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Biomedical subjects

S W Young

Publications and source records attributed to S W Young.

At least 19 recordsLinked to original sources
PubMed1997

Localization and efficacy analysis of the phototherapeutic lutetium texaphyrin (PCI-0123) in the murine EMT6 sarcoma model.

Lutetium texaphyrin (PCI-0123) is a pure, water-soluble photodynamic therapy (PDT) agent that is activated by tissue-penetrating far red light. The sensitizer is highly fluorescent and exhibits a strong, broad emission signal at 750 nm. In vitro cellular uptake studies revealed an increase in sensitizer retention with incubation time. Confocal laser scanning microscopy demonstrated that the intracellular localization site of PCI-0123 is the lysosomes. Ensuing illumination of the EMT6 cells led to lysosomal breakup, extensive cytoplasmic blebbing and subsequent cell death. Noninvasive spectral imaging analysis of PCI-0123 fluorescence depicted selective drug uptake, compared to surrounding normal tissue, in EMT6 mammary sarcomas syngeneic to BALB/c mice. The PCI-0123 PDT was shown to effectively treat the EMT6 murine sarcoma. Irradiation (732 nm light) 3 h postintravenous injection of 10 mumol PCI-0123 per kg gave 100% cures (no evidence of cancer), whereas light exposure at 5 h resulted in 75% cures. Hematoxylin and eosin histologic examination of photoirradiated tumors indicated apoptosis of the EMT6 neoplasms at early times post-PDT progressing, with time, to extensive necrotic areas. Gel electrophoresis of extracted photoirradiated tumors showed the typical apoptotic DNA ladder pattern that increased in intensity following PDT treatment.

Animals↗
PubMed1996

Gadolinium(III) texaphyrin: a tumor selective radiation sensitizer that is detectable by MRI.

Gadolinium(III) texaphyrin (Gd-tex2+) is representative of a new class of radiation sensitizers detectable by magnetic resonance imaging (MRI). This porphyrin-like complex has a high electron affinity [E1/2 (red.) approximately = -0.08 V versus normal hydrogen electrode] and forms a long-lived pi-radical cation upon exposure to hydrated electrons, reducing ketyl radicals, or superoxide ions. Consistent with these chemical findings, Gd-tex2+ was found to be an efficient radiation sensitizer in studies carried out with HT29 cells in in vitro as well as in in vivo single and multifraction irradiation studies with a murine mammary carcinoma model. Selective localization of Gd-tex2+ in tumors was confirmed by MRI scanning.

Animals↗
PubMed1996

Activation of mitogen-activated protein kinase by protein kinase C isotypes alpha, beta I and gamma, but not epsilon.

Treatment of CHO.T cells with either PMA or insulin led to the activation of MAP kinase by approximately 3-fold, and p90rsk by approximately 4-fold. Over-expression of the alpha, beta I or gamma isoforms of protein kinase C caused a substantial enhancement of the effect of PMA on the activation of MAP kinase and p90rsk, however, the effect of insulin was unchanged. Over-expression of the epsilon isoform of protein kinase C did not alter the effect of either PMA or insulin on the activation of MAP kinase and p90rsk. The results suggest that protein kinase C isotypes, alpha, beta I and gamma, but not epsilon, can mediate MAP kinase activation by PMA, and strongly support the hypothesis that protein kinase C isoforms can initiate distinct signalling pathways.

Animals↗
PubMed1996

Imaging of human colon cancer xenograft with gadolinium-texaphyrin.

RATIONALE AND OBJECTIVES: The authors explore the efficacy of gadolinium (Gd)-texaphyrin (PCI-0101), an expanded porphyrin, as a contrast medium for magnetic resonance imaging of nude mice implanted with the human colon cancer xenograft LS174T. METHODS: Magnetic resonance images were obtained in six nude mice 7 to 8 days after implantation of LS174T cells in dorsal subcutaneous tissues. Spin-echo T1-weighted images were obtained at baseline and at 5, 15, and 60 minutes after injection of 10 or 20 mumols/kg of Gd-texaphyrin. Delayed images were obtained at 24 and 48 hours after injection. Region-of-interest measurements were taken of the tumors and of enhancing tumor rims at all time points. Percent enhancement was calculated and compared among the various time points. RESULTS: All tumors were enhanced after injection of Gd-texaphyrin. Heterogeneous patterns of enhancement were seen, with peak enhancement seen at the 15-minute time point; however, greater enhancement was seen at 48 hours than at 24 hours after Gd-texaphyrin intravenous injection. CONCLUSIONS: Gadolinium-texaphyrin may prove to be a useful contrast medium for magnetic resonance imaging of tumors.

Animals↗
PubMed1996

Experimental acute cerebral ischemia with reperfusion. Evaluation with gadolinium-texaphyrin.

RATIONALE AND OBJECTIVES: The authors explore the potential usefulness of the new contrast medium gadolinium (Gd)-texaphyrin (PCI-0101) in magnetic resonance imaging of experimental acute cerebral ischemia with reperfusion. METHODS: Four New Zealand white rabbits underwent 2 hours of transorbital occlusion of the left internal carotid, anterior, and middle cerebral arteries, followed by 2 hours of reperfusion with normal saline. Immediately thereafter, the rabbits were injected with 25 mumol/kg of 2 mmol/L Gd-texaphyrin and killed by barbiturate overdose. Postmortem T1- and T2-weighted coronal scans were performed at 1.5 Tesla and correlated with histopathologic findings. RESULTS: Postcontrast T1-weighted images showed high signal within extensive cortical and basal ganglia infarcts. Areas of high signal on T1-weighted images were less extensive than on T2-weighted images, and corresponded to only a portion of the region of neuronal damage seen histologically. Signal intensity of infarcted brain on postcontrast T1-weighted images was significantly greater than normal brain in the contralateral hemisphere (P < 0.0014). CONCLUSIONS: Experimental reperfused infarcts only 2 hours old demonstrate contrast enhancement with Gd-texaphyrin.

Acute Disease↗
PubMed1996

Lutetium texaphyrin (PCI-0123): a near-infrared, water-soluble photosensitizer.

Lutetium texaphyrin, PCI-0123, is a pure, water-soluble photosensitizer with a large broad absorption band centered at 732 nm. The compound was tested for photodynamic therapy (PDT) effectiveness in a murine mammary cancer model. The texaphyrin macrocycle as illustrated by magnetic resonance imaging and 14C-radiolabeled texaphyrin studies was shown to be tumor selective; a tumor-to-muscle ratio of 10.55 was seen after 5 h. Lutetium texaphyrin, at a drug dose of 20 mumol/kg with irradiation 5 h postinjection at 150 J/cm2 and 150 mW/cm2, had significant efficacy (P < 0.0001) in treating neoplasms of moderate size (40 +/- 14 mm3) and also had significant efficacy (P < 0.0001) in treating larger neoplasms (147 +/- 68 mm3). The PDT efficacy was correlated with the time interval between PCI-0123 administration and light exposure. A 100% cure rate was achieved when photoirradiation took place 3 h postinjection compared to 50% for 5 h using 10 mumol/kg and 150 J/cm2 at 150 mW/cm2. The PDT efficacy was attributable to the selective uptake/retention of the texaphyrin photosensitizer in addition to the depth of light penetration achievable at the 732 nm laser irradiation.

Animals↗
PubMed1995

Influence of viscosity on WIN 39996 as a contrast agent for gastrointestinal magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors discuss the influence of viscosity on the imaging properties of WIN 39996 suspension. WIN 39996 suspension is a magnetically susceptible iron ferrite that provides negative (darkening) contrast enhancement in magnetic resonance imaging of the gastrointestinal tract. METHODS: The viscosity of WIN 39996 suspension was altered by various stress conditions (1 week to 4.5 months storage at temperatures of 5 degrees to 70 degrees C) or by various amounts of xanthan gum. Magnetic resonance imaging was performed in vitro on phantoms and in vivo on the gastrointestinal tract of anesthetized dogs. RESULTS: The results indicated that in vitro and in vivo imaging efficacies of WIN 39996 suspension depended on the viscosity, irrespective of the means by which the viscosity was altered. Specifically, the imaging quality was suitable at viscosities > or = 36.6 cp for in vitro imaging, and > 25 cp for in vivo imaging. The lower in vivo viscosity limit for magnetic resonance imaging compared with the in vitro limit may be due to gastrointestinal peristaltic activities continuously mixing the WIN 39996 suspension to prevent gravitational settling, and the enhancement of signal blackening by intraluminal WIN 39996 that was above and below the plane of image. CONCLUSIONS: It is speculated that the imaging quality of WIN 39996 suspension depends on the degree of dispersion of the magnetically susceptible iron ferrite in the WIN 39996 suspension, and that a minimum viscosity is needed to ensure such dispersion.

Animals↗
PubMed1994

Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase.

We have previously shown that insulin causes inactivation of glycogen synthase kinase-3 (GSK-3) in Chinese hamster ovary cells over-expressing the human insulin receptor (CHO.T cells). We now show that serum and phorbol ester also cause rapid inactivation of GSK-3, both in CHO.T cells and in the nontransfected parental cell line, CHO.K1 cells. Rapamycin was without effect on the inactivation of GSK-3 by insulin, serum or phorbol ester, indicating that the p70 S6 kinase pathway is not involved. In contrast, wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, blocked the effects of both insulin and serum on GSK-3 activity, and also substantially reduced the activation of both p90 S6 kinase (by insulin) and mitogen-activated protein (MAP) kinase (by insulin and serum). These findings imply (i) that GSK-3 activity is regulated by a cascade involving MAP kinase and p90 S6 kinase and (ii) that wortmannin affects an early step in the MAP kinase pathway. One can infer from this that GSK-3 may be an important regulatory enzyme for the control of several biosynthetic pathways, key enzymes in which are regulated by GSK-3-mediated phosphorylation. Wortmannin had a smaller effect on the activation of MAP kinase by phorbol ester, indicating that phorbol esters may stimulate MAP kinase by a different or additional mechanism to that employed by insulin or serum. Wortmannin had very little effect on the inactivation of GSK-3 by phorbol ester: possible reasons for this are discussed.

Amino Acid Sequence↗
PubMed1994

Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen-activated protein kinase. Comparison with the effects of insulin, growth factors and phorbol esters.

It has been proposed previously that the sustained activation of mitogen-activated protein kinase may be necessary for the differentiation of PC12 cells. Differentiation of PC12 cells is induced by many extracellular agonists including nerve growth factor (NGF) and cyclicAMP analogues, but not epidermal growth factor (EGF), insulin or phorbol esters. Our results demonstrate that: (i) 8-(4-chlorophenylthio)-cyclicAMP (CPT-cAMP) activates MAP kinase; this raises the possibility that the MAP kinase pathway may be activated by agents that act through adenylate cyclase; (ii) NGF and CPT-cAMP as well as phorbol esters promote sustained activation of MAP kinase. This suggests that while sustained MAP kinase activation may be associated with differentiation it may not be sufficient, and that other as yet unidentified parallel pathways may be involved.

Amino Acid Sequence↗
PubMed1994

Optimization of an oral magnetic particle formulation as a gastrointestinal contrast agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Magnetically susceptible iron oxide (MSIO) contrast agents for magnetic resonance imaging (MRI) of the gastrointestinal (GI) tract are limited because they produce magnetic susceptibility artifacts. To determine whether oral magnetic particles (WIN 39996) can be an effective MRI contrast agent without producing induced image artifacts, we optimized a liquid formulation of WIN 39996. METHODS: A range of concentrations (25-250 micrograms iron/mL) and viscosities (1-600 cP) was imaged in a phantom at 1.5 T using conventional spin-echo and gradient-recalled echo pulse sequences. Some formulations also contained titanium. RESULTS: All concentrations of WIN 39996 at 1 cP produced susceptibility artifacts. For formulations in the 150 to 600 cP range, the 125 to 150 micrograms/mL concentrations produced signal blackening and magnetic susceptibility image distortion comparable to an air control. Concentrations greater than 150 micrograms/mL were unacceptable because they produced significant susceptibility artifacts, while concentrations less than 125 micrograms/mL were undesirable because they produced insufficient signal blackening. CONCLUSIONS: These preliminary in-vitro studies suggest that an optimized liquid formulation of WIN 39996 can be produced that yields excellent negative contrast without producing image artifacts.

Artifacts↗
PubMed1994

Preclinical evaluation of gadolinium (III) texaphyrin complex. A new paramagnetic contrast agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Gadolinium III texaphyrin (Gd[III] texaphyrin) complex, a new magnetic resonance imaging contrast (MRI) agent, was evaluated. METHODS: In vitro relaxivity (1.5 T) and stability studies (5% dextrose) were conducted. Subchronic toxicity (8 males, 8 females; 2-20 mumol Gd(III) texaphyrin complex/kg body weight; 3 times per week for 3 weeks). Biodistribution and excretion studies were conducted in Sprague-Dawley rats; MRI studies were conducted in normal and tumor-bearing rats and rabbits. RESULTS: Relaxivity values were as follows: r1 = 19 (mumol/L.sec)-1 and r2 = 22 (mumol/L.sec)-1. The 21-day subchronic toxicity study revealed no abnormalities. The compound is stable. Biodistribution demonstrated liver uptake. Magnetic resonance imaging in normal (n = 34) and tumor-bearing (n = 4) rats and normal (n = 8) and tumor-bearing (n = 19) rabbits revealed: significant (P < .05) contrast enhancement of liver and kidney after 1-17 mumol/kg of Gd(III) texaphyrin complex. Gadolinium (III) texaphyrin complex (2.5 mumol/kg) produced significant contrast enhancement of liver carcinomas in rabbits (n = 8). Thigh V2 carcinomas (n = 22) had selective (P < .05) enhancement, 5 mumol/kg. In rat fibrosarcomas (n = 4), 17 mumol Gd(III) texaphyrin complex produced significant enhancement up to 24 hours. CONCLUSIONS: Gadolinium (III) texaphyrin complex appears to be an effective and safe MRI contrast agent.

Animals↗
PubMed1994

Event control.

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Goals↗
PubMed1994

Perflubron as an oral contrast agent for MR imaging: results of a phase III clinical trial.

PURPOSE: To assess perflubron for magnetic resonance (MR) imaging in the abdomen and pelvis in a multicenter trial. MATERIALS AND METHODS: MR images were obtained in 127 subjects before and after ingestion of perflubron with T1-, proton-density-, and T2-weighted sequences at 0.38, 1.0, or 1.5 T. Postcontrast images were compared with baseline images, and percentage of additional bowel darkened, distinction of bowel from adjacent tissue, and change in image artifact were graded. RESULTS: Perflubron increased the bowel darkening in over 92% of subjects with all sequences and field strengths. It improved definition of the left lobe of the liver and body and tail of the pancreas in 67%, 29%, and 42% of subjects, respectively, and of the uterus and bladder in 80% and 76%. Abnormal tissue was more conspicuous in 69% of subjects. Highest scores were achieved when the upper abdomen was imaged 5-30 minutes and the pelvis 10-40 minutes after ingestion. No image artifacts or side effects were attributed to perflubron. CONCLUSION: Perflubron is safe, and its efficacy was unaffected by pulse sequences, magnetic field strength, or time delay.

Abdomen↗
PubMed1993

Effects of tyrosine kinase inhibitors on protein kinase-independent systems.

Tyrosine kinase inhibitors have been widely used to probe the role of tyrosine phosphorylation in cellular signalling. These inhibitors exhibit an apparent specificity for tyrosine kinases over the serine/threonine kinases but little is known about their effects on other enzymes or biological systems. We demonstrate that genistein, erbstatin and alpha-cyanocinnamamides (tyrphostins) have inhibitory effects on fatty acid synthesis, lactate transport, mitochondrial oxidative phosphorylation and aldehyde dehydrogenase. We propose, therefore, that results obtained using tyrosine kinase inhibitors should be interpreted with caution, particularly if used at concentrations sufficient to inhibit these non-protein kinase-dependent events.

Aldehyde Dehydrogenase↗