Trace analysis of the oxazaphosphorines cyclophosphamide and ifosfamide in body fluids

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Capillary chromatography in cancer research

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CFU-S(11) activity does not localize solely with the aorta in the aorta-gonad-mesonephros region

The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site in the midgestation mouse conceptus and first contains colony-forming units-spleen day 11 (CFU-S(11)) at embryonic day 10 (E10). Because CFU-S(11) activity is present in the AGM region before the onset of hematopoietic stem cell (HSC) activity, CFU-S(11) activity in the complex developing vascular and urogenital regions of the AGM was localized. From E10 onward, CFU-S(11) activity is associated with the aortic vasculature, and is found also in the urogenital ridges (UGRs). Together with data obtained from organ explant cultures, in which up to a 16-fold increase in CFU-S(11) activity was observed, it was determined that CFU-S(11) can be increased autonomously both in vascular sites and in UGRs. Furthermore, CFU-S(11) activity is present in vitelline and umbilical vessels. This, together with the presence of CFU-S(11) in the UGRs 2 days before HSC activity, suggests both temporally and spatially distinct emergent sources of CFU-S(11). (Blood. 2000;96:2902-2904

Determination of ifosfamide by gas chromatography-mass spectrometry

Ifosfamide, an oxazaphosphorine, is thermally stable during elution in gas chromatography (GC) at temperatures above 200 °C, in contrast to its structural isomer cyclophosphamide. Both 2.65-µm and 0.32-µm OV-1 columns were efficient for GC of ifosfamide without derivatization. Mass spectrometry (MS), showed that intact ifosfamide was eluted without interference from naturally occurring metabolites in blood plasma. Ifosfamide can be monitored, by capillary GC—MS without derivatization, in blood plasma from cancer patients treated with the drug. Only a liquid-liquid extraction is required before injection of the sample. A single peak of ifosfamide is detected with molecular mass 260; fragmentation starts with loss of CH2Cl ([M — CH2Cl], m/z 211). The limit of determination for ifosfamide in human plasma was about 50 nM (10 ng ml-1). Recovery, quality of calibration curves and reproducibility were suitable for the rapid determination of ifosfamide in the range 0.01–1000 µg ml-1

Diffusive limits on the Penrose tiling

In this paper random walks on the Penrose lattice are investigated. Heat kernel estimates and the invariance principle are shown

Isolated hypoxic hepatic perfusion with tumor necrosis factor-alpha, melphalan, and mitomycin C using balloon catheter techniques: a pharmacokinetic study in pigs

OBJECTIVE: To validate the methodology of isolated hypoxic hepatic perfusion (IHHP) using balloon catheter techniques and to gain insight into the distribution of tumor necrosis factor-alpha (TNF), melphalan, and mitomycin C (MMC) through the regional and systemic blood compartments when applying these techniques. SUMMARY BACKGROUND DATA: There is no standard treatment for unresectable liver tumors. Clinical results of isolated limb perfusion with high-dose TNF and melphalan for the treatment of melanoma and sarcoma have been promising, and attempts have been made to extrapolate this success to the isolated liver perfusion setting. The magnitude and toxicity of the surgical procedure, however, have limited clinical applicability. METHODS: Pigs underwent IHHP with TNF, melphalan, and MMC using balloon catheters or served as controls, receiving equivalent dosages of these agents intravenously. After a 20-minute perfusion, a washout procedure was performed for 10 minutes, after which isolation was terminated. Throughout the procedure and afterward, blood samples were obtained from the hepatic and systemic blood compartments and concentrations of perfused agents were determined. RESULTS: During perfusion, locoregional plasma drug concentrations were 20- to 40-fold higher than systemic concentrations. Compared with systemic concentrations after intravenous administration, regional concentrations during IHHP were up to 10-fold higher. Regional MMC and melphalan levels steadily declined during perfusion, indicating rapid uptake by the liver tissue; minimal systemic concentrations indicated virtually no leakage to the systemic blood compartment. During isolation, concentrations of TNF in the perfusate declined only slightly, indicating limited uptake by the liver tissue; no leakage of TNF to the systemic circulation was observed. After termination of isolation, systemic TNF levels showed only a minor transient elevation, indicating that the washout procedure at the end of the perfusions was fully effective. CONCLUSIONS: Complete isolation of the hepatic vascular bed can be accomplished when performing IHHP using this balloon catheter technique. Thus, as in extremities, an ideal leakage-free perfusion of the liver can now be performed, and repeated, without major surgery. The effective washout allows the addition of TNF in this setting

In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour

Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorbicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 μmol/l, while intratumoral CsA levels amounted to 3.6 μmol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting

Drug resistance in rat colon cancer cell lines is associated with minor changes in susceptibility to cytotoxic cells

The development of resistance to anticancer drugs urges the search for different treatment modalities. Several investigators have reported the concomitant development of drug resistance and resistance to natural killer (NK), lymphokine-activated killer (LAK) or monocyte/macrophage cell lysis, while others described unchanged or even increased susceptibility. We investigated this subject in the rat colon carcinoma cell line, CC531-PAR, which is intrinsically multidrug-resistant (MDR), and in three sublines derived from this parental cell line: a cell line with an increased MDR phenotype (CC531-COL), a revertant line from CC531-COL (CC531-REV), which demonstrates enhanced sensitivity to anticancer drugs of the MDR phenotype, and an independently developed cisplatin-resistant line (CC531-CIS). In a 4-h51Cr-release assay we found no difference in susceptibility to NK cell lysis. No significant differences in lysability by adherent LAK (aLAK) cells were observed in a 4-h assay. In a prolonged 20-h51Cr-release assay an enhanced sensitivity to aLAK-cell-mediated lysis was observed in the revertant, P-glycoprotein-negative cell line and in the cisplatin-resistant cell line (CC531-CIS). None of the cell lines was completely resistant to lysis by aLAK cells. Therefore, a role for immunotherapy in the treatment of drug-resistant tumors remains a realistic option

A coupled agent-based model to analyse human-drought feedbacks for agropastoralists in dryland regions

Drought is a persistent hazard that impacts the environment, people's livelihoods, access to education and food security. Adaptation choices made by people can influence the propagation of this drought hazard. However, few drought models incorporate adaptive behavior and feedbacks between adaptations and drought. In this research, we present a dynamic drought adaptation modeling framework, ADOPT-AP, which combines socio-hydrological and agent-based modeling approaches. This approach is applied to agropastoral communities in dryland regions in Kenya. We couple the spatially explicit hydrological Dryland Water Partitioning (DRYP) model with a behavioral model capable of simulating different bounded rational behavioral theories (ADOPT). The results demonstrate that agropastoralists respond differently to drought due to differences in (perceptions of) their hydrological environment. Downstream communities are impacted more heavily and implement more short-term adaptation measures than upstream communities in the same catchment. Additional drivers of drought adaptation concern socio-economic factors such as wealth and distance to wells. We show that the uptake of drought adaptation influences soil moisture (positively through irrigation) and groundwater (negatively through abstraction) and, thus, the drought propagation through the hydrological cycle

On the role of longitudinal momenta in high energy hadron-hadron scattering

We demonstrate a new method for the calculation of inelastic scattering cross-section, which in contrary to the Regge-based methods takes into account the energy momentum conservation law. By virtue of this method it was shown that the main contribution to integral expressing inelastic scattering cross-sections comes not from the multi-Regge domain. In particular this leads to the fact that accounting of longitudinal momenta contribution to virtualities is sufficient and results in the new mechanism of cross-section growth. The necessity of taking into account the large number of interference contributions is shown and the approximate method for this purpose is developed. By considering the interference contributions from a single fitting constant achieved a qualitative agreement of the total and inelastic cross sections with experimental data.Comment: 38 pages, 19 figures (A misspelled author's name corrected