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Biomedical subjects

D Kessel

Publications and source records attributed to D Kessel.

At least 73 records · Page 4Linked to original sources
PubMed1997

Plasma levels of protoporphyrin IX in humans after oral administration of 5-aminolevulinic acid.

We report on the pharmacokinetics of PP formation and elimination in 4 patients after the administration of oral ALA (60 mg kg-1). After a brief distribution phase, plasma PP levels decline (half life = 8 h) and was almost undetectable by 48 h post-administration. This confirms pharmacokinetic clinical data which show that ALA in a shortened interval of skin photosensitization compared with other sensitizers such as Photofrin and 'HPD'. A brief summary of other clinical-toxicity findings is reported.

Administration, Oral↗
PubMed1997

On-line fluorescence of human tissues after oral administration of 5-aminolevulinic acid.

It is important to have a frame of reference for the timing of photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) so that PDT can occur when the tissue levels of protoporphyrin IX (PP) are at a maximum. This study describes a non-invasive fluorescence technique for detecting tissue PP levels after systemic ALA administration in patients with gastrointestinal cancer. The data suggest that the intensity of tumor surface fluorescence correlates with the tumor PP concentration. Spectrophotofluorometric measurements of skin and buccal mucosa also offer an easily acquired and rapid means for determining changes in plasma concentrations of PP. A number of potential variables, including blood flow, affect the intensity of fluorescence. We report that fluorescence measurements in situ are best adapted to the measurement of changes in the porphyrin levels in tissues rather than the absolute concentrations.

Administration, Oral↗
PubMed1997

Effects of fractionated 5-aminolevulinic acid administration on tissue levels of protoporphyrin in vivo.

The photodynamic therapy (PDT) of malignant tissues can be achieved via the administration of 5-aminolevulinic acid (ALA), which is naturally converted to the photoreactive substance protoporphyrin IX (PP). This study compares bolus with fractionated ALA dosing in order to determine whether one of these methods results in a higher tissue concentration of PP. Mice bearing a subcutaneously implanted colon-26 tumor were treated with ALA (200 mg kg-1), given intravenously either as a single bolus or as three equally divided doses at 50 min intervals. Tissue samples of tumor, kidney, skin, liver, skeletal muscle, colon and plasma were obtained 2, 3, 4 and 6 h later for the analysis of PP concentrations. Fractionated dosing results in significantly higher concentrations of PP at 4 and 6 h for kidney, 3 and 6 h for skin, 3 h for colon and 6 h for liver. In contrast, fractionated dosing has no significant effect on the PP concentrations of muscle and plasma. Fractionated dosing results in a significantly greater PP concentration in the tumor at 3 h relative to that observed for the bolus dose. However, from a consideration of the time of PP measurement, it is concluded that fractionated dosing may not cause a significant increase in the PP concentration in colon-26 tumors relative to that observed for the bolus dose.

Aminolevulinic Acid↗
PubMed1997

Initiation of apoptosis versus necrosis by photodynamic therapy with chloroaluminum phthalocyanine.

While chloroaluminum phthalocyanine is a highly effective photosensitizer of murine leukemia P388 or L1210 cells, the mode of cell death varies as a function of the PDT dose. When cells were incubated with 0.3 microM of the sensitizer, a light dose of 45 mJ cm-2 (670 +/- 5 nm) yielded a 90% apoptotic cell population within 60 min. The sensitizer localized throughout the cytoplasm and catalyzed both lysosomal and mitochondrial photodamage at this light dose. Higher light doses yielded progressively more membrane photodamage and inhibited the apoptotic response as determined by the examination of Höchst dye HO 33342-labeled nuclei, DNA fragmentation on gels and a poly(adenosylribose) polymerase (PARP)-cleavage assay. Pulse-field gel electrophoresis revealed nonspecific DNA degradation to particles > or = 50 kbp at the higher PDT doses but neither PARP cleavage nor apoptotic nuclei.

Animals↗
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↗
PubMed1997

The role of subcellular localization in initiation of apoptosis by photodynamic therapy.

Rapid initiation of apoptosis can be induced by photodynamic therapy, depending on the cell line and sensitizer employed. In this study, we evaluated the photodynamic responses to two structurally related photosensitizing agents, using the P388 murine leukemia cell line in culture. Photodamage mediated by tin etiopurpurin involved lysosomes and mitochondria and yielded a rapid apoptotic response; apoptotic nuclei were observed within 60 min after PDT. A drug analog, tin octaethylpurpurin amidine, targeted lysosomes, mitochondria and cell membranes; apoptotic nuclei were not observed until 24 h after PDT. These results, together with other recent reports, are consistent with the hypothesis that membrane photodamage can delay or prevent an apoptotic response to PDT.

Animals↗
PubMed1997

Analysis of renal artery geometry may assist in the design of new stents for endovascular aortic aneurysm repair.

BACKGROUND: Endovascular repair of infrarenal aortic aneurysms is a feasible technique, but up to 30 per cent of patients may be excluded on the basis of a short proximal aortic neck. METHODS: A dissection study was performed on 65 cadavers to measure the distance between the superior mesenteric and renal artery ostia, and to document the points of origin of the renal arteries. RESULTS: The interostial distance did not differ significantly between aneurysmal and non-aneurysmal aortas (P = 0.90 for the left renal artery; P = 0.72 for the right). The median distance was 0.7 cm. The renal arteries originated between 2 and 4 o'clock on the left and between 9 and 10 o'clock on the right. CONCLUSION: The relative consistency of the anatomy in this region may allow the development of a new stent which would increase the number of patients suitable for endovascular repair.

Aged↗
PubMed1996

The phosphatase inhibitor calyculin antagonizes the rapid initiation of apoptosis by photodynamic therapy.

DNA fragmentation and internucleosomal cleavage were rapidly initiated after lysosomal photodamage to murine leukemia cells, with apoptotic chromatin and DNA 'ladders' detected within 30 min after irradiation. Apoptosis was inhibited by concurrent exposure of cells to a 10 nM concentration of the serine-threonine phosphatase inhibitor calyculin A and promoted by a serine/threonine kinase inhibitor. These results indicate that a late stage in apoptosis requires serine/threonine dephosphorylation.

Animals↗
PubMed1996

Feasibility of photodynamic therapy using endogenous photosensitization for colon cancer.

A novel approach to photodynamic therapy (PDT) involves endogenous photosensitization by the oral administration of delta-aminolevulinic acid (ALA), a naturally occurring substance that is the precursor of protoporphyrin IX (PpIX). A 60-year-old man with adenocarcinoma of the sigmoid colon received ALA, 60 mg/kg by mouth. Six hours later, when the plasma level of PpIX had peaked, the tumor was exposed locally to red light at 633 nm to activate PpIX. Endoscopy and biopsy findings subsequent to this treatment showed unequivocal visible changes and necrosis. Six months later, the patient again underwent successful treatment without adverse effects. This report suggests a role for PDT using endogenous photosensitization in certain circumstances involving adenocarcinoma of the large intestine.

Adenocarcinoma↗
PubMed1996

Effects of sonodynamic and photodynamic treatment on cellular thiol levels.

Exposure of murine leukemia L1210 cells to ultrasound in vitro resulted in cell fragmentation; cells which survived this treatment were 100% viable and showed a transient decrease in intracellular thiol pools (expressed as glutathione equivalents). Depletion of thiol pools became progressively greater with increasing exposure of cells to ultrasound; this was not associated with leakage of thiols into the medium. Biochemically elevating glutathione levels or sonication in the presence of the anti-oxidant trolox offered only a minor degree of protection against sonotoxicity. Photodynamic therapy also resulted in depletion of intracellular thiol levels, and loss of cell viability. In the presence of trolox, both effects were reversed, although elevation of intracellular thiol levels did not protect cell from phototoxicity.

Animals↗
PubMed1996

Portable chest radiology in intensive care: a comparison of a new dual characteristic film-screen system (Insight) incorporating a flexible grid with a standard film-screen system.

Insight (Insight, Kodak, UK) is a new dual image receptor system which utilizes an asymmetric film screen combination. Conventional radiography was compared with the Insight system, in combination with a cassette incorporating a flexible grid, in fifty patients on the intensive care unit. Radiographs were analysed by intensive care junior medical staff, nursing staff and two groups of radiologists. Insight provided better visualization of lung parenchyma, mediastinal detail and position of endotracheal tubes than conventional radiography. Central venous catheters were generally seen better on conventional radiographs than on Insight. Insight system produces a significant improvement in plain chest radiography in the intensive care unit. In the absence of digital radiography it is a suitable technique for routine radiography in the intensive care unit.

Aged↗
PubMed1996

An apoptotic response to photodynamic therapy with endogenous protoporphyrin in vivo.

CDF1 mice bearing the colon-26 tumor were treated with aminolevulinic acid (200 mg kg-1) by tail-vein injection, with tumor sites irradiated 4 h later at 633 nm (75-120 J cm-2). 10 h after irradiation, samples of tumors were removed for histology studies and analysis of DNA fragmentation by static gel electrophoresis. The resulting patterns indicate an apoptotic response to photodynamic therapy with endogenously formed protoporphyrin.

Animals↗
PubMed1996

Phototherapy of cancer and atheromatous plaque with texaphyrins.

Cancer and cardiovascular disease are the leading causes of death in the western world. Photodynamic therapy (PDT) has demonstrated activity in the treatment of superficial cancerous lesions and as an intraoperative adjunct during surgical debulking. Texaphyrins are pure, synthetic water-soluble macrocycles that localize in both cancerous lesions and atheromatous plaque. Lutetium texaphyrin (PCI-0123) is activated by tissue-penetrating far red light (720-760 nm). Patient diagnosis and treatment planning is possible via magnetic resonance imaging (MRI) with the paramagnetic gadolinium texaphyrin (PCI-0120) or via fluorescence imaging using the diamagnetic PCI-0123. In this study it is shown that texaphyrins localize selectively in cancer and atheromatous plaque. PDT with PCI-0123 is found to cause selective photodamage to the diseased tissue. Specifically, PCI-0123 acts to eradicate the SMT-F murine mammary tumors and diet-induced atheromatous plaque in rabbits.

Animals↗
PubMed1996

Rapid initiation of apoptosis by photodynamic therapy.

Photodynamic therapy (PDT) of neoplastic cell lines is sometimes associated with the rapid initiation of apoptosis, a mode of cell death that results in a distinct pattern of cellular and DNA fragmentation. The apoptotic response appears to be a function of both the sensitizer and the cell line. In this study, we examined photodynamic effects of several photosensitizers on murine leukemia P388 cells. Two drugs, a porphycene dimer (PcD) and tin etiopurpurin (SnET2), which localized at lysosomal sites, were tested at PDT doses that resulted in 50% loss of viability (LD50), measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. An oligonucleosomal pattern of DNA degradation was observed within 1 h after irradiation. Neither sensitizer antagonized PDT-mediated internucleosomal DNA cleavage by the other. Very high PDT doses with either agent abolished this rapid internucleosomal cleavage. Exposure of cells to high concentrations of either sensitizer in the dark also resulted in rapid DNA fragmentation to nucleosomes and nucleosome multimers; this effect was not altered by the antioxidant 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox), although the latter could protect cells from cytotoxicity and apoptotic effects caused by LD50 PDT doses. Photodamage from two cationic sensitizers, which localized at membrane sites, caused rapid DNA cleavage to 50 kb particles; however, no further fragmentation was detected after 1 h under LD10, LD50 or LD95 PDT conditions. Moreover, the presence of either cationic sensitizer inhibited the rapid internucleosomal cleavage induced by SnET2 or PcD photodamage. The site of photodynamic action may therefore be a major determinant of the initiation and rate of progression of apoptosis.

Animals↗
PubMed1996

Delayed oxidative photodamage induced by photodynamic therapy.

Apoptotic DNA fragmentation was observed 60 min after photodynamic therapy of murine leukemia cells in culture, using either of two photosensitizers with predominantly lysosomal targets. When the radical scavengers trolox or alpha-tocopherol succinate were present during irradiation, the subsequent appearance of apoptotic cells was prevented, as was phototoxicity. Addition of either scavenger during the 60 min after irradiation provided only partial protection from apoptosis and phototoxicity; this protection was abolished if the addition was delayed for 10 min. These results are consistent with a model whereby long-persisting photoproducts continue the initiation of apoptosis for approximately 10 min after irradiation has ceased.

Animals↗