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71.
LL Siu G Attardo E Izbicka R Lawrence C Cerna L Gomez K Davidson C Finkle C Marsolais EK Rowinsky DD Von Hoff 《Canadian Metallurgical Quarterly》1998,9(8):885-891
BACKGROUND: BCH-4556 ((-)-2'-deoxy-3'-oxacytidine) is an L-nucleoside analogue shown to have broad preclinical anti-cancer activity, particularly against solid neoplasms such as prostate, renal, and hepatoma in vitro and in vivo, in contrast to cytosine arabinoside (ara-C) which is preferentially active against leukemia. MATERIALS AND METHODS: The antitumor activity of BCH-4556 was evaluated using human tumor colony-forming unit (HTCFU) assay, in which fresh tumor specimens were taken directly from patients with and without prior chemotherapy. RESULTS: Overall, in vitro responses (50% or less survival compared to untreated controls) were observed in 11% (two of 18), 29% (five of 17) and 50% (nine of 18) of specimens treated for one hour with BCH-4556 at 1, 10 and 100 micrograms/ml, respectively; and 16% (nine of 55), 32% (24 of 74), 48% (35 of 73) and 65% (11 of 17) of specimens treated continuously with BCH-4556 at 0.1, 1, 10 and 100 micrograms/ml, respectively. With the one-hour schedule, a significant difference in response rates was noted between 100 micrograms/ml and 1 microgram/ml (P = 0.02). With the continuous schedule, significant differences in response rates were observed between 1 microgram/ml and 0.1 microgram/ml (P = 0.02), between 10 micrograms/ml and 0.1 microgram/ml (P = 0.0001), as well as between 10 micrograms/ml and 1 microgram/ml (P = 0.01). A trend suggesting the superiority of continuous exposure was observed in paired specimens (n = 18) at comparable drug concentrations. Activity was noted against ovarian (nine of 16 = 56%), renal (three of four = 75%), and melanoma (two of two = 100%) HTCFU at 10 micrograms/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 micrograms/ml using the continuous exposure. Twenty-three specimens showed similar responses with both drugs; seven showed better responses with BCH-4556; and two showed better responses with paclitaxel (P = 0.18). CONCLUSIONS: Promising activity was observed with BCH-4556 against ovarian, renal, and melanoma HTCFU. There appeared to be a positive relationship between BCH-4556 concentration and response using both one-hour and continuous exposures. Continuous exposure to BCH-4556 provided high response rates especially at concentrations above 10 micrograms/ml. For both one-hour and continuous exposures, BCH-4556 had similar, and at times, greater potency than paclitaxel against the same tumor specimens in the present study. 相似文献
72.
A Bhandari DG Jones JR Schullek K Vo CA Schunk LL Tamanaha D Chen Z Yuan MC Needels MA Gallop 《Canadian Metallurgical Quarterly》1998,8(17):2303-2308
Phosphomannose Isomerase (PMI) has been shown by genetic methods to be an essential enzyme in fungal cell wall biosynthesis. The PMI inhibitor AF14049 was discovered as an unanticipated side product from high-throughput library screening against the enzyme from C, albicans. Solid-phase synthetic methods were developed and a series of libraries and discrete analogs synthesized to explore SAR around AF14049. 相似文献
73.
The effect of chronic in vivo glutathione (GSH) depletion by L-buthionine-[S,R]-sulfoximine (BSO) on intracellular and interorgan GSH regulation was investigated in mice both at rest and after an acute bout of exhaustive swim exercise. BSO treatment for 12 days decreased concentrations of GSH in the liver, kidney, quadriceps muscle, and plasma to 28, 15, 7, and 35%, respectively, compared to GSH-adequate mice. In most tissues, with the exception of the kidney, this decrease was associated with a concomitant decrease of glutathione disulfide (GSSG) such that the GSH/GSSG ratio was maintained. GSH depletion caused adaptive changes in several enzymes related to GSH regulation, such as liver glutathione peroxidase (-25%), kidney gamma-glutamyltranspeptidase (+20%), glutathione disulfide reductase (+131%) and glutathione sulfur-transferase (+53%). There was an apparent down-regulation of muscle gamma-glutamyltranspeptidase (-56%) in the GSH-depleted mice, which contributed to a conservation of plasma GSH. Exhaustive exercise in the GSH-adequate state severely depleted GSH content in the liver (-55%) and kidney (-35%), whereas plasma and muscle GSH levels remained constant. However, exercise in the GSH-depleted state exacerbated GSH deficit in the liver (-57%), kidney (-33%), plasma (-65%), and muscle (-25%) in the absence of adequate reserves of liver GSH. Hepatic lipid peroxidation increased by 220 and 290%, respectively, after exhaustive exercise in the GSH-adequate and -depleted mice. We conclude that GSH homeostasis is essential for the prooxidant-antioxidant balance during prolonged physical exercise. 相似文献
74.
The skeletal features of a moderately decomposed decapitated head recovered in 1993 are consistent with torticollis (wryneck) and inconsistent with other possible syndromes. Asymmetries of the face, cranial vault, mandible, and cervical vertebrae closely resemble published cases of paleopathological and recent torticollis. The laterally directed left occipital condyle and articulation of the basicranium and cervical vertebrae indicate that the head was tipped toward the left shoulder. Right-left asymmetries of areas of muscular attachments are compatible with a leftward head deviation. Mild arthritis of the atlantal-occipital and intervertebral joints, clinoid bridging, and thickening of the inner table of the frontal squamosa may not be related to the possible torticollis. The postural deviations of the head and neck may aid in the identification of this homicide victim, as did skeletal evidence to torticollis in an earlier case from Britain. 相似文献
75.
Protein shedding, or the proteolytic cleavage of a protein from the surface of a cell, is emerging as an important mechanism in the regulation of cellular activity but it is poorly understood. Growing evidence suggesting that protein shedding and protein function are closely linked may lead to new strategies for the treatment of a wide range of diseases. 相似文献
76.
LL Dever SM Smith D Dejesus M Masurekar D Patel ZC Kaminski WG Johanson 《Canadian Metallurgical Quarterly》1996,2(4):407-413
OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved. 相似文献
77.
Prolonged alcohol (ethanol) consumption leads to the development of alcohol tolerance and cross-tolerance to some benzodiazepines and barbiturates. In contrast, rats undergoing alcohol withdrawal are sensitized to the anticonvulsant effects of the endogenous GABA(A) receptor modulator, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP). Alterations in endogenous, cerebral cortical levels of 3alpha,5alpha-THP during alcohol withdrawal could contribute to the observed sensitization to 3alpha,5alpha-THP. Therefore, this study investigated plasma and brain levels of 3alpha,5alpha-THP, progesterone, and corticosterone during alcohol dependence and withdrawal in the rat. Plasma corticosterone, progesterone (a precursor of 3alpha,5alpha-THP) and 3alpha,5alpha-THP levels were unchanged in alcohol-dependent animals. Cerebral cortical levels of 3alpha,5alpha-THP decreased in dependent male animals, but not in dependent female rats. During alcohol withdrawal, plasma corticosterone and progesterone levels increased in male, but not female rats. However, neither plasma nor cerebral cortical 3alpha,5alpha-THP levels were altered from control levels in male or female rats during alcohol withdrawal. Plasma and brain levels of 3alpha,5alpha-THP were markedly higher in female compared with male rats. Cerebral cortical levels of 3alpha,5alpha-THP during the diestrus phase of the estrus cycle were approximately 4 to 6 ng/g, a concentration that may approach physiological relevance. These findings suggest that sensitization to 3alpha,5alpha-THP during alcohol withdrawal is not mediated by elevations in brain levels of endogenous 3alpha,5alpha-THP in male or female rats. However, elevations in circulating corticosterone and progesterone levels during ethanol withdrawal in male rats may underlie gender differences in allopregnanolone sensitivity during ethanol withdrawal. 相似文献
78.
EJ Roth AW Heinemann LL Lovell RL Harvey JR McGuire S Diaz 《Canadian Metallurgical Quarterly》1998,79(3):329-335
Migration of non-volatile and volatile compounds from 'microwave and roasting bags' (MRB), made of Nylon 6,6 (and some Nylon 6), into chicken meat, skin, and juices during roasting (200 degrees C/2 h) in a conventional oven was determined. For measurement of migration of non-volatile compounds, cooked chicken was freeze-dried, extracted with methanol after addition of 2-azacyclononane (internal standard) and the extract cleaned-up using liquid-solid adsorption chromatography (silica gel). High performance liquid chromatography (HPLC) in the reverse phase mode using a linear gradient of methanol in water was used to quantify seven Nylon 6 and Nylon 6,6 cyclic monomers and oligomers of molecular mass up to 678 daltons. Migration into chicken was 7.48 micrograms/g (8.26 mg/bag; 3.94 micrograms/cm2), 16% of the total non-volatile compounds contained in the MRB material. Individual migrants were also quantified. Migration of one volatile compound, 2-cyclopentyl cyclopentanone, into the roast chicken parts was measured. Extraction with diethyl ether, using a modified Likens-Nickerson system of concurrent steam distillation-solvent extraction with an internal standard (cyclohexanone) was performed for 10 h. Gas chromatography/mass spectrometry (GC/MS) in the selected ion mode (SIM) was used for quantification. An average of 14.0 (+/- 4.36) micrograms/bag (or micrograms/chicken) migrated, being 0.08% of the total 2-cyclopentyl cyclopentanone present in MRB. Loss of volatile compounds to the atmosphere is believed to have occurred since there was another, more volatile compound (cyclopentanone), present in MRB, at levels higher than 2-cyclopentyl cyclopentanone, but this was not detected in roast chicken. In general, the transference of MRB components into roast chicken can be considered not to present a hazard. 相似文献
79.
LL Koenigs RM Peter SJ Thompson AE Rettie WF Trager 《Canadian Metallurgical Quarterly》1997,25(12):1407-1415
The P450 2A6 catalyzed 7-hydroxylation of coumarin proceeded with a mean Km of 0.40 (+/-0.13) microM and Vmax of 6.34 nmol/nmol P450/min (36-fold variation) in microsomal preparations from a panel of 12 human livers. Substrate depletion was avoided during the kinetic determinations. 8-Methoxypsoralen (8-MOP) is a potent mechanism-based inactivator of human liver P450 2A6 and reconstituted purified recombinant P450 2A6 based on the following evidence: 1) 8-MOP causes time, concentration, and NADPH-dependent loss of P450 2A6 activity that is not reversed by potassium ferricyanide or extensive dialysis, 2) loss of P450 2A6 activity is associated with a loss of spectrally observable P450, 3) addition of nucleophiles or reactive oxygen scavengers to the incubations does not prevent inactivation of P450 2A6, and 4) 8-MOP-dependent P450 2A6 inactivation is inhibited (concentration dependent) by the addition of a competitive inhibitor (pilocarpine). Inactivation is selective for P450 2A6 at low concentrations of 8-MOP (2.5 microM) after short incubation time periods (3 min) and was characterized by a KI of 0.8 and 1.9 microM in a reconstituted and microsomal system, respectively, and a kinact of 1 min-1 and 2 min-1 in a reconstituted and microsomal system, respectively. A substrate depletion partition ratio of 21 was calculated for the inactivation of recombinant P450 2A6. Potency and selectivity suggest that 8-MOP could be a useful tool in vitro for evaluating P450 2A6 activity in various enzyme preparations. 相似文献
80.