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Biomedical subjects

D Kessel

Publications and source records attributed to D Kessel.

At least 55 records · Page 3Linked to original sources
PubMed1999

Current concepts in gastrointestinal photodynamic therapy.

OBJECTIVE: To review current concepts of photodynamic therapy (PDT) applied to the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA: PDT initially involves the uptake or production of a photosensitive compound by tumor cells. Subsequent activation of the photoreactive compound by a specific wavelength of light results in cell death, either directly or as a result of vascular compromise and/or apoptosis. METHODS: The authors selectively review current concepts relating to photosensitization, photoactivation, time of PDT application, tissue selectivity, sites of photodynamic action, PDT effects on normal tissue, limitations of PDT, toxicity of photosensitizers, application of principles of PDT to tumor detection, and current applications of PDT to tumors of the gastrointestinal tract. RESULTS: PDT is clearly effective for small cancers, but it is not yet clear in which cases such treatment is more effective than other currently acceptable approaches. The major side effect of PDT is cutaneous photosensitization. The major limitation of PDT is depth of tumor kill. As data from current and future clinical trials become available, a clearer perspective of where PDT fits in the treatment of cancers will be gained. Many issues regarding pharmacokinetic data of photosensitizers, newer technology involved in light sources, optimal treatment regimens that take advantage of the pharmacophysiology of photoablation, and light dosimetry still require solution. One can foresee application of differing sensitizers and light sources depending on the specific clinical situation. As technologic advances occur, interstitial PDT may have significant application. CONCLUSIONS: PDT has a potentially important role either as a primary or adjuvant mode of treatment of tumors of the gastrointestinal tract.

Gastrointestinal Neoplasms↗
PubMed1999

Stepping-table gadolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: preliminary experience.

PURPOSE: To compare stepping-table digital subtraction gadolinium-enhanced magnetic resonance (MR) angiography of the distal aorta and lower extremity arteries with conventional catheter digital subtraction x-ray angiography in patients with arterio-occlusive disease. MATERIALS AND METHODS: Twenty patients underwent both conventional catheter angiography and fast three-dimensional gadolinium-enhanced MR angiography of the aorta and outflow vessels at 1.5 T; the images were acquired in three consecutive imaging locations during a single infusion of a gadolinium chelate. RESULTS: Compared with catheter angiography, according to the findings of two blinded independent reviewers, MR angiography had sensitivities of 81% and 89% and specificities of 91% and 95%, respectively, for demonstration of insignificant (< or = 50%) stenosis versus significant (51%-100%) stenosis. For demonstration of occlusion, the sensitivity and specificity were 94% and 97%, respectively, by consensus. There was good interobserver correlation between the two readers overall (kappa = 0.65 for reporting the degree of narrowing in all lesions; 0.86, for reporting of insignificant versus significant stenoses; and 0.928, for reporting of occluded versus patient segments). CONCLUSION: Stepping-table digital subtraction contrast material-enhanced MR angiography has high accuracy compared with catheter angiography in patients with arterio-occlusive disease of the aorta and outflow vessels. These preliminary study results suggest that this technique may ultimately provide a safe, noninvasive, and cost-effective alternative to catheter angiography.

Aged↗
PubMed1999

Subclavian stents and stent-grafts: cause for concern?

PURPOSE: To report cases of stent and stent-graft fracture in the subclavian vessels. METHODS AND RESULTS: Three patients with self-expanding stents of 3 different types in 1 subclavian artery and 2 subclavian veins presented with recurrent symptoms 6 months to 2 years after stenting. All devices showed signs of compression with stent fracture. The covered stent in the subclavian artery was excised. Of the 2 venous patients, 1 was treated with first rib resection and the other refused further treatment. CONCLUSIONS: The subclavian vessels are prone to flexion during movement, and the vessels may be compressed by external structures, including the clavicle and first rib. Stents that have not been designed to withstand these forces may be damaged.

Adult↗
PubMed1999

Photoproduct formation from a zinc benzochlorin iminium salt detected by fluorescence microscopy.

When examined by fluorescence microscopy, tumor cells loaded with a zinc benzochlorin iminium salt showed a very faint deep-red fluorescence that was rapidly transformed to a substantially brighter red-orange fluorescence. Fourier transfer spectroscopy analysis with a red-sensitive detection system revealed that an initial fluorescence at 770 nm was gradually converted to 640 nm fluorescence during excitation. Image analysis showed that photoproduct formation was accompanied by a change in the site of drug localization from the cytoplasm to the nucleus. These studies illustrate the power of interferometry for the characterization of photoproducts and changes in sensitizer localization during photoproduct formation.

Animals↗
PubMed1999

Transport and localisation of m-THPC in vitro.

The hydrophobic photosensitising agent meta-tetrahydroxyphenylchlorin (m-THPC) must be formulated with an appropriate vehicle before administration. Studies were carried out with murine leukaemia cells in vitro to assess the role of formulation in drug pharmacokinetics. The rate-limiting step in m-THPC accumulation was the slow conversion of drug aggregates to monomers upon dilution into growth media. Only non-viable cells with damaged membranes showed a rapid drug uptake, otherwise m-THPC accumulation was a slow process. It was found that m-THPC was localised mainly at mitochondrial loci. Subsequent irradiation resulted in the release of cytochrome c into the cytosol, triggering a rapid activation of caspase-3, which led to an apoptotic response. Plasma distribution of m-THPC involved binding to lipoprotein species, with only a slight appearance of the drug in the albumin fraction.

Animals↗
PubMed1999

Enhanced responsiveness to photodynamic therapy-induced apoptosis after mitochondrial DNA depletion.

Several lines of evidence indicate that mitochondria are an especially sensitive target for photodamage. Reports of cross resistance between photodynamic therapy (PDT) and the drug cisplatin, along with evidence that depletion of mitochondrial DNA (mtDNA) sensitized cells to cisplatin suggested a study of the photodynamic responsiveness of murine leukemia control L1210 cells versus cells depleted of mtDNA. Loss of mtDNA led to an increased sensitivity to mitochondrial photodamage, while the cytotoxic effects of lysosomal photodamage were not affected. Cells depleted of mtDNA showed an enhanced apoptotic response to PDT involving a mitochondrial target, compared with control cells.

Animals↗
PubMed1998

Tumor versus vascular photodamage in a rat tumor model.

The [4-(5-nitro-2-furyl)-2-thiazoyl] formamide (FANFT)-induced urothelial tumor in the rat is found to express the mdr gene. The resulting multidrug resistance (MDR) phenotype results in the expression of an outward transport system that prevents cellular accumulation of certain weakly cationic agents. Among the latter is a photosensitizer with known efficacy for the FANFT tumor, the copper benzochlorin iminium salt. FANFT cells are protected from direct cell kill mediated by this drug, suggesting that the substantial delay in tumor regrowth from this tumor/sensitizer combination can be attributed to vascular effects.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Photodynamic therapy.

Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

Antineoplastic Agents↗
PubMed1998

Mitochondrial photodamage and PDT-induced apoptosis.

Four photosensitizers with specific targets (mitochondria, lysosomes and plasma membrane) were used to delineate the mechanism of PDT-induced apoptosis in murine leukemia cells. Additional studies were carried out with two sensitizers which caused photodamage to both mitochondria and lysosomes, but varied with regard to membrane photodamage. PDT induced an apoptotic response after mitochondrial photodamage, but not after selective damage to lysosomes or to the cell membrane. Moreover, the latter could delay or inhibit the appearance of apoptosis after mitochondrial photodamage. We had previously reported that exposure of cells to high porphycene concentrations caused an apoptotic response in the dark; this was also associated with mitochondrial damage. These results are consistent with recent proposals that release of mitochondrial components can trigger an apoptotic response. ATP depletion after mitochondrial photodamage does not appear to play a role in initiation of the apoptotic program.

Adenosine Triphosphate↗
PubMed1998

The induction of apoptosis by a positively charged methylene blue derivative.

Identifying the cellular responses to photodynamic therapy (PDT) is important if the mechanisms of cell death are to be fully understood. PDT with a methylene blue analog DO15 yielded mitochondrial photodamage whilst membrane and lysosomal integrity were maintained. Apoptosis was detected using the DNA stain HO342, by the appearance of 50 kb fragments and by DNA ladder formation. The release of mono- and oligonucleosomes was further quantified using an ELISA protocol. Large DNA fragments were observed immediately following illumination, and nucleosomes were detected at 1-2 h post-treatment. Increasing the dose 4-fold accelerated the apoptotic response to PDT. This is the first report of a thiazine photosensitiser inducing apoptosis and is consistent with recent proposals suggesting that release of mitochondrial components may play an important role in the mechanism of cell death.

Animals↗
PubMed1998

Hemodynamic effects of 5-aminolevulinic acid in humans.

Endogenous protoporphyrin IX (PpIX), which results from the oral administration of 5-aminolevulinic acid (ALA), is being investigated for its efficacy as a photosensitizing agent for photodynamic therapy (PDT). Clinical use of ALA has been associated with only mild gastrointestinal side effects. The hemodynamic effects of orally administered ALA in doses used for PDT are unknown. Six patients with a significant history of cardiac disease underwent Swan-Ganz catheterization prior to ALA administration and abdominal operation for PDT. Hemodynamic data collection began at least 1 h prior to ALA, and continued for at least 4 h subsequently, during which time no other medications were administered. When compared to measurements made prior to ALA administration, all patients displayed a significant decrease in systolic and diastolic blood pressures, pulmonary artery systolic and diastolic pressures as well as pulmonary vascular resistance. Five of the six patients also developed a decrease in systemic vascular resistance. No significant changes in pulmonary capillary wedge pressure, cardiac output or cardiac index was observed, but the mean pulse rate rose significantly. These findings cannot be explained on the basis of other cardiovascular depressants or to poor central volume status. Although no adverse sequela were appreciated as a result of the observed hemodynamic changes, this potential should be recognized in patients undergoing PDT using ALA.

Aminolevulinic Acid↗
PubMed1998

Sources of error in intra-arterial pressure measurements across a stenosis.

OBJECTIVE: To investigate potential errors associated with different techniques of intra-arterial pressure measurement at angiography. MATERIALS AND METHODS: An experimental model of an arterial stenosis was developed. Experiments were performed to assess the relevance of catheter position, catheter direction and catheter type on the recorded intraluminal pressure. Transstenotic pressure gradients were recorded with and without angiographic catheters crossing the stenosis. RESULTS: At physiological flow rates angiographic catheter type does not influence the recorded pressure. At high flow rates through tight stenoses there is a significant catheter-related difference in recorded pressure adjacent to a stenosis. Downstream pressures may be altered by up to 85 mmHg when standard angiographic catheters are placed across a stenosis. CONCLUSION: The different techniques employed to measure pressure differences across a model stenosis may introduce significant errors up to 85 mmHg. Care must be taken when pressure measurements alone are used to interpret the clinical significance of a stenosis. In low flow conditions there may not be a detectable pressure gradient across a 95% stenosis.

Angiography↗
PubMed1998

Photodynamic therapy of B16F10 murine melanoma with lutetium texaphyrin.

Photodynamic therapy (PDT) of pigmented melanoma has generally been unsuccessful because of insufficient light penetration in such tissues. In this study, the responsiveness of the heavily pigmented B16F10 murine melanoma to lutetium texaphyrin (PCI-0123), a water-soluble sensitizer with strong absorbance in the near infrared (700-760 nm), was examined. These studies were carried out in both normal and ApoE deficient C57BL/6 mice. The latter strain exhibits a lipoprotein profile more like humans (low density lipoprotein > high density lipoprotein) than rodents (high density lipoprotein >> low density lipoprotein). Under optimal conditions of drug dose, light dose, and interval between drug administration and irradiation--the median survival time of C57BL/6 tumor bearing mice was approximately doubled (29 d) compared with tumor bearing control animals (13 d). The life-span of the ApoE knockout mice was greater (33 d) than the C57BL/6 animals (23 d) when irradiation occurred 3 h after administration of a 10 micromol per kg drug dose. The greater efficacy of PDT in the ApoE deficient mice was associated with more rapid clearance of drug from the blood, greater accumulation of sensitizer in tumor tissue, and substantially greater drug binding to the very low density lipoprotein/low density lipoprotein plasma fraction. Confocal laser scanning microscopy showed that the predominant subcellular site of photosensitizer binding was to melanosomes; costaining was performed with Mel-5. Melanosomes are susceptible to oxidative stress. Photo-oxidation, mediated by PCI-0123 PDT, could potentially overload an already highly oxidized stressed state leading to cell death. The good tissue penetration depth achieved by PCI-0213 mediated PDT and the activation of melanosomes makes PDT of pigmented melanoma, for the first time, clinically relevant.

Animals↗
PubMed1997

Side effects and photosensitization of human tissues after aminolevulinic acid.

Aminolevulinic acid (ALA) is being used as a "prodrug" for photodynamic therapy. The side effects of ALA have been only anecdotally reported and these effects as well as pharmacokinetics of the photosensitizing end product of ALA, protoporphyrin IX (PpIX), in patients undergoing operation are unknown. This study systematically determines the side effects of ALA and pharmacokinetics of PpIX in patients undergoing abdominal surgery. Patients were given 30 or 60 mg/kg ALA preoperatively, kept in subdued light for 48 hr, and monitored clinically and with laboratory tests for 5 to 7 days and for at least 2 months thereafter. Periodic plasma samples and tissue biopsies were analyzed for PpIX concentrations using a photodiode array system. No patient developed symptoms of porphyria other than nausea and vomiting, which occurred in 20%. Nearly one-quarter of patients developed transient abnormal liver functions. No patient developed cutaneous phototoxicity, abnormal neurologic function, or unexpected postoperative laboratory tests. The times of peak plasma, skin, skeletal muscle, omental, mucosal, muscularis mucosal, and tumor concentrations of PpIX varied among patients. In general, PpIX concentrations were significantly greater with the higher dose of ALA. Tumor PpIX concentrations were significantly greater than in other tissues except liver. In conclusion, ALA, up to 60 mg/kg, is associated with minimal side effects in patients undergoing operation. Actual tissue concentrations of PpIX suggest that endogenous photosensitization using systemically administered ALA is a mode of PDT feasible for treatment of adenocarcinomas of the gastrointestinal tract in humans.

Adenocarcinoma↗
PubMed1997

Pharmacokinetics of N-aspartyl chlorin e6 in cancer patients.

We examined the pharmacokinetics of the photosensitizer N-aspartyl chlorin e6 in a group of cancer patients. While the drug persisted in plasma for as long as six weeks, there was no evidence of fluorescent NPe6 metabolites during this interval. Kinetics of drug elimination from plasma were consistent with a 2-compartment model with half-lives of approximately 9 hr (57%) and 134 hr (43%). The drug was bound to plasma albumin+other heavy proteins (65%) > HDL (35%) > > LDL (1-2%). These relative values did not change for as long as 21 days after drug administration. The long persistence of NPe6 in plasma was not associated with extended skin photosensitization.

Blood Proteins↗