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1.
LW Seymour H Soyez A De Marre MA Shoaibi EH Schacht 《Canadian Metallurgical Quarterly》1996,11(5):351-365
Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents. 相似文献
2.
PE Sipila VJ Wiebe GB Hubbard SK Koester VD Emshoff JU Maenpaa GT Wurz RC Seymour MW DeGregorio 《Canadian Metallurgical Quarterly》1993,(15):2138-2144
The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo. 相似文献
3.
BACKGROUND: Laparoscopic Nissen fundoplication is an effective procedure for the treatment of gastro-oesophageal reflux disease (GORD), but the underlying motility mechanisms that explain the success of this operation remain unclear. METHODS: Twenty patients with a history of GORD underwent stationary oesophageal manometry and prolonged ambulatory pH monitoring, both before and 3 months after fundoplication. RESULTS: Eighteen patients were completely cured of reflux symptoms and stopped all antireflux medication after operation. After fundoplication there was a significant increase (P < 0.01) in median resting lower oesophageal sphincter (LOS) pressure and length. Median residual LOS pressure during swallow-induced LOS relaxation also increased significantly after operation (P < 0.01). The number of reflux episodes decreased from a median of 48 to 3 after fundoplication (P < 0.01). The time at pH less than 4 decreased from 5.7 to 0 per cent in the supine position (P < 0.01), and from 9.8 to 0.2 per cent while upright (P < 0.001). CONCLUSION: Early subjective results at 3 months following laparoscopic antireflux surgery show improved symptoms. One of the mechanisms underlying the antireflux action of fundoplication is an increase in median residual LOS pressure at the gastro-oesophageal junction. This may be a purely mechanical effect of the fundic wrap extrinsic to the LOS. 相似文献
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5.
Free and bound hydrosoluble protein extracts were prepared from four anatomical areas of a multiple sclerosis (MS) cerebrum and from corresponding anatomical areas of a normal (non-MS) control. Increased levels of IgG and anti-myelin basic protein antibodies (anti-MBP) were detected in all MS samples and they were undetectable in the controls. IgG and anti-MBP from free (unbound) hydrosoluble protein extracts are defined as free IgG and free anti-MBP while IgG and anti-MBP from tissue bound protein extracts are defined as bound IgG and bound anti-MBP. IgG was purified from free protein extracts by protein G Sepharose affinity chromatography and anti-MBP was further isolated from purified IgG by antigen specific (MBP) Sepharose affinity chromatography. Free and bound anti-MBP were reacted with 20 synthetic peptides of human MBP prepared by the Fmoc method. Free anti-MBP, whether in the context of whole protein extracts, or as purified IgG or as purified antibody was completely neutralized by peptides #12, #15, #56 and #56* containing overall residues 75-106, partially neutralized by peptides #27, #16 and #21 containing overall residues 61-83 and did not react with the remaining 13 peptides. Tissue bound anti-MBP was completely neutralized only by peptides #12, #15, #56 and #56* (overall residues 75-106) and showed no reactivity towards the remaining 16 peptides including peptides #27, #16 and #21. Synthetic peptide specificity of free anti-MBP purified from MS cerebrum was identical to previously reported specificity of free anti-MBP from MS cerebrospinal fluid (CSF), while tissue bound anti-MBP, as well as bound anti-MBP from CSF had a more restricted synthetic peptide specificity than free anti-MBP. This suggests that the most likely epitope of anti-MBP is located between residues 84 and 95 of human MBP just proximal to the tri-proline sequence (99-101). 相似文献
6.
Resurgence has been shown in human and nonhuman operant behavior, but not in derived relational responses. The present study examined this issue. Twenty-three undergraduates were trained to make conditional discriminations in a three-choice matching-to-sample paradigm. The training resulted in three equivalence classes, each consisting of four arbitrarily configured visual stimuli. The same 12 stimuli were then reorganized, and the conditional discrimination training was repeated such that three new classes were possible. In a subsequent test of derived relations, most subjects showed response patterns that were consistent with the altered conditional discriminations. Subjects were then exposed to conditional discrimination trials under extinction. Most subjects continued to respond consistently with the most recently reinforced conditional discrimination trials. During the next phase, subjects were exposed to symmetry and equivalence trials. Responses consistent with the most recent training produced feedback saying that the responses were incorrect, whereas other responses produced no feedback. Most subjects showed a resurgence of responding that was consistent with their earlier training. Finally, subjects were exposed to conditional discrimination trials carried out in extinction. Most subjects continued to show a resurgence of responding that was consistent with their early training. 相似文献
7.
There is now strong evidence that the chorioretinal degeneration associated with ornithine-delta-aminotransferase (OAT) deficiency is a consequence of hyperornithinemia. Therefore development of a metabolic system for clearing ornithine from the circulation is being pursued as a potential treatment. The skin is considered an attractive location for such a metabolic system because autologous cells can be safely and easily utilized. This study was undertaken to determine the ornithine metabolizing capacity of epidermal keratinocytes expressing normal and superphysiologic amounts of OAT. The data show that overexpression of OAT in keratinocytes cultured from a gyrate atrophy patient restores ornithine metabolism and results in a rate of ornithine disappearance from the medium that is significantly higher than the rate of disappearance from the medium bathing normal keratinocytes. In addition, OAT activity determined in soluble protein prepared from sonicates suggests that the capacity to maintain plasma ornithine within the normal range is contained within an accomplishable graft of keratinocytes overexpressing OAT. However, the actual rate of ornithine disappearance from the media was significantly less than predicted from enzyme activity assays. Following ornithine metabolite production by intact cells suggests that ornithine metabolism is limited primarily by clearance of downstream metabolites, as opposed to substrate delivery. 相似文献
8.
During the early development of skeletal muscle, cardiac isotypes of several contractile proteins are known to be transiently expressed. We report here that skeletal muscle developing in vivo, as well as primary cultures derived from skeletal muscle, express mRNA encoding the cardiac dihydropyridine-sensitive calcium channel. The mRNA is detectable at high concentration at the earliest stage tested in vivo and diminishes rapidly in concentration as myofibers mature. The concentration of the cardiac calcium channel mRNA also diminishes during the in vivo development of skeletal muscle in a genetically paralyzed mouse (mdg), indicating that muscle contractile activity is not necessary for the down-regulation. In contrast, mRNA for the skeletal muscle-specific calcium channel accumulates gradually in developing skeletal muscle. A similar temporal pattern of expression is also seen in primary cultures of skeletal myotubes. These results raise the question of whether the cardiac calcium channel may be functionally important during the early development of skeletal myofibers. 相似文献
9.
10.
Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function 总被引:2,自引:0,他引:2
LS Robbins JH Nadeau KR Johnson MA Kelly L Roselli-Rehfuss E Baack KG Mountjoy RD Cone 《Canadian Metallurgical Quarterly》1993,72(6):827-834
Coat colors in the chestnut horse, the yellow Labrador retriever, the red fox, and one type of yellow mouse are due to recessive alleles at the extension locus. Similarly, dominant alleles at this locus are often responsible for dark coat colors in mammals, such as the melanic form of the leopard, Panthera pardus. We show here that the murine extension locus encodes the melanocyte-stimulating hormone (MSH) receptor. In mice, the recessive yellow allele (e) results from a frameshift that produces a prematurely terminated, nonfunctioning receptor. The sombre (Eso and Eso-3J) and tobacco darkening (Etob) alleles, which both have dominant melanizing effects, results from point mutations that produce hyperactive MSH receptors. The Eso-3J receptor is constitutively activated, while the Etob receptor remains hormone responsive and produces a greater activation of its effector, adenylyl cyclase, than does the wild-type allele. 相似文献