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PubMedDate not supplied

Enhancement of antitumor effects of new analogue of platinum, cis-diammine (glycolato) platinum (254-S) combined with hyperthermia in vivo.

Cis-diammine (glycolato) platinum (254-S) is a second generation platinum complex with reduced nephrotoxicity. In this study the antitumor effect of 254-S combined with hyperthermia in vivo in mice was studied. On the 6th day after inoculation of the Ehrlich ascites tumour cells, 254-S (15mg/kg) was administered intraperitoneally (i.p.) and hyperthermia was induced by using a circulating water bath at 42.5 degrees C for 45 min. The antitumour effect was evaluated by relative tumour volume. Furthermore, platinum concentration in tumour tissue was determined by using atomic absorption spectrophotometry. The most effective condition was found to be the combination of 254-S with hyperthermia. A significantly higher concentration of platinum in the tumour tissue was observed when treatment with 254-S was combined with hyperthermia, than with treatment using 254-S alone. Our study suggested that the accumulation of 254-S in the tumour tissue, and its retention at a high concentration within the tumour tissue long term was one of the reasons for the enhancement of antitumour effect of 254-S treatment when combined with hyperthermia.

Animals↗
PubMedDate not supplied

Pharmacokinetics of platinum following the administration of cis-(glycolato-O,O')[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) in dogs.

The pharmacokinetic study on cis-(glycolato-O,O') [(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]-platinum(II) (SKI 2034R, NSC D642489) was performed in beagle dogs. A single dose of 2.0 mg/kg of SKI 2034R was given by i.v. bolus to three beagle dogs. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for SKI 2034R declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2034R, as an active component, was 2.76 +/- 0.13 micrograms.h/ml (mean +/- S.D.), with an initial half-life of 0.15 +/- 0.09 hour, a terminal half-life of 0.96 +/- 0.12 hour, a total clearance of 12.07 +/- 0.67 ml/min/kg, and a steady-state volume of distribution of 0.82 +/- 0.06 1/kg.

Animals↗
PubMed2006

Determination of trace platinum by supramolecular catalytic kinetic spectrofluorimetry of beta-cyclodextrin-platinum-KBrO3-salicylaldehyde furfuralhydrazone.

A supramolecular catalytic kinetic spectrofluorimetric method was developed for the determination of platinum(IV) and the possible mechanism of catalytic reaction was discussed. The method was based on the fluorescence-enhancing reaction of salicylaldehyde furfuralhydrazone (SAFH) with potassium bromate, which was catalysed by platinum(IV) in a water-ethanol medium. beta-Cyclodextrin (beta-CD) obviously sensitized the determination at pH 5.20 and 25 degrees C. Under optimum conditions, the beta-CD-platinum-KBrO3-SAFH supramolecular kinetic catalytic reaction system had excitation and emission maxima at 372 and 461 nm, respectively. The linear range of this method was 0.60-180 ng ml-1 with a relative standard deviation of 1.2%, and the detection limit was 0.18 ng ml-1. Investigation of the mechanism and the effects of interferences is presented. The proposed method was applied successfully to determine trace platinum(IV) in the chemotherapeutic drug cisplatin and serum from patients with satisfactory results.

Journal Article↗
PubMed1986

A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).

A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.

Animals↗
PubMed2004

Improved targeting of platinum chemotherapeutics. the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models.

AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.

Acrylamides↗
PubMed2001

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate.

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.

Antineoplastic Agents↗
PubMed2000

Kinetics and mechanism for reversible chloride transfer between mercury(II) and square-planar platinum(II) chloro ammine, aqua, and sulfoxide complexes. Stabilities, spectra, and reactivities of transient metal-metal bonded platinum-mercury adducts.

The Hg2+aq- and HgCl+aq-assisted aquations of [PtCl4]2- (1), [PtCl3(H2O)]- (2), cis-[PtCl2(H2O)2] (3), trans-[PtCl2(H2O)2] (4), [PtCl(H2O)3]+ (5), [PtCl3Me2SO]- (6), trans-[PtCl2(H2O)Me2SO] (7), cis-[PtCl(H2O)2Me2SO]+ (8), trans-[PtCl(H2O)2M32SO]+ (9), trans-[PtCl2(NH3)2] (10), and cis-[PtCl2(NH3)2] (11) have been studied at 25.0 degrees C in a 1.00 M HClO4 medium buffered with chloride, using stopped-flow and conventional spectrophotometry. Saturation kinetics and instantaneous, large UV/vis spectral changes on mixing solutions of platinum complex and mercury are ascribed to formation of transient adducts between Hg2+ and several of the platinum complexes. Depending on the limiting rate constants, these adducts are observed for a few milliseconds to a few minutes. Thermodynamic and kinetics data together with the UV/vis spectral changes and DFT calculations indicate that their structures are characterized by axial coordination of Hg to Pt with remarkably short metal-metal bonds. Stability constants for the Hg2+ adducts with complexes 1-6, 10, and 11 are (2.1 +/- 0.4) x 10(4), (8 +/- 1) x 10(2), 94 +/- 6, 13 +/- 2, 5 +/- 2, 60 +/- 6, 387 +/- 2, and 190 +/- 3 M-1, respectively, whereas adduct formation with the sulfoxide complexes 7-9 is too weak to be observed. For analogous platinum(II) complexes, the stabilities of the Pt-Hg adducts increase in the order sulfoxide << aqua < ammine complex, reflecting a sensitivity to the pi-acid strength of the Pt ligands. Rate constants for chloride transfer from HgCl+ and HgCl2 to complexes 1-11 have been determined. Second-order rate constants for activation by Hg2+ are practically the same as those for activation by HgCl+ for each of the platinum complexes studied, yet resolved contributions for Hg2+ and HgCl+ reveal that the latter does not form dinuclear adducts of any significant stability. The overall experimental evidence is consistent with a mechanism in which the accumulated Pt(II)-Hg2+ adducts are not reactive intermediates along the reaction coordinate. The aquation process occurs via weaker Pt-Cl-Hg or Pt-Cl-HgCl bridged complexes.

Journal Article↗
PubMed2006

Palladium(II) and platinum(II) organometallic complexes with the model nucleobase anions of thymine, uracil, and cytosine: antitumor activity and interactions with DNA of the platinum compounds.

Pd(II) and Pt(II) complexes with the anions of the model nucleobases 1-methylthymine (1-MethyH), 1-methyluracil (1-MeuraH), and 1-methylcytosine (1-MecytH) of the types [Pd(dmba)(mu-L)]2 [dmba = N,C-chelating 2-((dimethylamino)methyl)phenyl; L = 1-Methy, 1-Meura or 1-Mecyt] and [M(dmba)(L)(L')] [L = 1-Methy or 1-Meura; L' = PPh(3) (M = Pd or Pt), DMSO (M = Pt)] have been obtained. Palladium complexes of the types [Pd(C6F5)(N-N)(L)] [L = 1-Methy or 1-Meura; N-N = N,N,N',N'-tetramethylethylenediamine (tmeda), 2,2'-bipyridine (bpy), or 4,4'-dimethyl-2,2'-bipyridine (Me2bpy)] and [NBu4][Pd(C6F5)(1-Methy)2(H2O)] have also been prepared. The crystal structures of [Pd(dmba)(mu-1-Methy)]2, [Pd(dmba)(mu-1-Mecyt)]2.2CHCl3, [Pd(dmba)(1-Methy)(PPh3)].3CHCl3, [Pt(dmba)(1-Methy)(PPh3)], [Pd(tmeda)(C6F5)(1-Methy)], and [NBu4][Pd(C6F5)(1-Methy)2(H2O)].H2O have been established by X-ray diffraction. The DNA adduct formation of the new platinum complexes synthesized was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the platinum complexes on plasmid DNA pBR322 were also obtained. Values of IC50 were also calculated for the new platinum complexes against the tumor cell line HL-60. All the new platinum complexes were more active than cisplatin (up to 20-fold in some cases).

Antineoplastic Agents↗
PubMed1993

Acquisition of platinum drug resistance and platinum cross resistance patterns in a panel of human ovarian carcinoma xenografts.

In vivo models of acquired resistance to the platinum-based agents cisplatin (CDDP), carboplatin (CBDCA), iproplatin (CHIP) and tetraplatin have been established using a panel of six parent human ovarian carcinoma lines, two (HX/110 and PXN/87) being derived from previously untreated patients. Resistance has been generated to CDDP (three lines), CBDCA (one line), CHIP (three lines) and tetraplatin (one line) either by treatment in vivo or (for one line to CDDP) through exposure in vitro and subsequent transfer to mice. With the four tumours where resistance was generated using CDDP or CBDCA, a complete cross-resistance to the remaining platinum agents studied was observed. In contrast, in one of three lines with derived resistance to the platinum (IV) agent, CHIP, (PXN/951) a retention in sensitivity was observed with CDDP and CBDCA. Only one of the six parent tumour lines (PXN/100) was markedly sensitive to tetraplatin. Where resistance was generated to tetraplatin (PXN/100T) there was some retention of activity by CDDP. For the CDDP-resistant line established in vitro, there was a close agreement between the cross-resistance profile obtained in vitro vs that obtained in vivo. This tumour panel may be useful in the elucidation of cellular and molecular resistance mechanisms to platinum drugs operative in vivo. Moreover, as they appear to mimic the clinical observations of shared cross-resistance between CDDP, CBDCA and CHIP, they may represent valuable preclinical evaluation models for the discovery of drugs capable of conferring responses in CDDP-refractory ovarian cancer.

Animals↗
PubMed1991

Toxicological and tumoricidal evaluations of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++)platinum( II) monohydrate, in rats.

The toxicities and antitumor activity of a new anticancer platinum compound, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +) platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight (less than 10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub-LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35-43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.

Animals↗
PubMed1993

Cytotoxicity of platinum(IV) and platinum(II) complexes containing 1R,2R-cyclohexanediamine as a ligand.

Several Pt(IV) and Pt(II) complexes containing 1R,2R-cyclohexanediamine (1R,2R-dach) as a carrier ligand were synthesized. The cytotoxicities and the uptake of the platinum complexes by leukemia L1210 cells were compared in order to study the correlation between their structures and cytotoxicities. [Pt(II)Cl2(1R,2R-dach)], [(Pt(II)(oxalato)(1R,2R-dach)], and [Pt(II)(malonato)(1R,2R-dach)], which have excellent anticancer properties, exhibited very high cytotoxicities and were easily taken up by leukemia L1210 cells. [Pt(IV)Cl4(1R,2R-dach)], trans(Cl)-[Pt(IV)Cl2(oxalato)(1R,2R-dach)], and trans(Cl)-[Pt(IV)Cl2(malonato)(1R,2R-dach)] also had high cytotoxicities. After a short incubation time, the uptake of [Pt(II)Cl2(1R,2R-dach)], [Pt(II)(oxalato)(1R,2R-dach)], and [Pt(II)(malonato)(1R,2R-dach)] by leukemia L1210 cells were respectively very similar to those of [Pt(IV)Cl4(1R,2R-dach)], trans(Cl)-[Pt(IV)Cl2(oxalato)(1R,2R-dach)], and trans(Cl)-[Pt(IV)Cl2(malonato)(1R,2R-dach)]. In addition, trans(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)] (Y2: oxalato or malonato) did not exhibit cytotoxicity towards leukemia L1210 cells, whereas trans(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)] (Y2: oxalato or malonato) were highly cytotoxic. The accumulation of trans(OH)-[Pt(IV)(OH)2Y2(1R,2R-dach)] in leukemia L1210 cells was much lower than that of trans(Cl)-[Pt(IV)Cl2Y2(1R,2R-dach)]. Platinum(IV) complexes, in which leaving groups are replaced by hydroxide groups, have decreased cytotoxic activity, because the hydroxide groups of the platinum(IV) complex reduce the uptake of platinum by the cells. trans(OH),cis(Cl)-[Pt(IV)(OH)2Cl2(1R,2R-dach)], which has hydroxide and chloride groups, was easily incorporated into the cells and exhibited the high cytotoxic activity. This behavior indicates that the chloride group apparently overcomes the ameliorating effect of the hydroxide group.

Animals↗
PubMed1999

Inhibition of peroxidase, trypsin, and alpha-chymotrypsin by platinum (II) and platinum (IV) complexes.

Effects of various complexes of platinum (II) and platinum (IV) on activities of trypsin, alpha-chymotrypsin, and peroxidase were compared. The platinum (II) complexes were found to inhibit these enzymes, though with variable efficiency. The platinum (IV) complexes at concentrations < or = 0.2 mM efficiently inhibited peroxidase but had no effect on the proteases. An enzymatic assay was developed to measure the most effective peroxidase inhibitor (cisplatin) at concentrations of 5-50 microM in the presence of fivefold excess of its isomer (transplatin).

Catalysis↗
PubMedDate not supplied

Influence of a novel platinum compound--cis-dichloro (dimethylsulphoxide) (1-beta-D-rybofuranosyl-1,2,4-triazolo-3-arboxyamide) platinum (II)--"Pt-rib-1"--on cell cycle and apoptosis in ClS91 and B16 mouse melanoma in vitro.

Cisplatin has a significant role in the treatment of selected human tumors including advanced melanoma, but new platinum compounds are still in focus of search for better properties. Modern drug design is often based on studies detecting the abilities of tested drug to induce apoptosis and disturb cell cycle. Aim of the study was to establish the influence of a platinum complex Pt-rib-1 on cell cycle and apoptosis occurrence in mouse melanoma B16 and ClS91 cells. Pt-rib-1 is a ribavirin derivative. previously characterized and described as cytotoxic to B16 and ClS91 mouse melanoma cells in vitro. The new platinum complex (Pt-rib-1); cis- dichloro (dimethylsulphoxide) (1- beta- D-ribofuranosyl- 1,2,4-triazolo -3- carboxyamide) platinum (II) was supplied. Cisdiaminodichloroplatinum (II), (cisplatin) was used in control groups. To detect apoptotic and necrotic cells, Annexin V- conjugated with fluorescein isothiocyanate (Annexin V-FITC, Immunotech) and propidium iodide (IP, Immunotech) were used. Apoptosis detection were done using fluorescence microscopy and flow cytometry. The total DNA content within the cell indicated phase of the cell cycle. DNA content was measured using flow cytometry. Values given represent the mean from three determinations. Results were presented as mean +/- standard deviation (SD). Statistical analysis was done using t-Student test. There were 70.4% of apoptotic cells in the ClS91 culture after 24 h incubation with Pt-rib-1 at a concentration of 2.04 x 10(-3) M (4 x IC50). In B16 group, 83.2 per cent of apoptotic cells was found after 24h incubation with Pt-rib-1 at high concentration (2.30 x 10(-3) M). A 24-h experiment shows a threshold at a concentration higher than 3 x IC50 responsible for apoptosis induction in B16 and ClS91 cells. After 48 h incubation with Pt-rib-1 the per cent of apoptotic cells increased gradually with rising concentrations of Pt-rib-1 up to a final concentration of 2.04 x 10(-3) M and 0.92 x 10(-3) M in ClS91 and B16 groups, respectively. Cell accumulation was observed in S phase after 48 h incubation with Pt-rib-1. The per cent of cells in S phase increased from 31 to 51.1% and 38.8 to 50.0% in ClS91 and B16 culture, respectively. There were no B16 and ClS91 cells in G2/M phase after incubation with higher concentrations of Pt-rib-1 (from 0.2 to 2.0 x 10(-5) M/dm3). Pt-rib-1 partially exhibits action of cisplatin. which has no specific influence on cell cycle and ribavirin. probably responsible for DNA synthesis delay.

Animals↗
PubMed1995

Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II), as determined by ex vivo pharmacodynamics.

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

Animals↗
PubMedDate not supplied

The role of glutathione (GSH) in determining sensitivity to platinum drugs in vivo in platinum-sensitive and -resistant murine leukaemia and plasmacytoma and human ovarian carcinoma xenografts.

Numerous studies performed in vitro have suggested a role for glutathione (GSH) in determining the sensitivity/resistance of tumour cells to various platinum-based drugs. Few studies have extended these findings into the in vivo setting. We have measured GSH levels in two murine (ADJ/PC6 plasmacytoma and L1210 leukaemia and their acquired platinum-drug-resistant sublines) and five human ovarian carcinoma (PXN/100, PXN/109T/C, SKOV3, HX/62 and OVCAR-3) tumour models of varying sensitivity to cisplatin. Results showed that relatively high GSH levels may be involved, at least partially, in determining platinum drug resistance in vivo in at least some of the tumour models studied (ADJ/PC6 carboplatin and tetraplatin resistant tumours; L1210 cisplatin and tetraplatin resistant tumours and the HX/62 and OVCAR-3 human ovarian carcinoma xenografts). However, in other tumours (e.g., the acquired cisplatin resistant ADJ/PC6 plasmacytoma) non-GSH mediated mechanisms of resistance (such as enhanced DNA repair) probably account for the resistance. Pretreatment of animals with oral buthionine sulfoximine (BSO), which resulted in approximately 70% depletion in tumour GSH levels, failed to potentiate the antitumour efficacy of either cisplatin (using the ADJ/PC6 and L1210 models) or the 1,2-diaminocyclohexane (DACH) platinum-drug, tetraplatin (using the ADJ/PC6 model). These BSO plus or minus cisplatin data suggest a limited role for such combinations in the clinic.

Animals↗
PubMed1984

Trypanocidal and antitumour activity of platinum-metal and platinum-metal-drug dual-function complexes.

A number of antitumour platinum-metal complexes related to cis-platin showed trypanocidal activity against Trypanosoma rhodesiense in vitro but not in vivo. New platinum- and rhodium-metal complexes of diamidine and plenanthridinium trypanocides are described which showed higher therapeutic indices than the parent drugs, due to increased activity in the former drug type and decreased toxicity in the latter. Some evidence of potentiation of antitumour activity was noted in these drug complexes. At the ultrastructural level, complex-treated trypanosomes showed a number of nuclear effects and other lesions specifically attributable to platinum-metal action. Some of the lesions were similar to those induced by cis-platin in tumour cells.

Animals↗
PubMed1995

Platinum(II) complexes containing iminoethers: a trans platinum antitumour agent.

The biological activity of cis and trans complexes of formula [PtCl2(HN = C(OMe)Me)2] has been investigated. The iminoether ligands can have either E or Z configuration about the C = N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumor activity for the complex with trans geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same trans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a trans platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the trans-isomer in the amine complexes, are instead greater for the trans- than for the cis- isomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Trans-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis- platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new trans platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.

Animals↗
PubMed1997

Measurement of short-term exposure to airborne soluble platinum in the platinum industry.

A number of cases of respiratory sensitization to soluble platinum have arisen in the U.K. over the last few years, despite measured 8 h TWA exposure levels below the current long-term exposure limit in most cases. One possible cause of sensitization may be as a result of high exposures over short periods. Short-term sampling has been hampered by inadequate sampling and analysis techniques. This investigation has used two types of personal inhalable sampler, with ICPMS analysis, to take 15 min TWA soluble platinum exposure measurements at three sites. The lower detection limit for soluble platinum salts was approximately 0.01 microgram m-3 for 15 min samples, allowing exposures two orders of magnitude below the exposure limit to be measured. It was found that the majority of short-term exposure levels were significantly below 0.006 mg m-3. No evidence was found for altered work practices during sampling, indicating that either sensitization is occurring at airborne exposure levels below the exposure limit, or there is an alternate route of exposure.

Air Pollutants, Occupational↗