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C Liebow

Publications and source records attributed to C Liebow.

At least 37 records · Page 2Linked to original sources
PubMed1993

Evaluation of porfimer sodium fluorescence for measuring tissue transformation.

BACKGROUND: Neoplastic tissue can be detected by its increased fluorescence compared with surrounding normal tissue after the injection of the tumor-localizing compound porfimer sodium (Photofrin; Quadra Logic Technologies, Vancouver, BC, Canada). In vivo fluorescence photometry is a nonimaging photodetector technique that detects specific 690 nm fluorescence of the porphyrin by subtracting nonspecific 612 nm excitation from 630 nm excitation. The technique was applied in the developmental stages of the 9,10 dimethyl-1,2-benzanthracene (DMBA)-induced hamster buccal cheek pouch carcinoma model to (1) quantitate and characterize porfimer sodium fluorescence and uptake as it relates to lesion progression and biochemical changes and (2) determine whether porfimer sodium-induced fluorescence will vary with promotional and inhibitory stimuli. METHODS: Groups of Syrian Golden hamsters had their cheek pouch buccal mucosa exposed to a 0.5% DMBA in acetone three times per week for 6 weeks (premalignant lesions), 12 weeks (squamous cell carcinomas), or other specified durations. The rate of malignant transformation was either promoted (by either carbon dioxide laser incision or continued DMBA application) or inhibited (by the administration of either somatostatin analogue RC-160 [D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2] or bombesin antagonist RC-3095 [D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leu psi (CH2NH)Leu-NH2]). Groups of DMBA-exposed hamsters were subsequently injected with 1.0 mg/kg of porfimer sodium during the various stages of tumor development. Twenty-four hours after injection, fluorescence levels were measured by in vivo fluorescence photometry. Samples of tumors, dysplastic mucosal tissue, and normal-appearing oral mucosa were biopsied and used for either tissue extraction assays, histopathologic examination, or tyrosine kinase activity assay as an index of rate of transformation. RESULTS: Results demonstrated that porfimer sodium is retained in DMBA-treated tissue. Fluorescence is completely accounted for by porfimer sodium uptake. The duration of exposure to carcinogen is proportional to porfimer sodium fluorescence. This relationship establishes that premalignant lesions can be distinguished from normal tissue by porfimer sodium uptake and fluorescence. The changes in increased tyrosine kinase activity paralleled the increase in porfimer sodium fluorescence. Alterations in the rate of tissue transformation produced equivalent alterations in porfimer sodium-induced fluorescence. CONCLUSIONS: These results suggest that porfimer sodium uptake and fluorescence can be used in a prognostic manner to diagnose and determine the course of transformation of individual lesions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Peptide analogues alter the progression of premalignant lesions, as measured by Photofrin fluorescence.

Somatostatin analogue RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 were infused at 2 micrograms per day via miniosmotic pumps implanted s.c. in hamsters with premalignant disease to examine the effect of these peptides on cancer promotion and progression. These analogues have been shown to inhibit growth of certain tumors, especially those that overexpress tyrosine kinase activity. Progression of premalignant lesions initiated by applying 0.5% 9,10-dimethyl-1,2-benzanthracene (DMBA) to the hamster buccal cheek pouch was measured by Photofrin-induced fluorescence 24 hr after injecting the porphyrin (1.0 mg/kg) by using in vivo fluorescence photometry. This method of monitoring progression was reaffirmed by the observations that fluorescence increased significantly as compared with controls in lesions receiving 4 additional weeks of continuous promotion by DMBA application (P < 0.01 in two independent trials) and in lesions receiving transient promotion by laser incision (P < 0.01 and < 0.05 at the same time in the two trials). Twelve weeks after treatment, fluorescence had decreased significantly among animals treated for 2 weeks with RC-3095 (control, 0.53 +/- 0.03 V vs. RC-3095, 0.28 +/- 0.03 V; P < 0.0005) or with RC-160 (control, 0.85 +/- 0.03 V vs. RC-160, 0.24 +/- 0.03 V; P < 0.0001). These data were obtained 20 weeks after DMBA initiation. Thus, treatment with RC-160 and RC-3095 decreased the progression, measured by fluorescence, compared with control animals. In addition, there was also an absolute continuous decrease in fluorescence for the 22 weeks after the cessation of RC-160 treatment. That the changes in tumor progression produced by RC-160 extended beyond the treatment period supports the hypothesis that the changes were irreversible. Histopathological analysis revealed normal tissue and/or mild-moderate dysplasia in hamster buccal mucosa treated with the RC-160 (an improvement compared to pretreatment), whereas 40% of the animals receiving no treatment after DMBA initiation developed invasive squamous cell carcinomas after 20 weeks. These results show that the antagonists of bombesin/gastrin-releasing peptide can delay the development of malignancies and the agonists of somatostatin can potentially reverse this development.

Animals↗
PubMed1993

Fluorescence detection of tumors. Early diagnosis of microscopic lesions in preclinical studies.

BACKGROUND: The growth of microscopic tumor lesions at or beyond treatment field margins poses a major problem in the diagnosis and treatment of cancer. Early detection techniques that clearly define the location or field spread of disease may improve the planning of disease treatment. METHODS: In vivo fluorescence photometry is a non-imaging technique that digitally displays relative fluorescence values in volts proportional to the luminescence intensity detected by a silicon photodiode. The sensitivity of the instrument has allowed the detection of micrometastases in preclinical studies. RESULTS: Statistical analysis demonstrates that the photosensitizer Photofrin (dihematoporphyrin ether and/or ester) (Quadra Logic Technologies, QLT, Vancouver, B.C., Canada), currently used for photodynamic therapy, administered in doses lower than those used in clinical studies, is useful for the detection of occult disease. With the drug doses used, cutaneous photosensitivity was avoided in the animal models tested. The results in Lobund-Wistar rats with transplantable prostatic adenocarcinoma (PA-III) demonstrated the utility of this technique in detecting clinically occult disease, with a prediction rate of approximately 94% with drug doses as low as 0.25-0.5 mg/kg. CONCLUSIONS: With the use of the hamster buccal cavity model involving the initiation and promotion of premalignant and malignant conditions by 9,10 dimethyl-1,2-benzanthracene, the technique could discern these two stages of disease with significance levels that were less than 0.05 and 0.01, respectively.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Nonparallel transport and mechanisms of secretion.

After many years of controversy, it is now clear that at least some cells and tissues that secrete more than one product can vary the composition of the secreted mixture as the result of the differential transport of various substances out of the cells that secrete them. In this article we discuss this phenomenon, non-parallel transport or secretion, and how it has and continues to inform us about how cells release the products they manufacture. We focus on expression of the phenomenon in the secretion of digestive enzymes by the exocrine pancreas, where it has been studied most extensively.

Animals↗
PubMed1991

Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous and autologous receptor-stimulated tyrosine phosphorylation.

Pancreatic cancers overexpress tyrosine kinase and luteinizing hormone-releasing hormone (LH-RH) receptor (LH-RHR)-mediated tyrosine phosphatase. LH-RHR is a 60-kDa protein. One of the substrates of epidermal growth factor (EGF)-stimulated tyrosine kinase activity and LH-RH- and somatostatin-stimulated tyrosine phosphatase activity is also a 60-kDa protein. This suggests the possibility that LH-RHR regulation by tyrosine phosphatase and tyrosine kinase is mediated by (de)phosphorylation of existing LH-RHR. To test this hypothesis, membranes of MIA PaCa-2 cells, a human dedifferentiated pancreatic cancer cell line, were incubated without hormone (control) or with 0.1 microM EGF or somatostatin analogue RC-160 for 1 hr at 4 degrees C to phosphorylate the 60-kDa protein. Competition binding experiments with I125-labeled [D-Trp6]LH-RH by displacement with a nonradioactive ligand showed that the LH-RH binding in 69% of the points was increased by EGF and 85% was decreased by RC-160 compared with controls (n = 61; both significant, P less than 0.001). The specific binding was altered, increasing 50-150% after preincubation with EGF and decreasing 60-70% after RC-160. No change was seen in the binding affinity constant after pretreatment with EGF or RC-160. This shows that phosphorylation regulates binding of LH-RH and may explain the up-regulation by EGF and down-regulation by RC-160 and by LH-RH of the LH-RH response.

Cell Line↗
PubMed1991

Effects of epidermal growth factor and analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation and dephosphorylation of tyrosine residues of specific protein substrates in various tumors.

Analogues of somatostatin (SS) and luteinizing hormone-releasing hormone (LH-RH) activate tyrosine phosphatases in MIA PaCa-2 human pancreatic cancer cell line membranes and inhibit growth. We compared the substrates phosphorylated by epidermal growth factor (EGF) to those dephosphorylated by the SS analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and [D-Trp6]LH-RH in cancer cell lines such as MIA PaCa-2 (human pancreatic cancer), HCPC (hamster cheek pouch carcinoma), A-549 (human lung cancer), HT-29 (human colon cancer), and R3230AC (breast cancer). EGF phosphorylated proteins of 170, 65, and 60 kDa and analogues of SS and LH-RH promoted the dephosphorylation of these proteins in MIA PaCa-2 and HCPC cell lines. The EGF receptor is 170 kDa. pp60src (60 kDa) is known to be a substrate for EGF receptor. The LH-RH receptor is also 60 kDa. The effects of RC-160 and [D-Trp6]LH-RH were quantitatively different. Examinations of HT-29, A-549, and R3230AC cancer cell lines revealed no phosphorylation by EGF or dephosphorylation by RC-160 and [D-Trp6]LH-RH. In addition to the 170-, 65-, and 60-kDa proteins, 35-kDa proteins were also phosphorylated in some cancer cell lines. This work demonstrates that analogues of SS and LH-RH can reverse the effects of EGF biochemically as well as functionally.

Amino Acid Sequence↗
PubMed1990

Bacteremia following laser and conventional surgery in hamsters.

The CO2 laser prevents bleeding by sealing blood and lymph vessels as it vaporizes tissue. Bacteremia following oral surgery might not occur under these conditions. To test this hypothesis, a 0.2-mm-deep incision 1 cm long was made in the right buccal cheek pouch of hamsters using either laser, electrosurgery, or a scalpel. Twenty minutes later, 1 mL of blood was taken from each animal by cardiac puncture, inoculated on a blood agar medium, and incubated anaerobically for 4 days; then the colonies were counted. Using an operational definition of bacteremia as five colonies or more per plate, there were no positive results out of 18 trials (0/18) for laser surgery, 7/8 for electrosurgery, and 8/12 for scalpel surgery. Based on the Student t test using the binomial distribution, the laser produced statistically less bacteremia than the other two methods (P less than .01). Because the five-colony cutoff was arbitrary, the nonparametric Wilcoxon Rank test was also used. Colony formation from blood from the laser group was significantly less than from the electrosurgery group (P less than .01) and the scalpel group (P less than .05). The laser surgery group was not statistically different from the control (nonsurgerized) group. These results suggest that there is a considerable bacteremia following scalpel and electrosurgery, but that laser surgery produces no bacteremia.

Animals↗
PubMed1989

Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase.

Several analogues of somatostatin were examined in the Mia PaCa-2 human pancreatic cancer cell line for their ability to promote tyrosine phosphatase activity affecting the receptors for the epidermal growth factor. The inhibition of growth of the Mia PaCa-2 cells in culture was also evaluated to determine the mechanism of action of somatostatin analogues and their relative effectiveness in inhibiting cancer growth. Of the analogues tested D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160) caused the greatest stimulation of tyrosine phosphatase activity. Analogue D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 (RC-121) had less effect but was more potent than somatostatin-14. Analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol) (SMS 201-995) produced no significant dephosphorylation. The analogues displayed the same order of activity in assays on growth inhibition of Mia PaCa-2 cells in cultures. Analogue (SMS-201-995) caused virtually no tyrosine phosphatase stimulation or growth inhibition in this cancer cell line, although it possesses a much higher antisecretory activity than somatostatin-14 in normal tissues. These observations indicate that somatostatin and some of its analogues can act as growth inhibitors in cancer cells through the activation of tyrosine phosphatase. These data reinforce the view that somatostatin analogue RC-160 and related compounds could be used for treatment of pancreatic cancer.

Antineoplastic Agents↗
PubMed1987

Specific end-product feedback regulation of pancreatic protein synthesis.

The potential for negative feedback regulation of the synthesis of individual enzymes was tested in the rabbit pancreas. Tissues were preincubated with individual pancreatic enzymes under conditions which have been shown to allow significant tissue absorption of these enzymes. The rates of synthesis of total proteins and amylase were then measured by following incorporation of labeled amino acids. Preincubation of lobules with amylase in the bath caused amylase synthesis to be inhibited by 50% without significantly inhibiting total protein synthesis. Preincubation of lobules with chymotrypsinogen significantly inhibited total protein synthesis without significantly inhibiting amylase synthesis. These data demonstrate specific end-product feed-back inhibition of protein synthesis in eukaryotes and may represent a pattern for regulation of protein synthesis in general.

Amylases↗
PubMed1986

Hormonal control of pancreatic cancer growth.

The effects of epidermal growth factor (EGF) and somatostatin-14 (SS) on growth of Mia PaCa-2 cells in cell culture were examined. EGF had no effect on cell growth in sera containing media but significantly increased growth in sera-free media. The effect of EGF was complete within 18 h. SS added with EGF entirely eliminated the growth stimulation of EGF. SS added to cells in culture with sera inhibited their growth as well.

Cell Division↗
PubMed1985

Stimulation by somatostatin of dephosphorylation of membrane proteins in pancreatic cancer MIA PaCa-2 cell line.

A membrane receptor and a cytosolic receptor for somatostatin were found in a human undifferentiated pancreatic cancer cell line (MIA PaCa-2). Binding of somatostatin to this membrane receptor activates dephosphorylation of a phosphotyrosyl-membrane protein whose phosphorylation was promoted by epidermal growth factor (EGF). Vanadate, a purported inhibitor of dephosphorylation, interferes with the action of somatostatin. These findings suggest a possible biochemical mechanism by which somatostatin may inhibit the growth of human pancreatic cancers.

Cell Line↗
PubMed1985

Permeability of zymogen granule membrane to protein.

The evidence that the membrane of the pancreatic zymogen granule is permeable to its contained secretory proteins is outlined. Included is a discussion of the nature and characteristics of the equilibrium-dependent release of protein from isolated granules, the evidence for the permeability of the granule membrane to digestive enzyme protein in situ, and the seeming paradox that isolated granules release protein in medium similar to that thought to exist in the cell. The permeability hypothesis is reconsidered here in light of recent claims of stable nonpermeable granules.

Amylases↗
PubMed1982

Histamine stimulation of digestive enzyme secretion by in vitro rabbit pancreas.

Histamine (10(-3) M) was found to stimulate pancreatic enzyme secretion from in vitro isolated rabbit pancreas preparations. Histamine produced a peak and then a sustained stimulated secretory rate. Secretion of amylase, lipase, trypsinogen, chymotrypsinogen, and total radio active protein were all found to be stimulated. Although fluid output was slightly increased by histamine, enzyme concentrations in secretion were elevated. This, along with the observed sustained release rate, rules out washout effects. Histamine produced a significant response at 10(-5) M with ED50 being about 3 x 10(-5) M and maximal responses produced by 10(-3) M. Histamine stimulation can be blocked with mepyramine (10(-4) or 10(-5) M) or mepyramine in combination with cimetidine. The observed behavior of the pancreas suggests a similarity with pepsinogen secretion in the stomach.

Amylases↗
PubMed1980

Pancreatic enzyme stimulation of intestinal chloride secretion.

Mucosal addition of pancreatic enzymes (i.e., chymotrypsinogen and amylase) to a short-circuited Ussing chamber containing a section of stripped rabbit ileum greatly increases short-circuit current (SCC). SCC increases slowly, requiring several hours to reach peak response to enzyme addition. Serosal addition of enzyme or mucosal addition of albumin produces no such response. Chloride flux in the absence of enzyme conforms to behavior predicted for predominantly paracellular movement. Chymotrypsinogen in the mucosal bath augments serosal-to-mucosal chloride flux in a manner consistent with an intracellular pathway. The chloride secretion produced by enzyme addition is of similar magnitude to the additional increment in SCC.

Action Potentials↗
PubMed1980

Secretory response of the rabbit pancreas to cholecystokinin stimulation.

To test the capability of the pancreas to change the proportions of proteins secreted in response to acute stimulation, we examined the effect of cholecystokinin-pancreozymin stimulation on the relative discharge of 16 radiolabeled secretory proteins from the in vitro rabbit pancreatic gland. [35S]-methionine was added to the bathing medium 4 h prior to the experimental period. Secretion was then collected from the pancreatic duct for two 1-h basal periods and for two 20-min periods following stimulation with 5.1 mM cholecystokinin. Proteins were separated by two-dimensional isoelectric focusing/sodium dodecyl sulfate gradient gel electrophoresis, and the proportion of each radiolabeled protein in the secretion was determined in each period. Statistical analysis of the relative distribution of radioactive proteins in secretion showed an increased variability in the distribution of secreted proteins following stimulation (P < 0.005). Procarboxypeptidase A, a protein tentatively identified as an acidic form of chymotrypsinogen, and a basic form of chymotrypsinogen were significantly more stimulated than the average radiolabeled protein by 25, 31, and 17%, respectively, whereas the acidic form of trypsinogen was significantly less stimulated by 18%.

Animals↗
PubMed1976

Equilibration of pancratic digestive enzymes across zymogen granule membranes.

Zymogen granules isolated from the rat pancreas released digestive enzyms in response to lowering the enzyme concentration of the medium in which the granules were suspended, and reabsorbed enzyme when the enzyme concentration of the medium was increased. The evidence suggests that the distribution of digestive enzyme between zymogen granule and medium is the result of an equilibrium process. This equilibrium is apparently expressed across the granule membrane since the disruption of the membrane barrier eliminated the delay in establishing new equilibrium between the bound and free enzyme. The release of enzyme was continuous (equilibration did not occur) when the suspending medium was continuously filtered, thereby maintaining a constant state of disequilibrium between intragranular enzyme and enzyme in the medium. The data suggest the following: (1) that digestive enzyme passes through the intact granule membrane bidirectionally, and (2) that there is a free cytoplasmic pool of digestive enzyme in intact cells which is in equilibrium with the enzyme content of the zymogen granule.

Amylases↗