SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Therapy related acute promyelocytic leukemia (ta-APL) is a rare complication of chemotherapy for other malignant tumors. We report two such cases, one of whom was exposed only to carboplatin two years before developing ta-APL and the other one was treated with cisplatin, etoposide and bleomycin five years prior to developing ta-APL.
We have developed panels of human lung cancer cell lines with acquired and inherent resistance to cisplatin. Three parental cell lines, NCI-H69/P (small cell), COR-L23/P (large cell), and MOR/P (adenocarcinoma), were grown in increasing concentrations of cisplatin over a period of 6-9 months. This resulted in the development of sublines, H69/CPR, L23/CPR, and MOR/CPR which were 3- to 8-fold resistant to cisplatin as determined by a 6-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. None of the resistant sublines showed a significant change in cellular glutathione content or sensitivity to cadmium chloride (an indicator of metallothionein content), although changes in glutathione-S-transferase activity were seen. The sublines each showed cross-resistance to melphalan. Cisplatin accumulation was unchanged in H69/CPR, 1.3-fold reduced in L23/CPR, and 2.0-fold reduced in MOR/CPR compared with their respective parent lines. In a panel of 10 small cell lung cancer cell lines, there was a 16-fold range of sensitivities to cisplatin. The panels have been used to examine cross-resistance between cisplatin, carboplatin, iproplatin, tetraplatin, and a series of 10 novel ammine/amine dicarboxylate platinum(IV) compounds. Whereas H69/CPR and MOR/CPR showed little or no cross-resistance to any of the other compounds, L23/CPR was generally cross-resistant to all of them. In the panel of small cell lines, whereas the ranking of sensitivity to carboplatin and cisplatin were similar, each of the other compounds provided individual patterns of sensitivity. There was always a wide range of sensitivities among the panel, ranging from 8- to 28-fold. Among the dicarboxylate compounds, there was a great range of potencies, with two compounds (JM273 and JM274) being approximately 100-fold more potent than cisplatin.
In vitro immune effects of Pt compounds of occupational and/or environmental importance, or those used in cancer treatment were studied. Spontaneous and PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) and in vitro release of TNF-alpha, IFN-gamma, and IL-5 were assessed in presence of high and very low concentrations of Pt salts: 10(-4) and 10(-7) M (NH4)2[PtCl6], (NH4)2[PtCl4], PtCl4, PtCl2, Na2PtI6, and cis-diaminedichloroPt (CisPt). Spontaneous and PHA-stimulated PBMC proliferation were both inhibited by 10(-4) M (NH4)2[PtCl6] and (NH4)2[PtCl4], while only PHA-stimulated proliferation was inhibited by 10(-4) M CisPt, without significant effects of the other Pt salts. TNF-alpha release from PBMC was reduced by 10(-4) M (NH4)2[PtCl6] and INF-gamma release was reduced by 10(-4) and 10(-7) M hexa- and tetrachloroplatinate and 10(-4) M Na2PtI6, but not by other Pt salts. IL-5 release (related to the Th2 immune response) was inhibited by 10(-4) M (NH4)2[PtCl6], (NH4)2[PtCl4] and Na2PtI6, but it was enhanced by both 10(-4) and 10(-7) M PtCl4. PtCl2 did not influence the immune effects. The study shows Pt salts have immune effects and their potency is ranked in the following order: (NH4)2[PtCl6] > (NH4)2[PtCl4] > Na2PtI6 and CisPt > PtCl4 > PtCl2. These results indicate that certain Pt salts affect lymphocyte proliferation and cytokine release. The intracellular mechanisms responsible for such effects have not been identified.
Explore the source record for details and available documents.
The sensitizing properties of different complex salts of platinum were defined in vivo by means of the popliteal lymph node (PLN) assay in mice. Hexa- and tetrachloroplatinates were confirmed to be highly immunogenic, inducing vigorous primary immune responses in the draining PLN following single subcutaneous injections. Flow-cytometric analysis revealed a dramatic increase in the total number of cells expressing proliferating cell nuclear antigen. The majority of these cells were of the T helper phenotype (CD4+) reflecting the T-cell dependence of the PLN response induced by Pt salts such as Na2[PtCl6] or Na2[PtCl4]. In contrast, [Pt(NH3)4]Cl2 failed to elicit a significant increase in PLN cell proliferation when compared with saline-treated controls. The differential immunogenicity of the Pt compounds found in vivo directly correlated with their capacity to modulate mechanisms of receptor-mediated endocytosis in murine Langerhans cells in vitro. The reactivity of Na2[PtCl6] or Na2[PtCl4] resembled that of potent contact sensitizers in this endocytosis assay whereas [Pt(NH3)4]Cl2 proved to be mert. These results suggest that [Pt(NH3)4]Cl2 might be less harmful to humans than hexa- or tetrachloroplatinates. As demonstrated with Pt compounds, monitoring of direct effects of low-molecular-weight chemicals on antigen-presenting dendritic cells in vitro is able to predict their sensitizing potential in vivo.
A newly developed reagent was tested for its applicability in in situ hybridization and in reversed hybridization of DNA fragments generated by PCR amplification. This Platinum-complex, designated universal linkage system (ULS), equipped, for instance, with biotin or fluorescein as hapten, enables versatile nonenzymatic "one step" labeling of genomic, cloned or amplified DNA. Here we demonstrate direct in situ detection of integrated human papilloma virus (HPV) DNA in cervical carcinoma cells using DNA probes labeled with fluorescein-ULS. In cervical smears the presence of HPV or Chlamydia trachomatis was assessed by PCR. To analyze the amplified DNA, a reversed hybridization assay was developed. Immobilized probes were incubated with amplimers that were labeled post-amplification through the action of the biotinylated (BIO)-ULS complex. This novel type of nonradioactive analysis appeared to be as sensitive as its isotopic or colorimetric equivalents. This labeling procedure is simple, versatile and can be included as a universal hapten linkage system in any PCR test or in situ hybridization assay aiming at the detection and identification of DNA or RNA molecules.
A single dose of cis-dichloro(dipyridine)platinum(II) (cis-PPC), when given to BDF1 mice bearing 1-day-old L1210 leukemia, suppressed the increase of spleen and liver ornithine decarboxylase (ODC) activity which occurs concomitantly with development of the leukemia. The inhibition of ODC, the rate-limiting enzyme in polyamine synthesis, appeared to correlate with the prolonged chemotherapeutic efficacy of a single dose of the platinum complex. These observations suggest an additional mechanism by which platinum complexes express their antitumor actions and, in addition, support the view that polyamine synthesis and excretion patterns can be used as predictors of chemotherapeutic response.
The nephrotoxicity of three platinum-containing antitumor agents was compared at doses that approximate the LD10 (cisplatin) or the LD50 (CI-973, carboplatin) doses. Male Wistar rats were administered single iv doses of 45 mg/kg CI-973, 6.5 mg/kg cisplatin, or 65 mg/kg carboplatin and observed for 4 days. Cisplatin treatment increased blood urea nitrogen (4x), creatinine (3x), glucose, and fractional electrolyte excretions, and decreased creatinine clearance by Day 4. These parameters were not significantly altered in CI-973- and carboplatin-treated animals. Cisplatin increased urinary excretion of LDH (six-fold), GGT (twofold), and NAG (twofold); CI-973 and carboplatin increased GGT excretion (approximately twofold). Cisplatin induced the following functional changes as a consequence of direct nephrotoxicity: decreases in GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increases in FF (fivefold). Functional changes, attributed to prerenal effects of CI-973, included a decrease in ERPF (35%) and an increase in FF (48%). No changes were seen following carboplatin treatment. All cisplatin-treated rats had proximal tubular necrosis in the outer stripe of the outer medulla, extending multifocally into inner cortical medullary rays. No renal lesions were detected by light or electron microscopy in the control or CI-973- or carboplatin-treated rats. Cisplatin produced marked nephrotoxicity as determined by biochemical, functional, and histopathologic endpoints. CI-973 and carboplatin were significantly less nephrotoxic than cisplatin.
Under the conditions of low speed centrifugation used in this study, the proportion of radioactively labelled DNA from Chinese hamster V79-379A cells sedimenting to the 700S region of an alkaline sucrose gradient was increased in a dose-dependent manner by prior treatment of the cells for 2 h with cis-platinum (II) diamminedichloride [cis-Pt(II)]. This increase was at the expense of material sedimenting in the 400-650S region. This profile was not modified by a 2-h post-treatment incubation prior to centrifugation. 6 h after treatment, the DNA from treated cells sedimented in a narrow band at a position corresponding to 350S. 21 h after exposure to the drug, a dose-dependent restitution of the DNA species sedimenting in the 450-650S range was observed. These results combined with other data relating to platinum binding allow the following conclusions to be reached: (1) cis Pt(II) treatment does not lead to the rapid formation of single-stranded breaks or alkali-labile sites in cellular DNA. (2) The time-dependent changes in sedimentation rate of DNA from treated cells may reflect the transient appearance of gaps following endonuclease attack at platinum-bound sites in DNA. (3) The likely ratio of inter to intra-strand DNA-platinum interactions suggests that such endonuclease attack is primarily at platinum induced inter-strand DNA cross-links.
Eleven patients with oral cancer were treated with the new platinum agent, nedaplatin, and 5-fluorouracil and simultaneous radiation therapy. The regimen was of 5 days' duration: 5-fluorouracil 400-500 mg/m(2) (days 1-5), nedaplatin 80-90 mg/m(2) (day 4), and a total radiation dose of 8-10 Gy (days 1-5). Of the 11 patients, 4 (36.4%) showed complete response and 5 (45.4%) showed partial response; the total response rate was 81.8%. Major side effects were hypochromia (27%), leukopenia (64%), granulocytopenia (55%), thrombocytopenia (36%), nausea and vomiting (82%), and mucositis (45%). Toxicity was grade 2 or less in most of the 11 patients. The results indicate that the regimen composed of combination chemotherapy with nedaplatin and radiation therapy is effective in the treatment of patients with squamous cell carcinoma of the oral region.
In order to compare the mechanistic properties of the antitumour-active trans platinum complex trans-[PtCl(2){Z-HN=C(OMe)Me}(NH(3))] (trans-Z) and of the antitumour-inactive isomer of cisplatin trans-[PtCl(2)(NH(3))(2)] (trans-DDP), the differential processing of the two compounds by SKOV-3 ovarian cancer cells has been investigated. trans-Z and trans-DDP enter cells with the same efficacy, but trans-Z shows a two-fold higher affinity for cellular DNA. The treatment with trans-DDP IC(50) determines an initial and transient cytostatic effect, paralleled by a moderate increase of apoptosis and by sequential and reversible arrests in S and G(2)/M phases of cell-cycle. In contrast, trans-Z IC(50) determines an initial cytotoxic effect, a more persistent and marked increase of apoptosis, and a more marked and prolonged arrest in S and G(2)/M phases of the cell-cycle. Treatment-induced gene expression modifications indicate that phenotypic effects of trans-DDP are driven by an initial and transient up-regulation of some genes related to cell-cycle checkpoint and arrest networks, whereas the more dramatic phenotypic effects of trans-Z are driven by a persistent up-regulation of more numerous genes involved in cell-cycle checkpoint and arrest networks, and in genome stability and DNA repair. Therefore, molecular and cellular events have been identified which are produced by trans-Z but not by trans-DDP, and which likely represent the mechanistic basis of antitumour activity of trans-Z in the SKOV-3 system.
The products resulting from reaction of cis-Pt(NH3)2Cl2 with d(CpCpGpG), d(GpCpG), d(pCpGpCpG), d(pGpCpGpC) and d(CpGpCpG) and from reaction of [Pt(dien)Cl]Cl with d(CpCpGpG) and d(GpCpG) have been characterized with the aid of proton NMR spectroscopy, circular dichroic spectroscopy and Pt analysis. The binding sites of the Pt compounds were determined by pH-dependent NMR spectroscopy. Binding of the two Pt compounds invariably occurs at the guanine N7 atoms. In all compounds containing [cis-Pt(NH3)2]2+ chelates are formed by coordination of platinum to two guanines of the same oligonucleotide. The resulting intrastrand-cross-linked oligonucleotides contain either d(GpG) . cisPt units, or d(GpCpG) . cisPt units. In the latter case the middle cytosine is not coordinated to platinum. As a result the conformational changes originating from these two chelates are different from each other. In the case of [Pt(dien)Cl]Cl as a starting product, two types of oligonucleotide adducts are formed, i.e. those with one Pt atom/molecule and those with two Pt atoms/molecule. The NMR spectra of the adducts containing only one Pt(dien)2+ show that only one adduct is formed, although two guanine bases are present. This indicates a preference for one of the N7 atoms in the molecule.
Explore the source record for details and available documents.
PURPOSE: BBR 3464 is a novel trinuclear platinum anticancer agent with a broad spectrum of preclinical antitumour activity. A phase I, open-label dose-escalating study was performed to determine the maximum tolerated dose (MTD) of BBR 3464 administered in combination with protracted venous infusional (PVI) 5-fluorouracil (5-FU) for up to six courses in patients with locally advanced and/or metastatic cancer. METHODS: Dose escalation was based on observation of toxicity at each dose level. BBR 3464 (0.6 mg/m(2) escalated to 0.75 mg/m(2)) was studied in combination with PVI 5-FU (200 mg/m(2) per day). RESULTS: Entered into the study were 14 patients. The most frequent toxicities were nausea, neutropenia, fatigue and diarrhoea. The protocol-defined MTD was not determined as 11/14 patients experienced grade 3 or 4 neutropenia that interrupted the planned administration of PVI 5-FU on day 15 (of 21). Although these events were not dose-limiting, as defined in the protocol, they imposed limitations on the dose of PVI 5-FU administered. Antitumour activity was observed: a partial response in one patient (7%) with invasive breast cancer. Stable disease was confirmed in three patients (21%). These four patients all completed the planned six courses of combined therapy. CONCLUSIONS: In light of the lack of septic events associated with the recorded neutropenia, it may be possible to safely continue PVI 5-FU despite the grade 3 or 4 neutropenia or modify the PVI schedule and administer therapy on days 1-15 of the 21-day cycle, but these modifications were not considered in this study.
Peripheral blood lymphocytes of patients with Fanconi's anemia (FA) were tested for their susceptibility to chromosome breakage by cis-platinum(II)-diamminedichloride [cis-Pt(II)], cis-platinum(IV)diamminetetrachloride [cis-Pt(IV)], and trans-platinum(IV)diamminetetrachloride [trans-Pt(IV)]. Low doses (0.1 microgram/ml) of the DNA-DNA cross-linking agents cis-Pt(II) and cis-Pt(IV) dramatically increased the chromosome breakage level in FA cultures without affecting the controls. The predominantly DNA-protein cross-linking compound trans-Pt(IV), however, was much less effective in producing chromosomal damage in FA. The differential response of FA cells to cis-Pt(IV) and trans-Pt(IV) suggests that the high susceptibility of FA to bifunctional cross-linking agents is due to an impairment of the cells to tolerate DNA-DNA cross-links, rather than DNA-protein cross-links.
We have previously reported the development of a two-column high performance liquid chromatography system for separation of platinum(II) complexes with the 1,2-diaminocyclohexane (DACH) carrier ligand (Mauldin et al., Anal. Biochem., 157: 129, 1986). Here we report the application of this technique to the study of the intracellular biotransformations of (DL)-trans-1,2-diaminocyclohexanemalonatoplatinum(II) [PtCl2(trans-DACH)] and (DL)-trans-1,2-diaminocyclohexanemalonatoplatinum(II) [Pt(mal)(trans-DACH)] in the L1210 cell line. The two-column high performance liquid chromatography system allowed separation and identification of both parent drugs and intracellular biotransformation products containing glutathione, methionine, cysteine, arginine, lysine, aspartate or glutamate, and serine or threonine. With the exception of the platinum-glutathione complex, the relative abundance of each biotransformation product was independent of drug concentration. The relative abundance of the platinum-glutathione biotransformation product increased with increasing platinum concentration, suggesting that platinum drugs cause an increase in intracellular glutathione levels in a dose-dependent manner. This hypothesis was verified by direct measurement of intracellular glutathione levels. In continuous uptake experiments, the intracellular levels of the parent compounds peaked between 2 and 5 h and declined to negligible levels by 24 h. In pulse-chase experiments, the chemical t1/2 for PtCl2(trans-DACH) and Pt(mal)(trans-DACH) inside the cell at 37 degrees C was determined to be 12-15 and 21-28 min, respectively. This is far shorter than previously determined rates for the displacement of either ligand in vitro. The platinum-amino acid complexes accumulated gradually throughout the 24-h incubation. The free trans-DACH carrier ligand also accumulated to a level approaching 20% of filterable counts during the 24-h incubation, probably due to trans-labilization of the carrier ligand by sulfur-containing nucleophiles. A combination of reverse phase high performance liquid chromatography and a DNA binding assay was used to identify and quantitate the reactive biotransformation products. As expected from previous studies (Mauldin et al., Cancer Res., 46: 2876, 1986), the PtCl2(trans-DACH)-treated cells had approximately 3 times more reactive platinum biotransformation product at early times, but the levels of reactive biotransformation product fell much more rapidly than in Pt(mal)(trans-DACH)-treated cells. In the PtCl2(trans-DACH)-treated cells, the major reactive biotransformation product was the aquachloro species at all time points tested. In Pt(mal)(trans-DACH)-treated
Explore the source record for details and available documents.
Explore the source record for details and available documents.