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Biomedical subjects

T J Dougherty

Publications and source records attributed to T J Dougherty.

At least 109 records · Page 6Linked to original sources
PubMed1987

The theory of photodynamic therapy dosimetry: consequences of photo-destruction of sensitizer.

Photodynamic dose is defined as the area under the curve of sensitizer level plotted as a function of light dose. This is a photochemical definition of dose. We will show that this definition is useful in predicting photobiological response. The photodestruction of sensitizer during photodynamic therapy is shown to result in an upper limit on the photodynamic dose which can be delivered by an unlimited light dose. This limit results in the opportunity to make total photodynamic dose uniform to considerable depths (one to two centimeters). The existence of thresholds for permanent tissue damage allows protection of normal tissue from the large light doses required to achieve this limiting dose deep in the tissue. Higher sensitizer levels in the tumor permit tumor destruction while the normal tissues are protected. A clinical trial to determine the proper level of injected dose necessary for these results is required. This theory of photodynamic therapy (PDT) dosimetry is tested in the DBA-SMT experimental mouse tumor system. Combinations of drug and light which are not reciprocal but are nearly equal by this theory are shown to give equivalent tumor control at seven days post treatment. Reciprocal combinations of drug and light fail to give equivalent results when they ae selected using the theory to choose a combination where reciprocity should fail.

Animals↗
PubMed1987

Alterations in peptidoglycan of Neisseria gonorrhoeae induced by sub-MICs of beta-lactam antibiotics.

Exposure of Neisseria gonorrhoeae to sub-MICs of selected beta-lactam antibiotics caused distortion of normal cell morphology. Analysis of the peptidoglycan indicated that the cells were accumulating increased quantities of disaccharide pentapeptide in their cell walls. The O-acetylated form of the disaccharide pentapeptide was not detected among the major peaks. The correlation of antibiotic binding to gonococcal penicillin-binding protein 2 and accumulation of non-O-acetylated disaccharide pentapeptide suggested an explanation for the previously observed relationship of penicillin-binding protein 2 and O-acetylation of peptidoglycan.

Acyltransferases↗
PubMed1987

Photodynamic therapy for palliation of locally recurrent breast carcinoma.

Fourteen women with locally recurrent breast carcinoma on the chest wall following mastectomy were given 30 courses of photodynamic therapy (PDT). All patients had been heavily pretreated with conventional modes of therapy (radiation therapy, chemotherapy, hormonal therapy, surgical resection). Twenty-two courses yielded a partial response; two courses yielded a complete response; four courses showed no response; one patient was treated as an adjunct to surgery; and one patient was lost to follow-up. Duration to response was variable, ranging from 6 weeks to 8 months. Several women had chest wall disease controlled for prolonged periods of time using repeated courses of PDT. Two women had re-epithelialization of ulcerated lesions. Complications were minimal and included pain (two patients), sunburn (two), and infection (one). These results suggest that treatment with PDT can aid in local control of chest wall recurrence following mastectomy in selected patients.

Adult↗
PubMed1986

Photodynamic therapy in patients with colorectal cancer.

A pilot study was conducted, in which photodynamic therapy (PDT), a technique in which malignant cells are destroyed by light after being previously photosensitized by a chemical compound, was tried in a group of 14 patients with recurrent or residual colorectal cancer in the pelvis. Three of the six patients with unresectable pelvic recurrences experienced a significant relief of pain after PDT. In two of the five patients who had an incomplete resection of their pelvic recurrences, there was also a substantial relief of pelvic pain after surgery and PDT. In one of these patients subsequent biopsies proved the disappearance of the residual pelvic microscopic disease after several sessions of PDT. Three patients had a recurrence from a squamous cell carcinoma primary of the anal canal. All recurrences were amenable to surgical resection. In one of the patients, PDT was used in an attempt to sterilize an area of residual tumor that was located over the left ischial tuberosity. The patient experienced good relief of pain, but died of her disease 7 months after PDT. In the other two patients, PDT was used as an "adjunct" after resection of their recurrences. One of these patients was free of disease and died of an unrelated cause 12 months after PDT. The other is alive and well. This study demonstrated that PDT can be safe and tolerable in patients with pelvic malignancies. PDT is capable of tumor destruction, can be used repeatedly in areas previously exposed to ionizing radiation, and may have a role in the prevention and management of pelvic-perineal recurrences from colorectal cancer.

Adult↗
PubMed1986

Photosensitization of malignant tumors.

Photodynamic therapy is a new, experimental method of treating malignant tumors by utilizing the relatively selective retention of the photosensitizer (hematoporphyrin derivative or dihematoporphyrin ether) and its ability to elicit an efficient photodynamic reaction upon activation with penetrating viable light. Application of this therapy to tumors in the bronchus, bladder, skin, and several other sites has demonstrated both safety and efficacy, even in advanced cases. Eradication of early stage tumors in the bronchus and bladder has been demonstrated. Selective retention of the photosensitizers in tumors is apparently related to the relatively large size of the aggregates of these materials causing phagocytosis by reticuloendothelial cells as well as preventing rapid clearance from tumor interstitial fluid and subsequent uptake in lipophylic components of cells. Upon light activation, generally delivered from lasers via fiber optics, the sensitizers generate singlet oxygen, the apparent cytotoxic agent, causing both vascular damage and injury to tumor cells.

Animals↗
PubMed1986

Haematoporphyrin derivative photosensitization and gamma-radiation damage interaction in Chinese hamster ovary fibroblasts.

The interaction of haematoporphyrin derivative (HPD) photosensitization and gamma-irradiation was studied with regard to clonogenicity of Chinese hamster ovary (CHO) fibroblasts. Exposure to either treatment alone resulted in shouldered response curves. Exposure to 4.2 Gy gamma-radiation immediately before graded doses of visible light had no effect on the shape of the visible-light survival curve; similarly, exposure to 8.75 kJ/m2 light immediately before graded doses of gamma-radiation had no effect on the shape of the gamma-radiation response curve. These data indicate that damage due to gamma-radiation and HPD photosensitization did not interact, suggesting that the mechanisms of cell killing are different.

Animals↗
PubMed1986

Genetic analysis and penicillin-binding protein alterations in Neisseria gonorrhoeae with chromosomally mediated resistance.

Eight recent isolates of Neisseria gonorrhoeae with high-level non-beta-lactamase-mediated penicillin resistance were investigated. The penicillin-binding proteins of these strains were found to have reduced affinity for radiolabeled penicillin. Testing for known resistance genes showed that these were present in the resistant isolates. Genetic transformation was used to construct strains with increasing levels of antibiotic resistance. Modification of the transformation protocol made it possible to isolate transformants at the highest (penicillin-resistant DNA donor) level of resistance. These transformants unexpectedly yielded two distinct penicillin-binding protein patterns when tested.

Bacterial Proteins↗
PubMed1985

Potentiation of photodynamic therapy by heat: effect of sequence and time interval between treatments in vivo.

Photodynamic therapy (PDT) utilizing hematoporphyrin derivative (Hpd) as photosensitizer and an argon-dye laser as the light source was used alone and in combination with a localized microwave hyperthermia treatment to treat the SMT-F mammary carcinoma in mice. A 30-min heat treatment at 44.5 degrees C was applied 0-8 hr before or after a standard photodynamic treatment (67.5 or 135 J/cm2, given 24 hr post-7.5 mg/kg Hpd). Potentiation of PDT by heat was found to be related to the sequence of the treatments and the time interval between them. When 44.5 degrees C for 30 min was applied immediately after a 15-min PDT treatment, significant potentiation was seen (58% long-term tumor control vs 3 and 10%, respectively, for PDT and heat alone). This potentiation decreased with increasing time between PDT and heat, with tumor control values decreasing to 36, 20, and 14%, when 2, 4, and 8 hr, respectively, were allowed between treatments. Only additive effects of the independent therapies were found when this heat treatment was applied 0-8 hr before PDT. In other experiments, mice were treated with single or fractionated 30-min PDT treatments (two 15-min treatments separated by 0-, 2-, 4- or 8-hr intervals). Decreases in tumor control were seen with increasing time interval; only minor differences in tumor control were seen when 4-8 hr was allowed between treatments compared to a single 15-min treatment.

Animals↗
PubMed1985

Whole bladder photodynamic therapy for transitional cell carcinoma of bladder.

Our preliminary studies indicate that the bulb-tip technique for whole bladder photodynamic therapy (PDT) illuminates the entire bladder mucosa and is applicable to the management of superficial transitional cell carcinoma of the bladder. This treatment modality may be an option to patients who are failures to other standard treatments. A randomized clinical study is needed to decide on PDT as a primary treatment of choice for transitional cell carcinoma of the bladder.

Aged↗
PubMed1985

Experimental photodynamic treatment of canine bladder.

In urology, important limiting factors in the application of hematoporphyrin derivative and photodynamic therapy appear to be the problems of standardization of dosimetry and the technique of transurethral photoradiation. Experimental photodynamic therapy on canine bladder with normal and altered epithelium was performed using an argon laser as an energy source. A 630 nanometer wavelength of light was delivered through a quartz-optical fiber with either a regular flat end for focal illumination or a bulb-type end which produced an isotropic light pattern. It was demonstrated that normal canine bladder was resistant to photodynamic therapy and that the bulb tip produced whole bladder illumination. With a moderate light dose of 18 to 30 Joules/cm.2 the effect following whole bladder illumination on the bladder was generalized and superficial. This approach appears to be ideal for treating superficial transitional cell carcinoma of the bladder. Additional work is needed in selecting appropriate energy doses.

Animals↗
PubMed1985

Involvement of a change in penicillin target and peptidoglycan structure in low-level resistance to beta-lactam antibiotics in Neisseria gonorrhoeae.

A penicillin-susceptible gonococcus and its low-level resistant penA transformant were examined with regard to their penicillin-binding proteins (PBPs) and their peptidoglycan structures. Treatment of the susceptible strain with its MIC of penicillin (0.01 microgram/ml) led to significant binding to PBPs 2 and 3 and a substantial decrease in the O-acetyl modification on the peptidoglycan. Peptidoglycan synthesis gradually ceased over an extended time. When the penA strain was treated with the same concentration of penicillin, only binding to PBP 3 was observed and there was no O-acetylation decrease, with continued peptidoglycan synthesis. This suggested that PBP 2 was the primary target in penicillin-susceptible gonococci and that this protein participated in the O-acetylation of peptidoglycan. Penicillin concentrations representing the MIC for the penA transformant (0.06 microgram/ml) caused significant binding to PBPs 1, 2, and 3 in the susceptible strain and PBPs 1 and 3 in the penA strain. In both strains the rate of peptidoglycan synthesis and the cross-linkage of the peptidoglycan made declined sharply, suggesting that significant inhibition of PBP 1 interfered with transpeptidation. A model for low-level resistance is proposed in which a decreased PBP 2 affinity leads to assumption of the role of primary target in the resistant transformant by PBP 1. The differences observed in peptidoglycan metabolism are a direct consequence of this change.

Acetylation↗
PubMed1985

Membrane permeability changes associated with DNA gyrase inhibitors in Escherichia coli.

Inhibition of DNA synthesis in Escherichia coli B/r by a DNA gyrase inhibitor results in cell death after a 50-min lag period. Examination of the cells under phase-contrast and electron microscopes revealed that they appeared to undergo plasmolysis coincident with the onset of cell death. The inhibited cells were also found to become susceptible to low levels of detergent at this time. With a fluorescent membrane probe, the level of membrane permeability was assessed and found to increase concurrently with the decrease in culture viability. Analysis of the cell envelope constituents revealed that, other than a shift in the protein/lipid ratio, the compositions of the cell membranes were unperturbed.

Bacterial Proteins↗
PubMed1985

Analysis of Neisseria gonorrhoeae peptidoglycan by reverse-phase, high-pressure liquid chromatography.

The muramidase digest of peptidoglycan from Neisseria gonorrhoeae was isolated and analyzed by the use of a reverse-phase, high-pressure liquid chromatography system. As was found previously in the case of Escherichia coli, gonococci peptidoglycan is also composed of a greater number of muropeptides than can be resolved with thin-layer chromatography systems. Preliminary classification of the muropeptide components into subclasses based on O-acetyl modification and degree of cross-linkage was achieved. Examination of a penicillin-susceptible strain and a highly resistant strain with two penicillin-binding protein alterations synthesized distinctly different peptidoglycan structures, as revealed by this technique.

Bacterial Proteins↗