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Biomedical subjects

D Kessel

Publications and source records attributed to D Kessel.

At least 145 records · Page 8Linked to original sources
PubMed1989

A dihydropyridine carrier system for sustained delivery of 2',3'-dideoxynucleosides to the brain.

The present study evaluates the utility of the dihydropyridine in equilibrium pyridinium salt redox system for the specific delivery and sustained release of a model 2',3'-dideoxynucleoside to the brain of mice as the initial effort in a search for agents that may prove effective in reversing the complicating neurological disorders of AIDS. The unsaturated nucleoside 2',3'-didehydro-2',3'-dideoxythymidine (1), which is effective in protecting ATH8 cells against the cytopathogenicity of HIV-1, was converted to the corresponding N-methyl-1,4-dihydronicotinate derivative, 4, in three steps. The 5'-O-nicotinate ester, 2, obtained by reaction of 1 with nicotinyl chloride, was converted in quantitative yield to the N-methylpyridinium salt 3 on treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave 4 in 50% yield. Pseudo-first-order rate constants for the oxidation of 4 to 3 were observed in plasma (k = 3.54 x 10(-5) s-1) and in homogenates of mouse liver (k = 9.2 x 10(-5) s-1) and brain (k = 8.85 x 10(-5) s-1). None of the chemical delivery system 4 could be detected in the brain of female BDF/1 mice at 1 h postinjection. The peak level of 3 in the brain occurred at 3 h with a half-life of 25 h. Both 1 and N-methylnicotinic acid (trigonelline, 5) were readily identified by HPLC in a brain homogenate derived from mice injected (25 mg/kg) with 4. TLC showed a low level penetration of mouse brain by 1 (0.44 microgram/g wet tissue) following injection of the corresponding labeled [methyl-3H]-2',3'-unsaturated nucleoside (25 mg/kg). The data indicate that 4 crosses the blood-brain barrier to be oxidized by cerebral tissue to the ionic structure 3, which is "locked therein". The sustained local release of a 2',3'-dideoxynucleoside, such as 1, from a chemical delivery system (4) represents a potentially useful approach to the treatment of AIDS dementia complex.

Animals↗
PubMed1989

Photosensitization with derivatives of chlorophyll.

The properties of several chlorophyll derivatives were examined: the methyl esters of pheophorbide A, pheophorbide B and pheophytin. In spite of structural differences, all products were equally effective sensitizers in vitro and were localized equally well by murine tumors in vivo after 1 h. But only the pheophytins persisted at neoplastic loci for 24 h. There was no evidence of hydrolysis of the methyl esters, but the phytyl ester linkage was labile in vivo.

Animals↗
PubMed1989

Determinants of photosensitization by purpurins.

Studies were carried out on two purpurins, NT2 and an analog, Sn.NT2H2. Both are photosensitizers, but the latter is substantially more effective against neoplastic cells in vivo. These hydrophobic dyes can be solubilized via Cremophor EL emulsions. We found both dyes to be approximately equitoxic to murine leukemia L1210 cells in culture, in terms of intracellular concentrations. But uptake of NT2 was 10-fold less efficient than Sn.NT2H2, i.e. a 10-fold higher extracellular level of NT2 was needed to produce an equitoxic response. Fluorescence measurements indicate that NT2 partitions to a very hydrophobic intracellular environments; its phototoxicity was related to inhibition of biosynthesis of DNA. In contrast, SN.NT2H2 was accumulated at more hydrophilic loci (the apparent dielectric constant is consistent with a membrane interface) and mediated photodamage at sites of membrane transport.

Animals↗
PubMed1989

Probing the structure of HPD by fluorescence spectroscopy.

Fluorescence emission spectra indicate that oligomers containing both hematoporphyrin and its dehydration products (vinyl porphyrins) comprise the tumor-localizing fraction of HPD. In the relatively polar solvent methanol, the vinyl porphyrins exhibit reduced fluorescence yields while the hematoporphyrin residues are relatively resistant to fluorescence quenching by Fe+3. In the less polar solvent tetrahydrofuran, fluorescence from oligomeric vinyl porphyrins was enhanced, and Fe+3-induced quenching of oligomeric hematoporphyrin promoted. These, together with other studies in biological systems, suggest a substantial degree of interaction among the porphyrin units contained in these oligomers, as a function of the polarity of the environment.

Hematoporphyrin Photoradiation↗
PubMed1989

In vitro photosensitization with a benzoporphyrin derivative.

Biophysical and photobiological properties of two benzoporphyrin derivatives were examined. These dyes exhibit substantial absorbance in the red, and are potent photosensitizers in vitro. After brief (0.5 h) incubations, phototoxicity was more closely correlated with membrane than with mitochondrial photodamage. Affinity of these dyes toward plasma lipoproteins are consistent with a mode of localization via the LDL-mediated mechanism utilized by the hematoporphyrin-derived product, HPD.

Cells, Cultured↗
PubMed1989

Determinants of photosensitization by mono-L-aspartyl chlorin e6.

The mono-N-aspartyl derivative of chlorin e6 (MACE) is a new photosensitizer being examined for use in anti-neoplastic photodynamic therapy. Studies were carried out to identify unique aspects of MACE localization by murine leukemia L1210 cells in vitro. Octanol/water partitioning studies were used to quantitate the hydrophobicity of MACE and two analogs, chlorin e6 and mesochlorin. Sites of cellular localization of these dyes were probed by fluorescence studies, and by examining loci of photodamage. These studies indicate that MACE, a hydrophilic dye, partitions to cytoplasmic loci. Data obtained with chlorin e6, a more hydrophobic dye, are consistent with binding at both membrane and cytoplasmic sites. A substantially more hydrophobic product, meso-chlorin, binds primarily to the cell membrane. While the tumor-localizing porphyrin product HPD binds to plasma LDL less than HDL, MACE and CE are predominantly bound to plasma protein and HDL. Patterns of distribution and localization of MACE differ substantially from those observed with HPD and other hydrophobic sensitizers. Phototoxic effects of MACE could not be specifically attributed to membrane or mitochondrial damage.

Animals↗
PubMed1989

Exploring multidrug resistance using rhodamine 123.

Accumulation of the dye rhodamine 123 was characterized by fluorescence in murine leukemia P388 cells and the Adriamycin-resistant subline, P388/ADR. Dye uptake by P388 cells was a slow, temperature-sensitive process, and involved binding at relatively hydrophobic and heterogeneous loci. Dye uptake by P388/ADR cells was temperature-insensitive, a steady state was quickly achieved, and the fluorescence emission spectrum suggested a relatively hydrophilic dye-binding site. Treatment of P388/ADR cells with verapamil resulted in enhanced accumulation of dye at hydrophobic loci. The fluorescence studies suggest that this dye may not reach the cytoplasm of P388/ADR cells, a result which may have implications with regard to the mechanism of multidrug resistance.

Animals↗
PubMed1988

Probing membrane alterations associated with anthracycline resistance using fluorescent dyes.

Properties of membranes of intact P388 murine lymphoblastic leukemia and a sub-line selected for resistance to adriamycin (P388/ADR) were examined using two fluorescent probes: diphenylhexatriene (DPH) and trimethylammonium diphenylhexatriene (T-DPH). Time-dependent changes in dye accumulation, fluorescence anisotropy, and lifetimes were measured. Accumulation of DPH, which eventually labels all cellular lipids, increased with time. Uptake of T-DPH, a more membrane-specific probe, reached a maximum in less than 1 min. No alteration could be detected in fluorescence anisotropy or lifetime of either dye associated with anthracycline resistance or anthracycline treatment. The rate of uptake of the T-DPH was not different in P388 versus P388/ADR cell lines, suggesting no differences in membrane "traffic". Calcium-channel antagonists could partially reverse anthracycline resistance in P388/ADR, but this was not accompanied by alterations in fluorescence parameters.

Animals↗
PubMed1988

Fast atom bombardment mass spectrometry of high-molecular-weight fraction of porphyrin-based photodynamic therapy drugs.

Photodynamic therapy (PDT) involves the treatment of tumor tissue with a photosensitizer and light to effect the delineation and/or eradication of the tumor. PDT is a two step process: (1) incorporation of photosensitizer into the cell where it must be retained by tumors in vivo; and (2) illumination of the tumor cell with light to effect cell death. Hematoporphyrin derivative (HPD) is a complex mixture of porphyrins currently used for PDT in the clinical setting. Hematoporphyrin-based oligomers of up to five subunits were determined using fast atom bombardment mass spectrometry of the high-molecular-weight fraction of the drug. Reduction of this fraction with LiAlH4 permitted determination of the covalent bond linking the monomers in these oligoporphyrins. Application of these analytical procedures to the determination of the composition of different preparations of HPD will be described.

Aluminum↗
PubMed1988

Determinants of porphyrin fluorescence emission spectra of atheromatous plaques.

Plaques were obtained via carotid endarterectomy and exposed to the fluorescent dye hematoporphyrin in vitro. Fluorescence emission spectra were used to characterize sites of dye binding. To provide additional information on the role of environment on fluorescence, model systems were studied involving micellar and premicellar systems. The data indicate two distinct fluorescence signals from plaque-bound porphyrin. These signals were at least 50-fold greater than the fluorescence from uninvolved regions of the vessel wall. Fluorescence emission at 618 nm was observed in all plaques examined. A second fluorescence signal at longer wavelengths was associated with the more complex plaques and could be mimicked by mixtures of porphyrin and detergent at a premicellar concentration. These studies suggest the presence of 2 different porphyrin-binding regions in the plaques examined. The first appears to be a predominantly aqueous site which may represent the interior of a cholesterol-rich micellar structure. The second is associated with 'hard' plaque, i.e., collagen and calcification.

Arteriosclerosis↗
PubMed1988

Interactions between porphyrins and mitochondrial benzodiazepine receptors.

Dicarboxylic porphyrins were reported to be potent inhibitors of the binding of benzodiazepines to peripheral drug receptors in mitochondria, but the reverse does not appear to be true. Moreover, the photosensitization of mitochondria by the tumor-localizing porphyrin dimer/oligomer fraction of 'HPD' was not inhibited by benzodiazepines in cell culture.

Animals↗
PubMed1988

Transport of an iron: anthracycline complex by murine leukemia cells.

Cytotoxicity and transport of daunorubicin (DNR) and of a DNR: iron complex were examined, using P388 murine lymphoblasts and P388/ADR, an anthracycline-resistant sub-line. The drug: iron complex was dissociated in the presence of serum or, in serum-free medium, at the cell surface. Moreover, DNR toxicity was not promoted when the drug was provided as an iron complex. While formation of a complex with iron can markedly potentiate reactivity of anthracyclines in cell-free systems, these complexes play a role in cytotoxicity of DNR only if generated in the intracellular environment.

Animals↗
PubMed1988

Photoproducts formed from photofrin II in cells.

Fluorescence and absorption spectra of light-exposed cells containing the tumour-localizing porphyrin preparation Photofrin II (PII) have been studied. Light exposure results in spectral changes that may be due to a photoinduced modification of the porphyrins without breakage of the porphyrin macrocycle and/or to a photoinduced displacement of the porphyrins in the cells. Photochemical reaction involving breakage of the porphyrin macrocycle also occur as can be seen from the loss of absorbance within the Soret band region during light exposure. Singlet oxygen may be involved in the photodegradation of PII in cells since the process is slowed down on bubbling N2 through the samples and is slightly faster in suspensions in Dulbecco's phosphate buffered saline (PBS) made of D2O compared with suspensions in PBS made of H2O. During light exposure a fluorescent product is formed in the cells with fluorescence excitation and emission characteristics similar to those of the "age pigment" lipofuscin (lambda exc = 350 nm, lambda em = 440 nm).

Cell Line↗