Determination of human body burden baseline date of platinum through autopsy tissue analysis.
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Results of analysis for platinum in 97 autopsy sets are presented. Analysis was performed by a specially developed emission spectrochemical method. Almost half of the individuals studied were found to have detectable platinum in one or more tissue samples. Platinum was found to be deposited in 13 of 21 tissue types investigated. Surprisingly high values were observed in subcutaneous fat, previously not considered to be a target site for platinum deposition. These data will serve as a human tissue platinum burden baseline in EPA's Catalyst Research Program. (+info)
1Alpha,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines.
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The majority of men who die from prostate cancer (PC) have hormone-refractory disease. To date, chemotherapeutic agents have had little or no impact on the survival of such patients. To explore a new approach for the treatment of hormone-refractory PC, we examined the combination effects of cis- or carboplatin with vitamin D. 1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its synthetic analogue, Ro 25-6760, have an antiproliferative effect on some prostate cancer cell lines. Consequently, the growth-inhibitory effects of the drugs were measured, both singularly and in combination with cis- or carboplatin, on PC cells. Our results show that although each of the drugs alone displayed antiproliferative activity, the growth inhibition of PC cells was further enhanced by the combination of 1alpha,25(OH)2D3 or Ro 25-6760 and either platinum agent. The greatest enhancement of inhibition occurred using smaller concentrations of the platinum compound in combination with higher concentrations of 1alpha,25(OH)2D3. Isobologram analysis revealed that 1alpha,25(OH)2D3 and platinum acted in a synergistic manner to inhibit the growth of PC cells. Our findings suggest that there is potential clinical value in combining 1alpha,25(OH)2D3 with platinum compounds for the treatment of advanced-stage human PC. (+info)
Increased platinum accumulation in SA-1 tumour cells after in vivo electrochemotherapy with cisplatin.
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Electrochemotherapy is an anti-tumour treatment that utilizes locally delivered electric pulses to increase cytotoxicity of chemotherapeutic drugs. The aim of our study was to determine whether anti-tumour effectiveness of electrochemotherapy with cisplatin is a consequence of increased plasma membrane permeability caused by electroporation that enables cisplatin binding to DNA. For this purpose, anti-tumour effectiveness of electrochemotherapy was evaluated on SA-1 tumours treated with electric pulses 3 min after intravenous injection of cisplatin (4 mg kg(-1)). Anti-tumour effectiveness was correlated with platinum accumulation in tumours and the amount of platinum bound to DNA, as determined by atomic absorption spectrometry. In tumours treated with electrochemotherapy, cell kill was increased by a factor of 20 compared with treatment with cisplatin only, as determined from tumour growth curves. The amount of platinum bound to DNA and platinum content in the tumours treated by electrochemotherapy was approximately two times higher than in cisplatin-treated tumours. Based on our results, we conclude that in vivo application of electric pulses potentiates anti-tumour effectiveness of cisplatin by electroporation that consequently results in cisplatin increased delivery into the cells. In addition, besides electroporation, immune system and tumour blood flow changes could be involved in the observed anti-tumour effectiveness of electrochemotherapy. (+info)
Radiologic and histopathologic evaluation of canine artery occlusion after collagen-coated platinum microcoil delivery.
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BACKGROUND AND PURPOSE: Platinum coil embolization is one of the significant advances in interventional neuroradiologic techniques that has been introduced this decade. Our purpose was to evaluate the angiographic and histologic effects of collagen-coated platinum microcoil delivery in the canine artery. METHODS: We embolized the bilateral internal maxillary arteries of 18 dogs; one uncoated and one collagen-primed coil was used in each dog. We evaluated all coils by angiography, macroscopy, and scanning electron microscopy within 30 minutes of embolization. We then studied a proportional number of coated and collagen-primed coils at either 1 or 3 days, or 1, 2, 3, 4, 8, 12, or 16 weeks postoperatively. RESULTS: Six (33%) of 18 arteries embolized with uncoated coils were occluded 30 minutes after delivery, whereas 11 (61%) of 18 arteries treated with collagen-primed coils were occluded within 30 minutes of embolization. Late occlusion (3 weeks after embolization) occurred in 2 (25%) of 8 arteries embolized with untreated coils, and 6 (75%) of 8 arteries embolized with collagen-primed coils. We calculated differences in late occlusion rates by the chi2 (chi-square) test, and found these differences were significant (P=.04). Histologic findings of arteries embolized with unprimed coils revealed endothelial cell growth was limited to the organized thrombi 4 weeks after coil delivery. In contrast, endothelial cells grew directly on the collagen-primed coils 3 days postoperatively, and coils were completely covered by endothelial cells within 2 weeks. We found an organized thrombus in the inner space of coils in angiographically occluded arteries, a finding that was not evident in angiographically patent arteries. CONCLUSION: Collagen-coated platinum coils can produce rapid and stable occlusion of embolized vessels. (+info)
Substrate specificity of ultraviolet DNA endonuclease (UVDE/Uve1p) from Schizosaccharomyces pombe.
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Schizosaccharomyces pombe ultraviolet DNA endonuclease (UVDE or Uve1p) has been shown to cleave 5' to UV light-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PP). This endonuclease is believed to function in the initial step in an alternative excision repair pathway for the removal of DNA damage caused by exposure to UV light. An active truncated form of this protein, Delta228-Uve1p, has been successfully overexpressed, affinity purified and partially characterized. In the present study we present data from a detailed substrate specificity trial. We have determined that the substrate range of Uve1p is much greater than was originally believed. We demonstrate that this DNA damage repair protein is capable of recognizing an array of UV-induced DNA photoproducts (cis-syn-, trans-syn I- and trans-syn II CPDs, 6-4PP and Dewar isomers) that cause varying degrees of distortion in a duplex DNA molecule. We also demonstrate that Uve1p recognizes non-UV-induced DNA damage, such as platinum-DNA GG diadducts, uracil, dihydrouracil and abasic sites. This is the first time that a single DNA repair endonuclease with the ability to recognize such a diverse range of lesions has been described. This study suggests that Uve1p and the alternative excision repair pathway may participate broadly in the repair of DNA damage. (+info)
Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines.
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2',2'-Difluorodeoxycytidine (gemcitabine, dFdC) and cis-diammine-dichloroplatinum (cisplatin, CDDP) are active agents against ovarian cancer and non-small-cell lung cancer (NSCLC). CDDP acts by formation of platinum (Pt)-DNA adducts; dFdC by dFdCTP incorporation into DNA, subsequently leading to inhibition of exonuclease and DNA repair. Previously, synergism between both compounds was found in several human and murine cancer cell lines when cells were treated with these drugs in a constant ratio. In the present study we used different combinations of both drugs (one drug at its IC25 and the other in a concentration range) in the human ovarian cancer cell line A2780, its CDDP-resistant variant ADDP, its dFdC-resistant variant AG6000 and two NSCLC cell lines, H322 (human) and Lewis lung (LL) (murine). Cells were exposed for 4, 24 and 72 h with a total culture time of 96 h, and possible synergism was evaluated by median drug effect analysis by calculating a combination index (CI; CI < 1 indicates synergism). With CDDP at its IC25, the average CIs calculated at the IC50, IC75 IC90 and IC95 after 4, 24 and 72 h of exposure were < 1 for all cell lines, indicating synergism, except for the CI after 4 h exposure in the LL cell line which showed an additive effect. With dFdC at its IC25, the CIs for the combination with CDDP after 24 h were < 1 in all cell lines, except for the CIs after 4 h exposure in the LL and H322 cell lines which showed an additive effect. At 72 h exposure all CIs were < 1. CDDP did not significantly affect dFdCTP accumulation in all cell lines. CDDP increased dFdC incorporation into both DNA and RNA of the A2780 cell lines 33- and 79-fold (P < 0.01) respectively, and tended to increase the dFdC incorporation into RNA in all cell lines. In the AG6000 and LL cell lines, CDDP and dFdC induced > 25% more DNA strand breaks (DSB) than each drug alone; however, in the other cell lines no effect, or even a decrease in DSB, was observed. dFdC increased the cellular Pt accumulation after 24 h incubation only in the ADDP cell line. However, dFdC did enhance the Pt-DNA adduct formation in the A2780, AG6000, ADDP and LL cell lines (1.6-, 1.4-, 2.9- and 1.6-fold respectively). This increase in Pt-DNA adduct formation seems to be related to the incorporation of dFdC into DNA (r = 0.91). No increase in DNA platination was found in the H322 cell line. dFdC only increased Pt-DNA adduct retention in the A2780 and LL cell lines, but decreased the Pt-DNA adduct retention in the AG6000 cell line. In conclusion, the synergism between dFdC and CDDP appears to be mainly due to an increase in Pt-DNA adduct formation possibly related to changes in DNA due to dFdC incorporation into DNA. (+info)
Interaction of the anti-cancer drug cisplatin with phosphatidylserine in intact and semi-intact cells.
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The anti-cancer drug cisplatin (cis-diamminedichloroplatinum(II)) forms a stable coordination complex with phosphatidylserine (PS) in model membrane systems (Speelmans et al., Biochemistry 36 (1997) 10545-10550). Because a similar interaction in vivo would be expected to have important physiological implications we studied cisplatin-PS interaction in human erythrocytes and tumor cell lines. Although cisplatin was efficiently taken up by intact erythrocytes, a cisplatin-PS complex was only detected in cells which had lysed as a result of prolonged storage or hypotonic shock. Despite the use of highly sensitive detection methods, and despite efficient cellular uptake of cisplatin, a complex could also not be detected in four human tumor cell lines, unless cells were permeabilized. In experiments in which cisplatin was incubated with PS-containing liposomes in the presence of an alternative cellular substrate, such as reduced glutathione, the relative affinity of cisplatin for PS was found to be low. Moreover, loading erythrocyte ghosts with physiological concentrations of glutathione strongly reduced cisplatin-PS complexation. Thus, in intact (tumor) cells a complex is not detected, most likely, because of the presence of higher affinity substrates. Though a transient complexation of cisplatin to PS cannot be excluded, our data suggest that cisplatin-PS does not play a direct role in the cellular (cyto)toxicity of cisplatin. (+info)
Induction of immune tolerance in adult rabbits undergoing heterotopic cardiac transplantation.
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OBJECTIVE: To induce experimental immune tolerance in rabbits and observe its effects on heterotopic cardiac transplantation. METHODS: Donor's splenic lymphocytes pretreated with platinum metal chelator were injected into the recipient's mesenteric-portal vein. Cyclosporin A was perfused through the donor's heart. RESULTS: The injection of donor's splenic lymphocytes before transplantation could significantly prolong the survival time of the heterotopically transplanted heart. The effect of two injections was better than that of one. Radioactive tracer studies showed that the 99mTc-HMPAO tagged lymphocytes injected into the recipient rabbit were later concentrated in the liver, though initially they were distributed in multiple organs. The induced immune tolerance was antigen-specific, and it neither affect the other immune functions of the lymphatic system prominently nor exert any harmful effect on the recipient's liver and renal functions. The perfusion of cyclosporin A through the donor heart could block the glycosyl groups, such as D-glucose, D-mannose or N-acetyl-galactosamine on the surface of the myocardial cells, thus might change the antigenic expression, effectively preventing rejection of the graft by the host, and might be considered as a new method to block graft rejection in cardiac transplantation. The combined use of the above-mentioned two methods acted on both the host and the donor, thus reducing the exposed antigens on the donor organ as well as the immune reaction against the donor antigens, and resulting in synergistic effect in inducing immune tolerance in adult rabbits, and resulting in relatively long-term survival of transplanted hearts. CONCLUSION: This report may provide the experimental basis for inducing immune tolerance in clinical transplantation. (+info)