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Biomedical subjects

D Kessel

Publications and source records attributed to D Kessel.

At least 127 records · Page 7Linked to original sources
PubMed1992

Properties of cremophor EL micelles probed by fluorescence.

Using 1-anilino,8-naphthalenesulfonic acid (ANS) as a probe, we examined properties of micelles of Cremophor EL, an amphipathic agent which can solubilize hydrophobic photosensitizing agents and promote their distribution to plasma lipoprotein. In aqueous solution, Cremophor micelles persisted for several hours after dilution below the critical micellar concentration (CMC). After equilibrium was reached, we found a CMC of 0.009% (wt/vol). Fluorescence data suggest that the micellar environment of ANS binding has a dielectric constant of approximately 27. Cremophor also reverses examples of multi-drug resistance associated with impaired accumulation of anti-tumor agents, e.g. daunorubicin. Although the latter drug is relatively hydrophilic, fluorescence spectroscopy and anisotropy studies indicate an association with Cremophor. Moreover, resistance reversal occurred only at Cremophor concentrations above the CMC.

Anilino Naphthalenesulfonates↗
PubMed1992

Porphyrin photosensitization of multi-drug resistant cell types.

The P388 murine leukemia and P388/ADR, a subline expressing the multi-drug resistance (MDR) phenotype, were examined with regard to the role of MDR as a determinant of responsiveness to photodynamic therapy in vitro. Mesoporphyrin was used as a model substrate. We found no differences in porphyrin accumulation nor transport alterations associated with exposure of P388/ADR cells to the verapamil analog DMDP. There was a significant correlation between photodamage to mitochondria vs loss of cell viability in both cell lines, and LD50 sensitizer levels were not significantly different in P388 vs P388/ADR. P388/ADR cells were partly resistant to porphyrin-catalyzed photodamage to amino acid transport, but this result was not associated with differences in sensitizer localization, as indicated by fluorescence studies. Moreover, photodamage to membrane transport was not associated with loss of viability. These studies suggest that cells which express the MDR phenotype are unlikely to be cross-resistant to photodynamic therapy.

Animals↗
PubMed1992

Lipoprotein-mediated distribution of N-aspartyl chlorin-E6 in the mouse.

The localization of many photosensitizing agents has been attributed to distribution of low density lipoprotein (LDL)-bound drug as a function of the relative numbers of LDL receptors in different tissues. While the chlorin derivative NPe6 is a potent photosensitizing agent in the mouse, it binds mainly to mouse plasma high density lipoproteins (HDL) and albumin, with only 1% bound to LDL. This pattern suggests only a minor role for the LDL-receptor pathway with regard to N-aspartyl chlorin e6 (NPe6) biodistribution. Moreover, patterns of accumulation of radioactive NPe6, LDL and HDL in murine tissues are consistent with the suggestion that distribution of NPe6 to different tissues cannot be explained on the basis of an LDL-mediated mechanism.

Animals↗
PubMed1992

Photodynamic therapy and neoplastic disease.

The selective photosensitization of neoplastic lesions is a new modality for eradication of early tumors and palliation of more advanced disease. There is a substantial amount of information relating to modes of photodamage, and the clinical role of this form of therapy is becoming clarified. New sensitizers are being developed with a view toward an enhanced photodynamic effect, utilization of simpler light sources, and elimination of concurrent skin photosensitization. The mechanism whereby efficacious photosensitizers localize in neoplastic, as compared with normal, adjacent tissue remains to be determined, although theories have been proposed. The photosensitizing agent used in most clinical protocols in Photofrin. This product is a complex mixture of porphyrin monomers, dimers, and higher oligomers, and interpretation of biologic and photophysical data is often difficult, although this is not universally appreciated.

Hematoporphyrin Photoradiation↗
PubMed1992

[Doppler echocardiography imaging of construction-induced regurgitation of technical heart valve prostheses].

The normal leakage flow in modern technical heart valve prostheses can be visualized by color-coded Doppler-echocardiography, provided that an adequate ultrasonic image quality can be achieved. Sometimes it may be difficult, however, to distinguish such a normal leakage flow from pathological regurgitation. We therefore mounted new specimens of five different types of prostheses (Bjørk-Shiley monostrut, Medtronic-Hall, Omnicarbon, Saint Jude Medical, Duromedics) into an invitro model, where the leakage flows could directly be visualized as emerging water jets. When the system was completely filled, the jets could also be registered by two-dimensional Doppler-echocardiography. For each valve, characteristic patterns for the localization of the principal jets were found. Besides the relative broad central jet in the Medtronic-Hall valve, all other jets arose mainly at the ring. They were detected at the hinges or the basis of the larger struts, respectively, and with asymmetrical mono-disc valves at the side of the smaller opening. The length and the orientation of the jets were found to change significantly with minimal variations of the position of the closing discs. This variability could be confirmed, when in a separate model the overall leakage flows were repeatedly measured. For patient examinations it seems useful to refer mainly to the localization of the jet origins. The comparison with reference values of jet-dimensions in Doppler images will rarely enable the examiner to distinguish between normal and pathological jets.

Echocardiography, Doppler↗
PubMed1991

Characterization of multidrug resistance by fluorescent dyes.

Fluorimetric techniques were used to examine accumulation of fluorescent probes by the P388 murine leukemia and an anthracycline-resistant subline, P388/Adriamycin(ADR), which expresses the multidrug-resistant phenotype. P388 could be differentiated from P388/ADR on the basis of fluorescence intensity measurements using 3 classes of cationic dyes that are sensitive to membrane potential differences: rhodamine esters, cyanines, and styrylpyridinium dyes. But fluorescence intensity differences were also observed with potential-insensitive dyes: zwitterionic rhodamines and an acridine orange derivative. In all cases, fluorescence intensity differences were caused by impaired dye accumulation, and could be eliminated by treatment of P388/ADR cells with verapamil. Moreover, fluorescence signals from 2 anionic potential-sensitive dyes, merocyanine 540 and a bis-oxonol, were identical in P388 and P388/ADR. None of these dyes could be used to delineate CCRF-CEM, a lymphoblastic leukemia of human origin from the CEM/VM-1 subline that exhibits a markedly atypical drug resistance pattern not based on an enhanced outward transport. But accumulation of both neutral and cationic dyes was impaired in CEM/VLB100, a subline of CCRF-CEM expressing mdr. These studies show that many cationic and neutral fluorescent probes are substrates for the enhanced outward drug transport system associated with P388/ADR cells, and cannot be used to probe membrane-potential differences in cells expressing the mdr phenotype. With several dyes, differences in fluorescence intensity were sufficient so that flow cytometry could be used to delineate P388 from P388/ADR and CCRF-CEM from CEM-VLB100. The latter technique may be useful for identifying malignant cell populations expressing multidrug resistance in patients with neoplastic disease.

Animals↗
PubMed1991

Unsaturated and carbocyclic nucleoside analogues: synthesis, antitumor, and antiviral activity.

A series of unsaturated analogues of nucleosides were prepared and their cytotoxic, antitumor, and antiviral activities were investigated. Alkylation of cytosine with (E)-1,4-dichloro-2-butene gave chloro derivative 2f, which was hydrolyzed to alcohol 2h. Cytosine, adenine, 2-amino-6-chloropurine, thymine, and (Z)-1,4-chloro-2-butene gave compounds 4c-f, which, after hydrolysis, afforded alcohols 4a, 4b, 4g, and 4h. Alkenes 4d and 4e were cyclized to heterocycles 12 and 13. Alkylation of 2,6-diaminopurine with 1,4-dichloro-2-butyne led to chloro derivative 6a, which was hydrolyzed to alcohol 6b. Allenic isomerization of 6b gave compound 5c. Chloro derivatives 2e-g, 4c-f, 5d, and 6c-e as well as pyrimidine oxacyclopentenes 9c and 9d are slow-acting inhibitors of murine leukemia L1210 of IC50 10-100 microM. The most active were analogues 4c, 4d, 4e, and 6e (IC50 10-20 microM). The corresponding hydroxy derivatives were less active of inactive. Inhibition of macromolecular synthesis with compounds 4c, 4d, 6e, 9c, and 9d follows the order: DNA greater than RNA greater than or equal to protein. Cytotoxic effects of 4c, 6e, and 9d are not reversed with any of the four basic ribonucleosides or 2'-deoxyribonucleosides. Inhibitory activity of cytosine derivative 9c is reversed with uridine and 2'-deoxyuridine but not with the corresponding cytosine nucleosides. Zone assays in several tumor cell lines show that active compounds are cytotoxic agents with little selectivity for tumor cells. Analogue 6c showed 16.7% ILS in leukemia P388/o implanted ip in mice at 510 and 1020 mg/kg, respectively. Cytallene (5b) and 6'beta-hydroxyaristeromycin (10) exhibited significant activity against Friend and Rauscher murine leukemia viruses. The rest of the hydroxy derivatives, with the exception of 4a, were moderately effective or inactive as antiviral agents. None of the chloro derivatives or oxacyclopentenes exhibited an antiviral effect at noncytotoxic concentrations. Z-Olefin 4b and 2-aminoadenallene (5c) are substrates for adenosine deaminase.

Adenosine Deaminase↗
PubMed1991

Sites and efficacy of photodamage by tin etiopurpurin in vitro using different delivery systems.

Photosensitization by tin etiopurpurin (SnET2) was determined in cell culture using sensitizer dissolved in ethanol or solubilized via three different delivery systems: Cremophor EL, gamma-cyclodextrin or Molecusol (a more water-soluble cyclodextrin derivative). Sensitizer uptake was substantially more efficient when the delivery systems were employed, in terms of intracellular level needed to lethally photosensitize cells. We observed photodamage at both membrane and mitochondrial loci, but the former was better correlated with loss of viability.

Animals↗
PubMed1991

Artifacts in fluorescence emission spectroscopy related to Wood's anomaly.

Fluorescence emission spectra of porphyrins acquired with a monochromator using a 1500 line/mm holographic grating were affected by polarization-induced effects (Wood's anomaly) which affected the transmission of different wavelengths of light. This effect resulted in a blue-shift in the emission optimum, and distortions in the fluorescence spectrum at longer wavelengths. These anomalies could be eliminated by insertion of polarizers, orientation = 0 degrees, in emission and excitation paths. A monochromator with a 1200 line/mm holographic grating was essentially free from these distortions.

Artifacts↗
PubMed1991

Photophysical and photobiological properties of diporphyrin ethers.

Spectral properties of several diporphyrin ethers were assessed in different solvents and after accumulation by leukemia L1210 cells in vitro. To facilitate studies in a variety of solvents, both tetramethylesters of the diporphyrin ethers and free acids were employed. For comparison, studies on the corresponding porphyrin monomers were also carried out. The joining of two porphyrins by an ether linkage had several consequences. We observed a blue shift in the Soret band of the ethers, but not of the corresponding simple porphyrins, in protic solvents. This phenomenon is likely related to ether aggregation under conditions which promote H-bonding. The presence of an ether linkage was associated with enhanced fluorescence at 630-640 nm and decreased fluorescence lifetimes and yields, especially in protic solvents. The ether linkage was unaffected by intracellular enzymes, but porphyrin esters were readily hydrolyzed upon accumulation by L1210 cells. The joining of two hematoporphyrin molecules by an ether linkage promoted dye accumulation by L1210 cells. In contrast, accumulation of mesoporphyrin and protoporphyrin was thereby retarded.

Animals↗
PubMed1991

Photosensitization by synthetic diporphyrins and dichlorins in vivo and in vitro.

A group of polycarboxylic diporphyrins, two dichlorins and a porphyrin-chlorine dimer, with rings linked by methylene groups, were examined to help identify structures which can mediate photodynamic tumor eradication in vivo. Among the features sought were short persistence of normal tissue photosensitization and substantial absorbance at wavelengths longer than 630 nm. Both objectives were achieved, with pertinent structure-activity relationships partly characterized. The relative hydrophobicity of the different sensitizers was an important determinant of their accumulation in cell culture, but not of in vivo effectiveness. These compounds showed affinity for protein and high-density lipoprotein components of serum. Their distribution may be mediated by a different mechanism than that which occurs with more hydrophobic sensitizers like hematoporphyrin derivative which have greater affinity for low-density lipoproteins and less for protein components of serum, as compared with the products examined in this study.

Animals↗
PubMed1991

Intracellular localization of a chalcogenapyrylium dye probed by spectroscopy and sites of photodamage.

Site(s) of intracellular localization of a photosensitizing chalcogenapyrylium dye were assessed using murine leukemia cells in culture. While the dye exhibited substantial dark toxicity, additional damage was elicited by irradiation. The fluorescence emission spectrum of intracellular dye suggests an initial moderately hydrophobic site of localization (dielectric constant approx. 20). This might represent a membrane interface. But longer incubations led to alterations in both fluorescence emission and absorbance spectra, indicative of both dye migration to a more hydrophilic cellular site and dye biotransformations. Dye-induced cytotoxicity, in either light or dark, was associated with mitochondrial, rather than membrane damage.

Animals↗
PubMed1990

Synthesis and in vitro evaluation of some modified 4-thiopyrimidine nucleosides for prevention or reversal of AIDS-associated neurological disorders.

Oxygen-sulfur exchange at the C-4 carbonyl of several modified pyrimidine nucleosides, including 3'-azido-3'-deoxythymidine (AZT), is described in an effort to enhance the lipophilicity and, thereby, the delivery to the central nervous system of the sulfur analogues without compromising the anti-HIV activities of the parental structures. Preparation of 3'-azido-3'-deoxy-4-thiothymidine (3) proceeded from 4-thiothymidine (1) and utilized the same methodology developed for the initial synthesis of AZT. Thiation of 2',3'-didehydro-3'-deoxythymidine (4a) and 2',3'-didehydro-2',3'-dideoxyuridine (4c) was carried out with Lawesson's reagent on the corresponding 5'-O-benzoate esters, 4b and 4d, to give 5a and 5c, respectively. The latter, on alkaline hydrolysis, gave 2',3'-didehydro-3'-deoxy-4-thiothymidine (5b) and 2',3'-didehydro-2',3'-dideoxyuridine (5d), respectively. The same series of reactions were applied to the 5'-O-benzoate esters of 2',3'-dideoxyuridine (6a) and 3'-deoxythymidine (6b) to give 2',3'-dideoxy-4-thiouridine (7d) and 3'-deoxy-4-thiothymidine (7b), respectively. Characterization of the saturated and unsaturated thionucleosides included mass spectrometric studies. Under electron impact conditions, the thiated analogues gave more intense parent ions than the corresponding oxygen precursors. The lipophilicity of thymidine and the 3'-deoxythymidine derivatives are enhanced significantly, as indicated, by increases in corresponding P values (1-octanol-0.1 M sodium phosphate) upon replacement of the 4-carbonyl oxygens by sulfur. Compounds 5b, 5d, 7b, and 7d were evaluated for their effects on HIV-induced cytopathogenicity of MT-2 and CEM cells. Only 5b and 7b were moderately active in protecting both cell lines against the cytolytic effect of HIV. The inhibitory effects of analogues 5b, 5d, 7b, and 7d on thymidine phosphorylation by rabbit thymus thymidine kinase were evaluated. Only 3 showed moderate affinity (Ki = 54 microM) for the enzyme. The generally weak anti-HIV activities of the remaining thio analogues are consistent with correspondingly low susceptibilities to thymidine kinase phosphorylation as estimated from the respective Ki values of the synthetic nucleosides. However, the phosphorylation of the 5'-monophosphate derivatives to their respective 5'-triphosphates must also be considered in connection with the weak in vitro anti-HIV effects of these thiated compounds.

AIDS Dementia Complex↗