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Biomedical subjects

D Kessel

Publications and source records attributed to D Kessel.

At least 91 records · Page 5Linked to original sources
PubMed1995

Photosensitization with derivatives of chlorin p6.

Biophysical and photobiological properties of three derivatives of chlorin p6 were examined. These agents can be considered as lysyl analogs of the aspartyl chlorin NPe6. Lysyl chlorin p6 diester (LCP) and the triester analog (LCP2) were readily accumulated by murine leukemia L1210 cells, localized in lysosomes, and were relatively inefficient photosensitizing agents in vitro. In contrast, lysyl chlorin e6 imide (LCI) was poorly accumulated, concentrated in mitochondrial and plasma membranes, but was more efficacious. LCI was the most effective agent with regard to photosensitization of a murine tumor in vivo, but all three agents caused substantially more toxicity than was observed with NPe6.

Animals↗
PubMed1995

Modes of photodynamic vs. sonodynamic cytotoxicity.

We compared effects of ultrasound-induced vs. photodynamic cytotoxicity in cell culture. The photodynamic effects mediated by mesoporphyrin caused a delayed toxic reaction, the presence of a "shoulder" on the dose-response curve, indicating the capacity for limited repair of photodamage. In contrast, ultrasound-induced loss of viability resulted from rapid cell destruction and was proportional to the time of sonication. Photodynamic damage to cells before exposure to ultrasound potentiated cell breakage but did not affect the clonogenicity of the surviving cell population. Photodamage after exposure to ultrasound decreased the viability of cells which had survived ultrasonic treatment.

Animals↗
PubMed1995

Effect of density-gradients on the binding of photosensitizing agents to plasma proteins.

The binding of photosensitizing agents to low-density lipoprotein is considered an important factor in tumor localization. We examined the affinity of a group of photosensitizers, varying in charge and hydrophobicity, for LDL, under conditions designed to determine whether the high salt concentration involved in conventional KBr gradients affected the results. Density-gradients containing KBr vs D2O were evaluated; the latter can delineate VLDL and LDL from other plasma components, while the KBr gradient readily resolved VLDL, LDL, HDL and albumin. Distribution of the photosensitizers to plasma fractions was assessed, along with the effect of Cremophor EL, an emulsifier used for formulation of water-insoluble drugs. Both the D2O and KBr gradients provided similar results with regard to the affinity of anionic, neutral or cationic photosensitizers for LDL. The use of Cremophor EL for drug formulation was associated with an altered electrophoretic lipoprotein profile. In some cases, affinity of CRM-solubilized sensitizers for plasma components varied with the density-gradient employed. The high salt concentration used in density-gradient fractionation had little effect on the affinity of photosensitizing agents to low-density lipoprotein but may introduce artifacts when emulsifiers are used in drug formulation.

Blood Proteins↗
PubMed1995

Interactions of Solutol HS 15 and Cremophor EL with plasma lipoproteins.

Two emulsifying agents, Solutol HS15 and Cremophor EL, were compared with regard to their effects on human plasma lipoproteins in vitro and on mouse plasma lipoproteins in vitro and in vivo. Both agents promoted binding of a hydrophobic photosensitizing agent (C8KC) to a circulating plasma species of low bouyant density. Persistence of this material was greater with Cremophor than with Solutol. Experiments carried out with labeled Solutol indicated that the vehicle itself is a component of this new species. High concentrations of either vehicle ( > or = 0.06%) led to decreased electrophoretic mobility of human LDL and HDL in vitro. In the mouse, a different effect was observed, resulting in complex changes in electrophoretic mobility of plasma lipoproteins. The plasma half-life of C8KC in the circulation of the mouse was correlated with the persistence of an altered electrophoretic lipoprotein pattern. Since Solutol and C8KC showed similar half-lives, this result suggests that the plasma half-life of the sensitizer is correlated with the persistence of the vehicle. While Solutol and Cremophor were designed to be vehicles for drug formulation, they also influence persistence of some drugs in the circulation.

Animals↗
PubMed1995

Selective photodynamic inactivation of a multidrug transporter by a cationic photosensitising agent.

We have characterised sites of photodamage catalysed by the cationic photosensitiser tetrabromorhodamine 123, using P388 murine leukaemia cells and a subline (P388/ADR) which has a multidrug resistance phenotype and hyperexpresses mdr1 mRNA for P-glycoprotein. Fluorescence emission spectra were consistent with sensitiser localisation in hydrophobic regions of the P388 cell, and in more aqueous loci in P388/ADR. Subsequent irradiation resulted in photodamage to the P388 cells, resulting in loss of viability. In contrast, P388/ADR cells were unaffected except for an irreversible inhibition of P-glycoprotein, leading to enhanced accumulation of daunorubicin and rhodamine 123 and a corresponding increase in daunorubicin cytotoxicity. These results are consistent with the premise that substrates for P-glycoprotein are confined to membrane loci associated with the transporter, and indicate a very limited migration of cytotoxic photo-products in a cellular environment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Sites of photodamage in vivo and in vitro by a cationic porphyrin.

Localization and photodynamic efficacy of a monocationic porphyrin (MCP) were assessed using murine leukemia cells in culture. This sensitizer localized at surface membrane loci and catalyzed selective photodamage to membrane structures. Although both cationic and hydrophobic, this porphyrin was not recognized by the multidrug transporter, which excludes many cationic agents from cells that express multidrug resistance. Photodynamic studies with the murine radiation-induced fibrosarcoma tumor model indicated moderate photosensitization of neoplastic lesions in vivo at 3 h, but not at 24 h after sensitizer administration. Pharmacokinetic studies indicate that plasma levels, not tissue levels were the major determinant of photodynamic therapy (PDT) response. Consistent with this observation, vascular damage and disturbances of tissue perfusion followed PDT. These effects were more pronounced in tumor-bearing skin than in normal skin. The therapeutic response to MCP appeared to be related mainly to secondary, probably vascular, effects.

Animals↗
PubMed1995

Interactions between N-aspartyl chlorin e6, detergent micelles and plasma lipoproteins.

Addition of plasma to the photosensitizing agent N-aspartyl chlorin e6 (NPe6) in Triton X-100 micelles results in a blue-shift of fluorescence emission, corresponding to a change in the average environmental dielectric constant from 8 to 32. This effect was not observed with anionic or cationic detergents or with several other sensitizers including a close analog, chlorin e6. The apolipoprotein fraction of high-density lipoproteins (HDL) was found responsible for this blue-shift. These results indicate a highly selective interaction between HDL apolipoproteins and NPe6 molecules. Addition of the HDL apolipoprotein to NPe6 incorporated into Triton micelles decreased the fraction of NPe6 molecules accessible to Cd(2+)-induced fluorescence quenching but resulted in an increase in the Stern-Volmer quenching constant (an index of quenching efficiency).

Antineoplastic Agents↗
PubMed1995

Dimethylformamide as an enhancer of cavitation-induced cell lysis in vitro.

Polar solvents, including dimethylformamide (DMF), have been investigated as anticancer drugs, but their potential usefulness is constrained by hepatotoxic side effects. The ability to enhance drug cytotoxicity with ultrasound would be valuable in creating locally intense chemotherapy while minimizing effects peripheral to the treatment site. The effects of continuous wave ultrasound (US) (985 kHz; 0.5-2.5 W/cm2) were evaluated on cultured HL-60 human promyelocytic leukemia cells alone and with a noncytotoxic DMF dose (0.11 M). The cells were insonified in a configuration that created no cell lysis without the introduction of albumin-stabilized microbubbles into the exposure chamber. When microbubbles were introduced, US with bubbles induced cell lysis, and the presence of DMF significantly increased the lysis induced by ultrasound with bubbles. The necessary presence of microbubbles for the DMF-US synergism to occur suggests that a likely mechanism is acoustic cavitation, initiated by the presence of microbubbles as nuclei. Detection of subharmonics confirmed the presence of cavitation, and cell lysis was well correlated with the subharmonic amplitude. The results show that albumin-stabilized microbubbles, similar to those currently used as US contrast agents, may provide a significant source of nuclei and improve prospects for cancer therapy using acoustic cavitation. The evidence presented supports the hypothesis that cell damage is due to a sonochemical rather than to a sonomechanical process.

Cell Membrane↗
PubMed1995

Bronchopulmonary infection with Pseudomonas aeruginosa in patients infected with human immunodeficiency virus.

BACKGROUND: Pseudomonas aeruginosa infection is uncommon in HIV infected patients and is usually nosocomially acquired and associated with risk factors such as neutropenia or central lines. We have recently noted an increase in the number of respiratory isolates of Ps aeruginosa in hospitalised HIV positive patients and sought to describe the clinical correlates of this observation. METHODS: A retrospective case notes review of HIV positive patients admitted to a specialist unit for respiratory investigations from January 1989 to December 1993 was undertaken in order to identify those with Ps aeruginosa respiratory infection and to describe associated risk factors, patterns of presentation and radiographic abnormalities. RESULTS: Of 617 patients admitted 38 (6%) had Ps aeruginosa respiratory infection (notes were incomplete in 1 patient). All patients had advanced HIV disease; median CD4 = 0.02 x 10(9)/l. Two distinct presentations were seen; 9 patients had a fulminant course as part of a sepsis syndrome, 28 patients had an indolent presentation (18 had a single episode and 10 relapsed on one or more occasions, despite successful treatment of the initial episode). Infection was community acquired in 24 patients. Many patients had risk factors traditionally associated with Ps aeruginosa including neutropenia or indwelling central venous catheters, but 13 had no obvious risk factor. Most patients were receiving systemic pneumocystis prophylaxis and/or broad spectrum antibiotics; 20 had co-existent symptomatic sinus disease. A wide variety of chest radiographic abnormalities were seen including interstitial shadowing, mimicking pneumocystis pneumonia in 12 patients, lobar pneumonia in 2 and bronchial wall thickening in 13 patients. CONCLUSIONS: Ps aeruginosa respiratory infection occurs with increased frequency in patients with advanced HIV disease; in a significant proportion infection is community acquired. Although recognised risk factors were present in two thirds of patients it appears that advanced HIV immunosuppression, use of systemic pneumocystis prophylaxis and/or broad spectrum antibiotics and sinus disease are important risk factors. The diagnosis should be considered in patients with advanced HIV disease who present with new respiratory symptoms.

Adult↗
PubMed1995

Fractionation of Cremophor EL delineates components responsible for plasma lipoprotein alterations and multidrug resistance reversal.

Treatment of cancer patients with 3-h infusions of taxol formulated with Cremophor EL resulted in a marked decrease in the electrophoretic mobility of all plasma lipoproteins. Cremophor was fractionated by reverse-phase chromatography to determine which components were responsible for this behavior. Effects of different Cremophor fractions on reversal of multidrug resistance, amino acid transport, and cytotoxicity also were evaluated using murine leukemia cells in culture. Lipoprotein alterations were caused by Cremophor components of intermediate hydrophobicity, which also antagonized amino acid transport and decreased viability of murine leukemia cells. Cremophor components responsible for reversal of multidrug resistance were of greater hydrophobicity. The lipoprotein-altering components of Cremophor could be selectively removed without affecting either taxol solubilization or multidrug-resistant reversal.

Animals↗
PubMed1994

Accumulation and metabolism of adenallene by murine leukemia L1210 cells.

Accumulation of the anti-HIV agent adenallene was examined in murine leukemia L1210 cells. Initial studies indicated an unusual result: accumulation of labeled adenallene was enhanced by decreasing the temperature of incubation, and (at 37 degrees C) by extracellular adenine, but not adenosine, cytosine, or thymine. We found that these phenomena resulted from the rapid deamination of intracellular adenallene to hypoxallene. Exodus of the latter was impaired at low temperatures and antagonized by hypoxanthine, the deamination product of adenine. In the presence of a deaminase inhibitor, adenallene transport was temperature-insensitive and nonsaturable and not affected by nucleoside transport inhibitors (dilazep, nitrobenzylthioinosine, and dipyridamole). These results support the view that adenallene enters cells by diffusion and is deaminated to hypoxallene, whose exodus occurs via a temperature-sensitive process exhibiting some structural specificity. We found no evidence of adenallene phosphorylation in L1210 cells.

Adenine↗
PubMed1994

The alteration of plasma lipoproteins by cremophor EL.

Cremophor EL (CRM) is a non-ionic amphipathic emulsifier which has been used as a parenteral vehicle for many hydrophobic drugs. At concentrations above 0.4 mg ml-1, CRM alters lipoproteins so as to reduce their electrophoretic mobility; high density lipoprotein (HDL) is somewhat more sensitive than low density lipoprotein (LDL) in this regard. The same phenomenon was observed with Triton X-100 and Tween-80, two other non-ionic detergents. Ultracentrifugation experiments show that CRM alters the density of HDL resulting in a product with approximately the same specific gravity as LDL. Administration of mesoporphyrin solubilized with CRM to the mouse resulted in a rapid clearance of porphyrin bound to this new HDL species. Such a phenomenon may account for reports which indicate that CRM promotes the distribution of photosensitizing agents to neoplastic tissues.

Animals↗
PubMed1994

Effects of Cremophor EL on distribution of Taxol to serum lipoproteins.

The clinical formulation of the anti-tumour agent Taxol involves the use of a mixture of ethanol and Cremophor EL. Gel electrophoresis and density-gradient ultracentrifugation were used to detect effects of Taxol infusions on serum lipoproteins. Use of the Cremophor vehicle results in a decrease in the electrophoretic mobility of serum lipoproteins along with the appearance of a lipoprotein dissociation product. These effects persist during a 24 h infusion and for at least 1.5 h afterwards, and can be reproduced in vitro using purified high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In control serum, Taxol binds to albumin > HDL, but after serum is exposed to Cremophor EL in vitro or in vivo substantial binding of Taxol to the lipoprotein dissociation product(s) was observed. The latter could represent an important factor in taxol biodistribution.

Centrifugation, Density Gradient↗
PubMed1994

Porphyrin-induced enhancement of ultrasound cytotoxicity.

We examined the effect of ultrasound on the murine leukaemia L1210 cell line in culture, in the presence of porphyrins varying widely in their capacity to sensitize cells to light. These porphyrins enhanced ultrasound-induced cell damage in vitro only when present in the incubation medium. When cells containing intracellular porphyrins were exposed to ultrasound, cell viability was not altered. Moreover, there was no correlation between the efficacy of a given porphyrin for light- versus ultrasound-induced cytotoxicity. Loss of viability was associated with inhibition of amino acid transport and cell fragmentation, suggesting disruption of the integrity of the cell membrane. Ultrasound-induced cell damage occurred only in the presence of cavitation nuclei.

Animals↗
PubMed1994

Photosensitization with a chlorin-thiobarbiturate conjugate.

The photobiologic properties of a chlorin-thiobarbiturate conjugate were examined. In addition to the characteristic 670 nm chlorin absorbance, the conjugate exhibited new absorbance bands at 517 and 743 nm, but these were not a part of the fluorescence emission spectra, nor was fluorescence observed at wavelengths > 670 nm. The action spectrum indicated that the long-wavelength absorbance of the conjugate was not involved in phototoxicity in cell culture, and that only irradiation at wavelengths associated with the chlorin moiety yielded a cytotoxic effect. In vivo cytotoxicity elicited by 745 nm irradiation is attributed to thermal effects.

Animals↗
PubMed1994

Impaired accumulation of a cationic photosensitizing agent by a cell line exhibiting multidrug resistance.

Transport and accumulation of copper benzochlorin iminium salt (CDS1), a cationic photosensitizing agent, were examined using the P388/ADR murine leukemia, which exhibits the MDR (multidrug resistance) phenotype, and the wild-type parent cell line, P388. The recent availability of radioactive CDS1 permitted kinetic studies at drug levels in the submicromolar range. Exclusion of CDS1 by P388/ADR cells could be demonstrated, indicating that this agent is a substrate for the outward transport system associated with MDR. These results have implications with regard to the efficacy of cationic photosensitizers against this common neoplastic phenotype. The CDS1 was readily accumulated by P388 cells and by P388/ADR cells when the outward transport system was inhibited. Under these conditions, CDS1 was tightly bound and could not be washed out even when the outward transport system was reactivated.

Animals↗