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PubMed1981

Effects of anticancer platinum compounds on Escherichia coli strains with normal and defective DNA repair capacity.

The effect of anticancer platinum compounds on isogenetic strains of Escherichia coli with normal or defective DNA repair capacity were studied. Cisdichlorodiammineplatinum (II) causes DNA damage that is repairable by the repair systems of bacteria, and the DNA lesion becomes mutational when processed by the excision repair system. Dinitrato (1R, 2S-cyclohexanediamine) platinum (II) exhibits similar killing activity on E. coli strains with both normal and defective DNA repair capacity. Thus, this compound may cause DNA damage that cannot be repaired by bacteria, or its killing activity may be due to effects other than DNA damage.

Antineoplastic Agents↗
PubMed1991

Role of DNA replication in carrier-ligand-specific resistance to platinum compounds in L1210 cells.

L1210 cell lines have been described that are sensitive to most platinum compounds (L1210/0), resistant to ethylenediamine (en)-Pt but sensitive to diaminocyclohexane (dach)-Pt (L1210/DDP), and resistant to dach-Pt but sensitive to en-Pt (L1210/DACH). We have examined the effect of the dach and en carrier ligands on the ability of Pt-DNA adducts to inhibit DNA replication. Alkaline sucrose gradient sedimentation was used to determine the influence of both carrier ligands on the inhibition of replicon initiation and DNA chain elongation. Initiation of replicons was inhibited by Pt-DNA adducts to a greater extent than chain elongation in all three cell lines. Inhibition of replicon initiation was affected by the nature of the platinum carrier ligands only in the L1210/DACH cells in which 7.8-fold more dach-Pt adducts than en-Pt adducts were required to reach 63% inhibition. However, a strong carrier ligand effect was observed on the inhibition of DNA chain elongation in both the L1210/DDP and L1210/DACH cell lines. The L1210/DDP cell line required 4-fold more en-Pt adducts than dach-Pt adducts to inhibit DNA chain elongation by 63%. In the L1210/DACH cell line, 2.7-fold more dach-Pt adducts than en-Pt adducts were required for 63% inhibition. The L1210/0 cell line demonstrated no carrier ligand specificity for inhibition of chain elongation. Significant replicative bypass of Pt-DNA adducts was observed even in the L1210/0 cell line in that greater than 50 Pt-DNA adducts per 100 kb were required for 63% inhibition. The same level of inhibition was reached with 1.25 adducts of benzo[a]pyrene diolepoxide I per 100 kb. These data suggest that L1210 cells are capable of substantial replicative bypass of Pt-DNA adducts. Furthermore, the bypass of Pt-DNA adducts is increased in resistant L1210 cells and is markedly dependent on the nature of the platinum carrier ligand.

Animals↗
PubMed1989

The mutagenic and carcinogenic properties of three second generation antitumour platinum compounds: a comparison with cisplatin.

The cytotoxicity, mutagenicity and transforming potentials of three second generation platinum compounds have been investigated in mammalian cells. All the compounds showed positive response in two assay systems in Chinese hamster V 79 cells, i.e. measurement of mutation induction at the HGPRT locus and of DNA damage as indicated by sister chromatid exchange frequencies. At equitoxic doses, the compounds in order of decreasing mutagenicities were cisplatin, spiroplatin, carboplatin and iproplatin. The BHK transformation assay reflected a similar order in the potential carcinogenicity of the drugs. Cisplatin was highly carcinogenic, followed by spiroplatin. In comparison, carboplatin and iproplatin were potentially weak carcinogens.

Animals↗
PubMed2003

[Immediate type allergies due to metal compounds: platinum salts].

Immediate type allergies due to metal compounds containing chromium, nickel, cobalt and platinum are rare. However, allergies to platinum salts represent a major health hazard in few precious metal refineries and catalyst productions. Sensitization can be shown with a highly specific and sensitive skin prick test. A dose-response relationship has clearly been established by prospective longitudinal studies, however the definition of a valid threshold limit is difficult due to the high variability of exposure. Smoking is a predicting factor, whereas atopy is not. Prognosis depends on the duration of symptomatic exposure in high exposure areas. Secondary prevention (medical surveillance) is effective in the prevention of persistent symptoms and bronchial hyperresponsiveness.

Humans↗
PubMed1986

Effects of the bidentate malonate ligand on the utilization and cytotoxicity of platinum compounds in the L1210 cell line.

Previous studies have investigated the cytotoxicity of platinum(II) compounds with bidentate leaving ligands, but little is known about their uptake or mechanism of action inside the cell. We have compared the uptake and intracellular effects of cis-1,2-diaminocyclohexanemalonatoplatinum(II) [Pt(mal)(cis-DACH)] and cis-1,2-diaminocyclohexanedichloroplatinum(II) [PtCl2(cis-DACH)] in the L1210 cell line. In the 3-h colony formation assay, PtCl2(cis-DACH) is almost 10 times more cytotoxic than Pt(mal)(cis-DACH). However, when the time of incubation with platinum drug is increased from 3 to 24 h the cytotoxicity of PtCl2(cis-DACH) changes relatively little while the cytotoxicity of Pt(mal)(cis-DACH) increases over 10-fold. As a consequence, Pt(mal)(cis-DACH) is only slightly less cytotoxic than the dichloro compound by 24 h. These data can readily be explained by differences in the time course of uptake. Pt(mal)(cis-DACH) is initially taken by the cell at a much slower rate than PtCl2(cis-DACH), but the uptake continues linearly for at least 24 h with the malonate compound, while uptake for the dichloro compound begins to plateau between 5 and 8 h. The earlier plateauing of PtCl2(cis-DACH) uptake is most likely to be due to a quicker approach to equilibrium between intracellular and extracellular concentrations of unchanged drug which is caused by a more rapid inactivation of PtCl2(cis-DACH) in the media coupled with the more rapid uptake of PtCl2(cis-DACH) by the cells. When compared at equal cytotoxicity, the uptake of platinum into the intracellular pool of low molecular weight platinum compounds is significantly greater for Pt(mal)(cis-DACH) even though the rate of platinum incorporation into DNA is essentially the same for both compounds at early times. These data suggest that a smaller percentage of the low molecular weight platinum is in a reactive form inside the cell for Pt(mal)(cis-DACH). While the inhibition of cell survival exactly parallels incorporation of platinum into DNA for both compounds, there is a significant lag before the onset of inhibition of DNA synthesis for Pt(mal)(cis-DACH). This observation suggests that the conversion of monoadducts to diadducts may be slower for platinum compounds with bidentate leaving ligands.

Animals↗
PubMed1978

Effects of certain antitumor platinum compounds on kidney esterases.

In a study of the biochemical mechanism of renal toxicity of certain antitumor platinum compounds, particularly cis-dichlorodiammineplatinum(II) (NSC-119875), qualitative and quantitative studies of the soluble nonspecific kidney esterases were carried out using (C57BL/L X DBA/2) mice. There was a major suppression of the testosterone-dependent esterases of treated male mice; these levels dropped to levels below those found in untreated females within 72 h after certain of the drugs were administered. This effect appeared to be in inverse relationship to the numerical value of the LD50 values of the compounds investigated.

Animals↗
PubMed1995

Cycloplatam: a novel platinum compound exhibiting a different spectrum of anti-tumour activity to cisplatin.

Cycloplatam is a novel platinum compound which has shown anti-tumour activity in murine tumour models. In this study, cycloplatam was found to have anti-tumour activity in vitro and in vivo in human tumour models. In 15 cell lines (mainly ovarian), cycloplatam showed similar cytotoxicity as cisplatin, using the sulphorhodamine B assay. Determination of the resistance factor (IC50 of cisplatin-resistant divided by IC50 of parental cell line) clearly showed lower values for cycloplatam than for cisplatin. In the parental ovarian cell line CH1 and the cisplatin-resistant CH1 cisR model, we observed no cross-resistance of cycloplatam and cisplatin. The in vitro anti-tumour activity was confirmed in human tumour xenografts using the clonogenic assay. Mean IC70 values of cycloplatam were 0.54 microgram/ml (1.25 microM) and of cisplatin 0.42 microgram/ml (1.4 microM), respectively. In the murine subcutaneously implanted ADJ/PC6 plasmacytoma in vivo cycloplatam showed less activity than cisplatin, with a 2-fold smaller therapeutic index than cisplatin. In ovarian cancer xenografts cycloplatam was less active than cisplatin. However, anti-tumour activity of cycloplatam in lung cancer xenografts was quite different from cisplatin. In LXFS 538, a model moderately sensitive to cisplatin, a partial remission was observed, but in LXFL 529, a cisplatin-sensitive model, cycloplatam was inactive, cycloplatam thus demonstrating a different spectrum of anti-tumour activity. Based on these results, further preclinical investigations with other tumours, such as cisplatin-sensitive and -resistant gastric cancer models, are warranted with cycloplatam.

Animals↗
PubMedDate not supplied

Antitumor effects of a new lipophilic platinum compound, trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)platinum(IV), in mice.

A new lipophilic platinum (Pt) compound, trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)Pt(lV) (C5-OHP), was compared with cisplatin (CDDP) by intraperitoneal injection for antitumor activities against 3 different mouse models, L1210 leukemia, LMFS sarcoma with high metastatic potential and spontaneous mammary tumor. C5-OHP cured both CDDP-sensitive and -resistant L1210 leukemia frequently. CDDP did not cure the leukemia, although it prolonged the survival of diseased mice significantly. C5-OHP cured early and advanced LMFS sarcomas more frequently than CDDP. Cured mice had acquired antitumor immunity, indicating the pivotal role of the immune system in induction of the cure of tumors. It is likely tllat C5-OHP can eradicate tumor cells more effectively than CDDP by virtue of its weaker suppressive effects on the immune system. C5-OHP but not CDDP could cure mammary tumors. C5-OHP manifested a curative effect against LMFS tumors by oral route. These results indicate that C5-OHP is a promising anticancer agent worthy of clinical trial.

Animals↗
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↗
PubMed1991

Sequence-dependent termination of mammalian DNA polymerase reaction by a new platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-plati num(II) monohydrate).

We examined the mechanism of the inhibition of DNA synthesis by a new platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato+ ++)-2-platinum(II) monohydrate (DWA-2114R), a derivative of the antitumor drug cis-diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA-2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose-dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second-strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase alpha were strongly arrested at guanine-guanine sequences (GG). Stop bands were also observed at adenine-guanine sequences (AG) guanine-adenine-guanine sequences (GAG) and mono-guanine sequence (G). Calf testis DNA polymerase beta was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.

Animals↗
PubMedDate not supplied

Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds.

BACKGROUND: The anticancer activity of cisplatin derives from its ability to crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic notch at the damage site, which can be specifically bound by damage-recognition proteins, thus shielded from NER-activity. We aimed at preventing resistance by enhancing this mechanism using more hydrophobic platinum compounds. METHODS: We synthesized three platinum analogs with increased hydrophobic characteristics. Performing MTT-assays, the efficacy of cisplatin and the novel agents was compared in a fibroblast and eight brain tumour cell lines. RESULTS: Among the novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 = 2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x 10(-6) M). CONCLUSIONS: Comparison of the novel compounds supports the hypothesis that increased hydrophobicity contributes to higher antitumour-activity. Other advantageous characteristics of cisplatin might relate to its remaining highest efficacy.

Antineoplastic Agents↗
PubMed1997

Combination treatment with docetaxel (Taxotere) and platinum compounds for non-small cell lung cancer.

There is a strong rationale for combining docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and platinum compounds for use in the treatment of non-small cell lung cancer (NSCLC). The compounds are active as single agents and have no overlapping toxicity profiles. The first dose-finding study reported a response rate of 46%, and recommended doses of 75 mg/m2 for docetaxel and 75 to 100 mg/m2 for cisplatin, given concomitantly every 3 weeks. Three other studies confirmed a response rate of 33% to 48% in previously untreated patients. Dose-limiting but rapidly reversible neutropenia was observed. A European trial has investigated the use of alternating cycles of docetaxel 100 mg/m2 and cisplatin 120 mg/m2 in patients with previously untreated metastatic or nonresectable NSCLC. Preliminary results indicate that the overall response rate (33% of 39 evaluable patients) is similar to that achieved with docetaxel alone. A second trial is investigating alternating therapy using docetaxel 100 mg/m2 and a combination of cisplatin 100 mg/m2 and vinorelbine 30 mg/m2. Response rates are higher (49%) and toxicities, especially hematologic toxicities, are lower than in the first study. A third trial is investigating sequential treatment using docetaxel 100 mg/m2, cisplatin 120 mg/m2, and vindesine 3 mg/m2. Preliminary results indicate a response rate of 30% among 25 patients enrolled thus far. Compared with monotherapy, docetaxel/platinum combinations appear to offer the potential for improved response rates in patients with NSCLC. The use of alternating schedules offers the further possible advantage of improving tolerability while retaining effective doses. Further studies are in progress or planned to elucidate optimal doses and schedules.

Antineoplastic Agents, Phytogenic↗
PubMedDate not supplied

[Preclinical trials of polyplatillen, the antitumor activity of a complex platinum compound with DNA on a leukemia P388 model in a HEp-2 cell culture (1)].

The authors studied the antitumour activity of a new complex platinum compound (DDP-DNA) in mice with leukemia P-388 and in cell culture. DDP-DNA was introduced intraperitoneally 24 hours after inoculation of 2 x 10(6) tumour cells. It was established that by its antitumour activity DDP-DNA was not inferior then DDP. The antiproliferative activity of nontoxic doses of the preparation in cell culture has been shown.

Animals↗
PubMed2004

Inhibition of cell growth, induction of apoptosis and mechanism of action of the novel platinum compound cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4'-6-diamidine-2'-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique. When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue. Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.

Animals↗
PubMed2006

Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma.

BACKGROUND: The young age of neuroblastoma patients makes them especially prone to the ototoxic effects of widely used treatments that feature aggressive use of platinum compounds. We present data defining the extent of the problem in a large series of neuroblastoma patients whose induction included high-dose cisplatin/etoposide (HD-P/E) as used in both the Memorial Sloan-Kettering Cancer Center N7 regimen and the Children's Oncology Group A3973 study. METHODS: N7/A3973 patients were divided into 3 groups: Group 1 had hearing tested after induction, that included 2 cycles of HD-P/E (cumulative cisplatin = 400 mg/m(2)); Group 2 had hearing tested after induction, that included 3 cycles of HD-P/E (cumulative cisplatin = 600 mg/m(2)); and Group 3 had hearing tested following carboplatin-containing myeloablative therapy administered after induction, that included 2 cycles of HD-P/E. Ototoxicity was scored by the Brock method. RESULTS: All 3 groups had similar clinical characteristics, including median age at diagnosis of about 3 years. Little or no hearing loss in the speech range (Grade 0/1) was documented in 21 (32%) of the 65 Group 1 patients, 5 (10%) of the 50 Group 2 patients, and 9 (15.5%) of the 58 Group 3 patients. Severe (Grade 3/4) deficits affected 25% of Group 1, 54% of Group 2, and 50% of Group 3 patients. Patients < 5 years at diagnosis had greater ototoxicity than older patients had, with adolescents/adults being the least affected. Findings were stable in repeated assessments over 2 or more years. CONCLUSIONS: Ototoxicity is a serious and pervasive problem in this patient population. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed.

Antineoplastic Agents↗
PubMed1992

Modification of the physicochemical and pharmacological properties of anticancer platinum compounds by commercial 5-fluorouracil formulations: a comparative study using cisplatin and carboplatin.

The influence of a commercial formulation of 5-fluorouracil (5-FU) on the stability and pharmacological properties of two platinum derivatives, cisplatin and carboplatin, was studied to determine whether the drugs could be mixed in containers or intravenous lines. When cisplatin was incubated in a French commercial formulation of 5-FU (Fluoro-uracile, Roche, France), high-performance liquid chromatographic (HPLC) studies demonstrated a rapid disappearance of the parent platinum compound, the extent of the degradation being 75% after 3.5 h. These studies also revealed that the degradation was not caused by a reaction between 5-FU and cisplatin but rather resulted from an interaction between cisplatin and trometamol, the excipient used in the French 5-FU formulation to buffer the solution at pH 8.2. The sole presence of trometamol in a cisplatin solution for 24 h at 30 degrees C resulted in the complete inhibition of both the ability of cisplatin to bind in vitro to human serum albumin and the antitumor activity of the cytostatic agent against P388 leukemia in mice (T/C% = 88% for cisplatin+trometamol vs greater than 333% for cisplatin). When cisplatin was incubated at the same pH in trometamol-free sodium hydroxide solutions (the excipient used in 5-FU formulations in several countries, including the United States and the United Kingdom), the parent compound was transformed into reactive species that were toxic to mice (T/C% = 40% in P388 leukemia). The degradation determined for a carboplatin-trometamol admixture using HPLC was similar to that found for cisplatin but occurred at a slower rate (0 after 3.5 h incubation and 55% after 24 h). The antitumor activity of carboplatin in P388-bearing mice was not significantly altered by a 24-h period of preincubation in the presence of trometamol (T/C% = 209% vs 241% for treatment with carboplatin in the absence of trometamol). As in the case of cisplatin, incubation of carboplatin for 24 h in a sodium hydroxide solution resulted in a toxic effect (T/C% = 64%). Our results thus demonstrate the incompatibility of both cisplatin and carboplatin with commercial formulations of 5-FU.

Animals↗