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ELOXATIN (Oxaliplatin) is a novel platinum containing anti-cancer agent with a diaminocyclohexane carrier ligand which has been approved in several major European countries. Clinical studies have demonstrated that the compound exhibits marked activity against colorectal cancers in combination with 5-fluorouracil (5-FU). The aim of this work was to develop and validate a highly sensitive inductively coupled plasma mass spectrometry assay for the determination of oxaliplatin-derived platinum in plasma ultrafiltrate, plasma and whole blood and to apply this technique to clinical pharmacokinetic studies with oxaliplatin. Ultratrace detection of platinum in plasma ultrafiltrate was achieved using ultrasonic nebulisation combined with ICP-MS. This technique allows detection of platinum at the 0.001 microg Pt/ml level in only 100 microl of matrix. Assays in blood and plasma utilised a standard Meinhardt nebuliser and spray chamber, achieving detection limits of 0.1 microg Pt/ml in 100 and 200 microl of matrix, respectively. The assays were validated (accuracy and precision within +/- 15%) over the concentration ranges: 0.001-0.250 microg Pt/ml in plasma ultrafiltrate and 0.1-10 microg Pt/ml for plasma and whole blood. The effect of sample digestion. dilution, long term frozen storage and quantitation in the presence of 5-FU were also investigated and validated. The method was used to monitor platinum exposure following oxaliplatin administration (130 mg/m2) to cancer patients. Following a 2 h i.v. infusion, peak platinum levels declined in a triphasic manner in all blood compartments. Free platinum was detected in plasma ultrafiltrate at low levels (0.001 0.010 microg Pt/ml) for up to 3 weeks. In conclusion, a highly sensitive and specific assay has been developed for the determination of platinum in biofluids. This method enabled characterisation of the long term exposure to platinum in patients following oxaliplatin treatment.
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PMID:Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: application to clinical pharmacokinetic studies with oxaliplatin. 1110 33

The study has been concerned with DNA ploidy and its significance for prognosis of different neoplasms. The investigation included 314 patients: primary cancer of the lung (96), head and neck (146) and large bowel (72). Patients received surgery alone or surgery plus either radiotherapy or chemotherapy; they were followed up for 6-20 months. DNA levels were assayed in resected material using an ICP-22 flow cytometer. Diploid and aneuploid cancers were detected in 20.4-53.6 and 43.6-79.6%, respectively. The recurrence rates in cases of aneuploid cancers were more than 3 times those of diploidy (21.0-43.2 and 4.5-14.5%, respectively). Overall 5-year survival in diploid patients was twice that in aneuploid ones. Similarly, survival after surgery alone, preoperative chemotherapy and postoperative radiotherapy among diploid patients was longer than in aneuploid ones. Hence, DNA ploidy examination of tumors is of great informative value in prognosing tumor process and working out individually-tailored approach to treatment.
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PMID:[DNA flow cytometry in the prognostication of certain malignant neoformations]. 1182 89

Herpes simplex virus type 1 (HSV-1)-based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV-1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV-1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV-1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose-dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency-dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication-selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low-dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low-dose radiation further potentiated the effect. These results suggest that replication-selective HSV-1 mutants may be potent oncolytic agents for the treatment of cervical cancer.
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PMID:Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation. 1191 86

DNA damaging agents such as cisplatin arrest cell cycle progression at either G1, S, or G2 phase, although the G1 arrest is only seen in cells expressing the wild-type p53 tumor suppressor protein. We have reported that 7-hydroxystaurosporine (UCN-01) overcomes S and G2 phase arrest and enhances the cytotoxicity of cisplatin. Abrogation of arrest appears to be selective for cells defective in p53 and therefore provides a potential, tumor-targeted therapy. Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting access to the tumor. A screen of related indolocarbazoles identified analogues with both beneficial and undesirable properties. This led to a synthetic program to develop a novel analogue rationally designed to overcome the obstacles observed with the other analogues. We report the synthesis and analysis of a novel analogue, ICP-1. This analogue abrogated S and G2 phase arrest and enhanced cytotoxicity induced by cisplatin only in p53 defective cells. ICP-1 also abrogated arrest and enhanced cell killing induced by the topoisomerase I inhibitor SN38. Analysis of proteins that regulate cell cycle arrest suggest both drugs inhibit checkpoint kinases Chk1 and/or Chk2. In contrast to UCN-01, checkpoint abrogation by ICP-1 was only slightly inhibited by human plasma. UCN-01 and ICP-1 differed significantly in other regards. UCN-01 potently enhanced the activity of 1-beta-D-arabinofuranosylcytosine in both p53 wild-type and mutant cells, whereas ICP-1 was inactive in this combination. This property of UCN-01 was independent of its ability to inhibit protein kinase C because more specific inhibitors of protein kinase C failed to enhance cell killing induced by 1-beta-D-arabinofuranosylcytosine. High concentrations of UCN-01 also inhibit C-TAK1 that results in S phase-arrested cells directly entering mitosis, but this property was not observed with ICP-1. Hence, ICP-1 appears to be a more selective inhibitor of the S and G2 cell cycle checkpoint than previously studied analogues and is worthy of study in preclinical tumor models.
Mol Cancer Ther 2002 Oct
PMID:A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest and enhances cytotoxicity: similarities and differences to the cell cycle checkpoint abrogator UCN-01. 1248 30

The analytical challenges of Pt determination by ICP-SFMS posed by different human tissues and fluids have been critically assessed. Investigated samples were (1) urine, (2) serum of cancer patients sampled during chemotherapy with carboplatin, (3) microdialysates (20 micro L sample volume) collected from tumor and non-tumor tissue, and, finally-for the first time-(4) human lung tissue to study background concentrations of inhaled platinum. Sample preparation involved microwave digestion and open vessel treatment or simple dilution (microdialysates). Depending on the sample preparation and introduction systems used (microconcentric nebulization, ultrasonic nebulization with and without membrane desolvation) excellent procedural detection limits (3s criterion) of 0.35 pg g(-1) for urine, 420 pg g(-1) for serum, 400 pg g(-1) for lung tissue and 13 pg g(-1) for microdialysates could be obtained. Ultratrace concentrations of 1-40 pg g(-1), and 1000-3000 pg g(-1) were measured in urine and human lung tissue, respectively, as typical for samples in environmental studies. Quantification was carried out by IDMS and standard addition in the case of urine samples. Internal standardization could not correct for non-spectral interferences in external calibration. In the serum and microdialysates of patients during chemotherapy with carboplatin, elevated Pt levels ranging between 0.01 and 10 micro g g(-1) were determined by external calibration ((195)Pt isotope). For all investigated samples spectral interferences could be excluded by following different strategies. High-resolution control measurements ((194)Pt, (195)Pt) were performed in the case of elevated Pt levels, i.e. for microdialysates and serum samples. An Hf/Pt ratio of 0.4 was determined in human lung samples. An HfO formation ratio of 0.2% was assessed for standard solutions at the present experimental conditions, revealing that the contribution of (179)Hf(16)O, (178)Hf(17)O, (177)Hf(18)O to the (195)Pt isotope signal used for quantification was not significant.
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PMID:Platinum determination by inductively coupled plasma-sector field mass spectrometry (ICP-SFMS) in different matrices relevant to human biomonitoring. 1269 3

Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G2 checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G1 checkpoint resulting in a dependence on the G2 checkpoint during cell replication. Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include gammaH2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A. This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.
Mol Cancer Ther 2004 Apr
PMID:G2 checkpoint abrogators as anticancer drugs. 1507 95

For several years organo-germanium containing medicine has been used for special treatments of e.g. cancer and AIDS. The active substances contain germanium as beta-carboxyethylgermanium sesquioxide ((GeCH2CH2COOH)203/"Ge-132"), spirogermanium, germanium-lactate-citrate or unspecified forms. For humans, germanium is not essential and in general the toxicity of the mentioned organo-germanium compounds is low. Acute and chronic toxic effects of inorganic germanium dioxide have been demonstrated. It is obvious that especially inorganic germanium has a higher potential of negative effects. Therefore, a widespread analytical product control is indispensable. Inductively coupled plasma mass spectrometry (ICP-MS) is the preferred technique and different applications were developed for controlling various parameters: (i) A speciation method using high performance liquid chromatography (HPLC) coupled with quadrupole (Q-) ICP-MS was developed for the identification of organo-germanium species in medicine. (ii) The nuclear magnetic resonance (NMR) technique was applied to confirm the molecular structure and to determine the molecule concentration. (iii) The total concentration of germanium in the medicine was determined in the diluted sample by high resolution (HR-) ICP-MS. (iv) For a general overview, a multi-element screening method of 56 elements with HR-ICP-MS was developed. The semi-quantitative mode was used for quantification and elements of higher abundance are reported. (v) Investigations about matrix-based interferences on masses of isotopes, which are generally determinable without remarkable problems. Isotopes like e.g. 85Rb, 88Sr, 89y, 90Zr, 93Nb and the isotopes of Ba are strongly interfered by different Ge-based molecules and need to be analysed in a higher resolution mode than used for other common matrices.
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PMID:Analytical product study of germanium-containing medicine by different ICP-MS applications. 1548 58

Cisplatin causes apoptosis of dorsal root ganglia (DRG) neurons. The amount of platinum binding to DNA correlates with cisplatin toxicity in cancer cellsGenomic DNA platinum content of cultured embryonic DRG neurons and PC12 cells was assayed using inductively coupled plasma mass spectrometry (ICP-MS). Throughout these studies, "cisplatin" refers to the specific drug; "platinum" to the bound form of the drug that is measured in ICP-MS.. Cisplatin binds neuronal DNA more than a neuron-like dividing cell line (PC12); 10-fold at 24 h and 24-fold greater at 72 h. Difference in platinum accumulation was not due to dividing versus post-mitotic state, or to a difference in rate of repair. There was overall greater accumulation of platinum in DRG neurons. In vivo DNA-Platinum binding in adult (300 g) rat DRG was greater than in multiple other tissues. Concomitant treatment with high-dose NGF prevented cisplatin-mediated neuronal apoptosis in vitro but did not reduce adduct formation. Our results show that NGF does not alter platination of DNA, indicating that it interrupts the platinum death pathway after adduct formation. In addition, disproportionate platinum accumulation may explain why a drug aimed at killing rapidly dividing cells causes sensory neurotoxicity.
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PMID:Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. 1568 59

Arsenobetaine, two arsenosugars, dimethylarsinate and several unidentified arsenic species were detected in extracts of the haemolymph of the Dungeness crab, Cancer magister, by using HPLC-ICP-MS. This is the first report of the presence of arsenosugars in the haemolymph/blood of marine animals. Total, extractable and residual arsenic concentrations were determined by ICP-MS. The concentration of total arsenic was in the range of 1.4-3.8 [micro sign]g ml(-1). Nearly all (98%) the arsenic was found to be extractable, and accounted for primarily by arsenobetaine, two arsenosugars and dimethylarsinate. The results demonstrate that arsenic compounds present in the diet of crabs are not fully metabolized in the gut. They are, at least partly, taken up into the haemolymph. The concurrence of arsenobetaine and arsenosugars suggests that the use of repeated haemolymph sampling in crustaceans could facilitate investigations into the kinetics of the biotransformation pathways of arsenic compounds. Finally, the present study clearly demonstrates the unique capabilities of HPLC-ICP-MS for the detection and identification of minor arsenic components amongst the predominant arsenobetaine.
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PMID:Arsenic compounds in the haemolymph of the Dungeness crab, Cancer magister, as determined by using HPLC on-line with inductively coupled plasma mass spectrometry. 1569 92

Garlic (Allium sativum) and onion (Allium cepa) are widely known for their biological properties but are far from having revealed all of their secrets even if the compounds involved in the biological mechanisms, flavenols, sulphur and seleno compounds have been identified. The beneficial effect of garlic on health including protection against cardiovascular diseases and cancers results from all of these compounds although their individual involvement is complex. Garlic and onion, broccoli, wild leek, have the ability to accumulate the selenium (Se) from soil. These Se-enriched plants present a greater protection against carcinogenesis than the common plants and two Se-compounds possessing anti-cancer activity have been identified: Se-methyl selenocysteine and gamma-glutamyl-Se-methyl selenocysteine. However, several Se-compounds from Se-enriched garlic or onion remain unidentified. The techniques for the detection of Se-species are numerous but few methods are able to identify the detected compounds. The very small quantities of Se-compounds present and the clear lack of standards do not make their analysis straightforward, particularly for non-enriched samples. Over the last 10 or so years development of the synthesis of Se-compounds and the use of GC-AED or EC/HPLC-ICP-MS have shown considerable possibilities. These techniques have allowed advances in the identification of Se-compounds, some of which are analogues of S-compounds in plants and yeasts. When these techniques are coupled to EC/HPLC-APCI-MS-MS, they provide a lot of information about the Se-biosynthesis in garlic. This has allowed the preferential formation of methylated compounds in Se-biochemistry to be identified, in contrast to the sulphur biochemistry of the Allium spp. in which compounds containing propenylic groups predominate. This review focuses on the recent advances in the analytical methods of Se-compounds in garlic and onion and particular attention is given to the biological properties of Se-species identified in Se-enriched plants.
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PMID:Seleno-compounds in garlic and onion. 1648 Sep 95


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