were able to take up Bamets, but not cisplatin, severalfold more efficiently than wild-type cells. This uptake was enhanced by butyrate-induced expression of both carriers. Uptake of both Bamets by Ntcp-transfected CHO cells was stimulated by extracellular sodium. The amount of Bamets, but not cisplatin, taken up by XO was enhanced when expressing OATP-A, OATP-C, NTCP, OCT1, or OCT2, a nonhepatic OCT isoform used for comparative purposes. Bamet uptake by XO was inhibited by known substrates of these carriers (glycocholate for NTCP and OATP-C, ouabain for OATP-A, and quinine for OCT1 and OCT2). Drug uptake versus substrate concentration revealed saturation kinetics (K(m) was in the 8-58 microM range), with the following order of efficiency of transport (V(max)/K(m)) for Bamet-R2: OATP-C > OCT2 > OATP-A > NTCP > OCT1; and the following order of efficiency of transport for Bamet-UD2: OATP-C > OCT2 > OATP-A > OCT1 > NTCP. Increasing the generation of cationic forms of Bamets by incubation in the absence of chloride increased drug uptake by OATP-A, OCT1, and OCT2 but reduced that achieved by NTCP and OATP-C. These results suggest a role for carriers of organic anions and cations in Bamet-R2 and Bamet-UD2 uptake, which may determine their ability to accumulate in liver tumor cells and/or be taken up and efficiently excreted by hepatocytes.

Animals↗
PubMed1987

Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity.

Ultrafilterable platinum (UP) disposition was studied in 22 cancer patients receiving their first course of cisplatin (50 to 140 mg/m2) by two-hour infusion. UP plasma and urinary platinum levels were quantitated using a high-performance liquid chromatographic (HPLC) assay, which was selective for cisplatin and active platinum metabolites. Creatinine clearance was determined in all patients at the time of the pharmacokinetic studies and ranged from 58 to 214 mL/min. Creatinine clearance was a poor predictor of UP disposition in patients, probably as a consequence of the complex renal clearance mechanism for UP in the human kidney, which involves both tubular secretion and reabsorption. However, the peak plasma level of UP was closely related to the area under curve (AUC) of UP (r2 = .831), P less than .0001) and was significantly correlated with the decline in creatinine clearance observed after four courses of cisplatin therapy to 12 of the patients (r2 = .727, P less than .005). Cisplatin dose and the AUC of UP were less satisfactory predictors of the change in creatinine clearance with four courses of therapy (r2 = .488, P less than .025 and r2 = .623, P less than .005). The large interpatient variability in all the parameters of cisplatin disposition measured in this study suggested that there may be a role for individualization of cisplatin dosage based on a peak level obtained in the first course of therapy. Longer term infusion of cisplatin could also be justified.

Adult↗
PubMed1993

Synthesis, structure and antitumor activity of a new water-soluble platinum complex, (1R,2R-cyclohexanediamine-N,N')[2-hydroxy-4-oxo-2-pentenoato(2-)-O2] platinum(II).

The reaction of dihydroxo(1R,2R-cyclohexanediamine)platinum(II) with 2,4-dioxopentanoic acid gave a water-soluble complex, (1R,2R-cyclohexanediamine-N,N')[2-hydroxy-4-oxo-2-pentenoato (2-)-O2] platinum(II). The structure of the complex was determined by X-ray crystal analysis. The data indicated a chelation of the acetylacetonato part of 2,4-dioxo-pentanoic acid to platinum(II). The complex showed moderate antitumor activity against murine leukemia L1210 in mice (T/C = 195% at a dose of 200 mg/kg) and high activity against cisplatin-resistant L1210 leukemia (T/C = 275% at a dose of 25 mg/kg).

Animals↗
PubMed1999

Expression of p53 in cisplatin-resistant ovarian cancer cell lines: modulation with the novel platinum analogue (1R, 2R-diaminocyclohexane)(trans-diacetato)(dichloro)-platinum(IV).

The compound (1R,2R-diaminocyclohexane)(transdiacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug-induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH-acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC50, 1.2-3.3 microM) than it was against those harboring wild-type p53 (IC50, 2.8-9.9 microM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC50, 0.17-1.5 microM) than it was in mutant or null models (IC50, 2.7-11.3 microM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH-acetato-Pt by 3-5-fold, which confirmed the drug's dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild-type and mutant p53 cells in G2-M, whereas DACH-acetato-Pt arrested wild-type p53 cells in G1 and mutant p53 cells in G2-M. The G1 arrest by DACH-acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (< or =25 microM) of DACH-acetato-Pt induced marked increases in p53 and p21Waf1/Cip1 expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21Waf1/Cip1 until the drug concentration was increased to 125 microM. In HPV 16 E6 transfectants of OVCA-429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21Waf1/Cip1 were abrogated. This suggests that p21Waf1/Cip1 increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.

Antineoplastic Agents↗
PubMed2000

Transfer of 4'-chloro-2,2':6',2"-terpyridine platinum(II) between human serum albumin, glutathione and other thiolate ligands. A possible selective natural transport mechanism for the delivery of platinum(II) drugs to tumour cells.

The antitrypanosomal and antitumour activities of (2,2':6',2"-terpyridine)platinum(II) complexes have been postulated to be due to their ability to inhibit irreversibly the NADPH/FAD redox enzymes trypanothione reductase and human thioredoxin reductase respectively. Here we show that these platinum(II) complexes metallate recombinant human albumin (rHA) at the single free thiol group (Cys-34). Moreover, the (2,2':6',2"-terpyridine)platinum(II) complex can be transferred from rHA to other thiols, such as 2-hydroxyethanethiol or glutathione. Human serum albumin could therefore provide a natural transport mechanism for the selective delivery of these agents to tumor cells by the enhanced permeability and retention (EPR) mechanism.

2,2'-Dipyridyl↗
PubMedDate not supplied

In vitro and in vivo antineoplastic activity of a new platinum antineoplastic agent, (R)-(-)-1,1-cyclobutanedicarboxylate (2-aminomethylpyrrolidine)-platinum (II) (DWA2114R) on freshly separated human tumor cells and human tumor xenografts transplanted in nude mice--a comparison with cis-diammine-dichloroplatinum (CDDP).

The in vitro antimetabolic effect of a newly synthesized platinum antineoplastic agent, DWA2114R, on 72 fresh human tumors was compared with that of cis-platinum (CDDP). DWA2114R is reported to have a lower nephrotoxicity than CDDP, but is as strong an inhibitor of DNA synthesis as CDDP. In vitro IC50 was assessed in 10 tumors; the IC50 of DWA2114R ranged between 9.2 and 107 microM (mean +/- S.D., 45.9 +/- 36.6) and that of CDDP ranged between 0.9 and 40 microM (18.3 +/- 15.1). DWA2114R had an antitumor spectrum similar to that of CDDP. Primary esophageal and pancreatic cancers were sensitive to DWA2114R, and cells separated from malignant effusion or metastatic lymph nodes were more sensitive than those from primary lesions. Nude mice were transplanted with 3 kinds of human tumor xenografts (esophageal, pancreatic and bile duct cancer lines), and were then treated with CDDP or DWA2114R at 4 times the clinical doses. CDDP significantly inhibited the growth of all the 3 lines, and DWA2114R inhibited the growth of 2 of the lines. The effect of DWA2114R on body weight was smaller than that of CDDP. These results suggest that DWA2114R may be less potent than CDDP but may be useful as a new platinum antineoplastic agent with lower grade of side effects than CDDP.

Adenocarcinoma↗
PubMedDate not supplied

[Interaction of DNA molecules with divalent platinum coordination complexes. II. Effect of the nature and location of ligands in the first platinum coordination sphere].

The interaction of DNA molecule with some coordination compounds of the divalent platinum: cis-DDP, trans-DDP, [(NH3)4Pt]Cl2 and K2PtCl4 was studied. It was shown that the transition of the cis-DDP, trans-DDP, and [PtCl4]2- to aquo-complexes is necessary for their binding with DNA in solution. It was shown that the labile chloride groups are responsible for the formation of the energetically strong binding. The distance between chloride groups in cis-DDP is optimal for incorporation of two groups of DNA bases into the first coordination sphere of platinum. The complexes are also stabilized with phosphate in the external coordination sphere of platinum. The sterical non-conformity between the DNA structure and positions of chloride groups and the orientation of the amino groups in trans-DDP are the main obstructions for the formation of bidentate DNA-trans-DDP complexes. The existence of more than two vacant positions for binding with DNA in [PtCl4]2- does not stabilise the complex. The compound [(NH3)4Pt]Cl2 cannot produce coordination bonds with DNA, because its first coordination sphere is completed with amino groups; it interacts with DNA, forming principally different complexes.

Circular Dichroism↗
PubMedDate not supplied

Third generation antitumor platinum(II) complexes of the [1-(fluoro/difluorophenyl)-2-phenylethylenediamine]platinum(II) type.

The diastereomeric 1-(fluoro/difluorophenyl)-2-phenylethylene-diamines (4-fluoro: erythro-1/threo-1; 2,4-difluoro: erythro-2/-threo-2; 2,6-difluoro: erythro-3/threo-3) and the diastereomeric 1-(4-fluorophenyl)-2-(3-hydroxyphenyl)ethylenediamines (erythro-4/-threo-4) were synthesized from appropriately substituted stilbenes by reaction with IN3 and subsequent LiAlH4 reduction. Coordination of the 1,2-diphenylethylenediamines to platinum was carried out by use of K2PtI4. The water-soluble aquasulfato-platinum(II) complexes (erythro/threo-1-PtSO4-erythro/threo-4-PtSO4) were obtained from the diiodoplatinum(II) complexes by reaction with Ag2SO4. Additionally erythro/threo-1-PtSO4 and erythro/threo-4-PtSO4 were transformed into the dichloroplatinum(II) complexes (erythro/threo-1-PtCl2, erythro/threo-4-PtCl2) by treatment with KCl. In contrast to the less effective erythro-configurated sulfatoplatinum(II) complexes the threo-analogues showed comparable or even superior activities to cisplatin on the human MDA-MB-231 breast cancer cell line. On the MXT-M-3.2 breast cancer of the mouse only erythro- and threo-4-PtSO4 caused similar effects like cisplatin. The strong inhibitory effect of the diastereomeric sulfatoplatinum(II) complexes on the P-388 leukemia of the mouse was equal to that of cisplatin. On the latter tumor threo-4-PtCl2 was the most active among the less toxic dichloroplatinum(II) derivatives.

Animals↗
PubMed1998

Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial.

OBJECTIVES: In an effort to critically examine the antitumor activity of altretamine (hexamethylmelamine) as salvage therapy of platinum-refractory ovarian cancer, the Gynecologic Oncology Group initiated a Phase II trial of the agent administered in this clinical setting. METHODS: Altretamine was administered at a dose of 260 mg/m2 orally for 14 days in a 28-day course. Treatment was continued until disease progression or unacceptable side effects prevented further therapy. A total of 36 patients (median age: 56.5) were treated on this trial, of whom 33 were evaluable for toxicity and 30 for response. All patients had previously received either cisplatin or carboplatin and paclitaxel. RESULTS: The major side effect was emesis (grade 3-4, 7/33, 21%). The objective response rate was 10% (one complete response, two partial responses). CONCLUSION: We conclude that altretamine has limited activity in platinum-refractory ovarian cancer.

Administration, Oral↗
PubMed1982

Prophage induction and mutagenicity of a series of anti-tumour platinum(II) and platinum(IV) co-ordination complexes.

11 platinum compounds with nitrogen donor ligands, previously tested for anti-tumour activity, were studied for induction of prophage lambda and for mutagenicity in the Ames assay, with various strains of Salmonella. The compounds included cis and trans isomers of Pt(II) and Pt(IV) complexes and were tested with and without metabolic activation. All the cis compounds elicited prophage induction, whereas the trans compounds were inactive. Mutagenicity was found only in strains containing the R factor, indicating that SOS-type repair processes are required for the conversion of initial DNA lesions into mutations. Mutation induction was also influenced by the excision-repair process. The 2 trans compounds were not, or only slightly, mutagenic; all other compounds were mutagenic in at least one strain, exhibiting a 2-20-fold increase over the spontaneous background level. Addition of liver homogenate had no significant effect on the number of mutants. One compound induced exclusively frameshift mutations. The other mutagenic compounds induced frameshift mutations as well as base-pair substitutions. 7 compounds were more mutagenic for the repair-proficient than for the repair-deficient strains; only one showed the opposite effect. This suggests that for mutagenicity testing of platinum compounds, repair-proficient strains are more sensitive indicators. The differences in response of the various strains are more sensitive indicators. The differences in response of the various strains toward the compounds suggest the formation of different DNA lesions and/or a selective action of repair processes on these lesions. In general, a good qualitative correlation was observed between prophage-inducing capacity, mutagenicity in bacterial and mammalian cells and anti-tumour activity.

Antineoplastic Agents↗
PubMed2001

Speciation of platinum compounds: a review of recent applications in studies of platinum anticancer drugs.

This is a review of investigations involving speciation studies of five important platinum-containing drugs used in cancer treatments. The information presented here is drawn from recent reports published during the period 1995-1999. The work includes detection, separations and identifications of degradation and biotransformation products. In addition, important information is reported on the number and nature of products of reactions of platinum anticancer drugs with thiol compounds. HPLC is employed effectively for separations of reaction products in speciation investigations. Information derived from speciation is very helpful in studies of pharmacokinetics as well as side effects and toxicities of the drugs as they are administered to patients.

Antineoplastic Agents↗
PubMed2001

Validation of an AAS method for the determination of platinum in biological fluids from patients receiving the oral platinum derivative JM216.

A flameless atomic absorption spectrometric (AAS) method has been developed and validated for the determination of platinum (Pt) in human plasma, plasma ultrafitrate and urines from cancer patients receiving the orally available platinum derivative, JM216. Sample pretreatment is minimal for urine, which is diluted with 10% HCl prior to AAS analysis. Pt analysis in plasma requires the application of the matrix modifier 5% Triton X-100 directly onto the integrated L'vov platform of the graphite furnace prior to the addition of plasma samples. For Pt in ultrafiltrates, enhanced sensitivity is achieved by pre-concentrating ultrafiltrate samples onto the platform prior to the ashing/atomisation step. The AAS program was set specifically for each considered matrix enabling to achieve limit of quantitations as low as 50, 10 and 5 ng Pt ml(-1) for urine, plasma and plasma ultrafiltrate, respectively. The calibration was linear (r(2)>0.993) over the working range 5-150 ng Pt ml(-1). The method has been validated according to the Recommendations on Bioanalytical Methods Validation. The stability of Pt in samples has been explored, as well as the specificity of the method. In the urine intra-assay precision of control samples at 60, 90 and 140 ng Pt ml(-1) is always lower than 3.0, 1.3 and 4.7%, respectively, with concentrations not deviating more than -5.5 to -1.0% from their nominal values, while inter-assay precision is within 5.7-7.7% and inter-assay deviation within the -1.9 to +4.3% range. Intra-assay precision of plasma control samples at 20, 70 and 140 ng Pt ml(-1) is always lower than 8% and concentrations never deviating more than 7.1% from their nominal values. Inter-assay precision of plasma control samples is always lower than 9% with inter-assay deviation from their nominal concentrations within the -3.9 to +1.8% range. In plasma ultrafiltrate, intra-assay CVs of control samples at 12, 25 and 45 ng Pt ml(-1) are always lower than 2.6, 1.7 and 6.8%, respectively, with concentrations not deviating more than -2.6 to -0.2% from their nominal values, while inter-assay CVs are within 5.1-9.5% and inter-assay deviation within the -1.6 to +5.3% range. The proposed method has, therefore, the required performance to measure Pt in biological samples and has been successfully applied to the determination of Pt in samples from cancer patients receiving JM216 in a phase I (daily administration for 14 days, dose escalation 10-50 mg m(-2)) and a phase II (fixed dose 120 mg m(-2) over 5 days) clinical study. In phase I study, both total and ultrafiltrable Pt accumulated upon repetitive dosings, showed long elimination half-lives (t(1/2)) and were measurable 2 weeks after the end of JM216 administration.

Administration, Oral↗
PubMed2006

Total platinum concentration and platinum oxidation states in body fluids, tissue, and explants from women exposed to silicone and saline breast implants by IC-ICPMS.

Ion chromatography-inductively coupled plasma-mass spectrometry was used to determine the total platinum concentration and platinum oxidation states in samples from women exposed to silicone and saline breast implants. Samples included the following: whole blood, urine, hair, nails, sweat, brain tissue, breast milk, and explants. Mean Pt concentration in samples from women exposed to silicone breast implants were as follows: whole blood, 568.1 +/- 74.77 pmol/L (n = 9); urine, 1.77 +/- 0.847 mug/g of creatinine (n = 10); hair, 2.13 +/- 2.984 ng/g (n = 9); nails, 0.88 +/- 0.335 ng/g (n = 9); sweat, 1.90 +/- 1.691 ng/g (n = 9); breast milk, 1.09 +/- 0.316 mug/L (n = 6). Pt in explanted silicone breast implant gel (n = 9) occurred mainly in the +2, +4, and +6 oxidation states. Pt in whole blood (n = 7) and breast milk samples (n = 6) from women exposed to silicone breast implants occurred mainly in the +2 and +4 oxidation states. Saline breast implant fluid (n = 2) did not contain detectable levels of Pt. This is the most comprehensive report, to date, to show that women exposed to silicone breast implants have Pt levels that exceed that of the general population, and the first report, to date, to document the various Pt oxidation states present in samples from women exposed to silicone breast implants.

Adult↗
PubMed2002

A novel isomerization on interaction of antitumor-active azole-bridged dinuclear platinum(II) complexes with 9-ethylguanine. Platinum(II) atom migration from N2 to N3 on 1,2,3-triazole.

The reactions of the dinuclear platinum(II) complexes, [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-pz)](NO(3))(2) (1, pz = pyrazolate), [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-1,2,3-ta-N1,N2)](NO(3))(2) (2, 1,2,3-ta = 1,2,3-triazolate), and a newly prepared [[cis-Pt(NH(3))(2)](2)(mu-OH)(mu-4-phe-1,2,3-ta-N1,N2)](NO(3))(2) (3, 4-phe-1,2,3-ta = 4-phenyl-1,2,3-triazolate), whose crystal structure was determined, with 9-ethylguanine (9EtG) have been monitored in aqueous solution at 310 K by means of (1)H NMR spectroscopy. The dinuclear platinum(II) complexes 1-3 each react with 9EtG in a bifunctional way to form 1:2 complexes, [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-pz)](3+) (4), [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-1,2,3-ta-N1,N3)](3+) (5), and [[cis-Pt(NH(3))(2)(9EtG-N7)](2)(mu-4-phe-1,2,3-ta-N1,N3)](3+) (6). The reactions of 2 and 3 involve a novel isomerization, in which the Pt atom, initially bound to N2 on the 1,2,3-ta, migrates to N3 after the first substitution by N7 of 9EtG. This isomerization reaction has been unambiguously characterized by 1D and 2D NMR spectroscopy and pH titration. The reactions of 2 and 3 with 9EtG show faster kinetics, and the second-order rate constants (k) for the reactions of 1-3are 1.57 x 10(-4), 2.53 x 10(-4), and 2.56 x 10(-4) M(-1) s(-1), respectively. The pK(a) values at the N1H site of 9EtG were determined for 4-6 from the pH titration curves. Cytotoxicity assays of 1-3 were performed in L1210 murine leukemia cell lines, respectively sensitive and resistant to cisplatin. In the parent cell line, 2 and 3 exhibit higher cytotoxicity compared to cisplatin, especially, 2 is 10 times as active as cisplatin. 1 was found to be less cytotoxic than cisplatin, but still in the active range and more active than cisplatin in a cisplatin-resistant cell line.

Animals↗