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Biomedical subjects

T J Dougherty

Publications and source records attributed to T J Dougherty.

At least 127 records · Page 7Linked to original sources
PubMed1985

Photodynamic therapy.

Photodynamic therapy for treatment of malignant tumors uses certain porphyrins as relatively tumor-selective photosensitizers. A wide variety of tumors take up and retain these materials, which can result in complete eradication of the local tumor provided that light of the proper wavelength and sufficient dose is used. This therapy appears to be particularly applicable to treatment of early-stage lung and bladder cancer and can be palliative for several other more advanced cancers.

Animals↗
PubMed1985

Tumor destruction and kinetics of tumor cell death in two experimental mouse tumors following photodynamic therapy.

The effect of photodynamic therapy (PDT) on tumor growth as well as on tumor cell survival in vitro and in vivo was studied in the EMT-6 and RIF experimental mouse tumor systems. In vitro, RIF cells were more sensitive towards PDT than were EMT-6 cells when incubated with porphyrin (25 micrograms/ml, dihematoporphyrin ether) and subsequently given graded doses of light. In vivo, both tumor types responded to PDT (EMT-6, dihematoporphyrin ether, 7.5 mg/kg; RIF, dihematoporphyrin ether, 10 mg/kg; both followed 24 hr later by 135 J of light at 630 nm/sq cm) with severe vascular disruption and subsequent disappearance of tumor bulk. However, whereas the cure rate for EMT-6 tumors was 90%, it was 0% for RIF tumors. Raising the light dose to 200 J/sq cm resulted in 100% cures for EMT-6 tumors accompanied by damage to the surrounding tissues and 13% cures for RIF tumors. Tumor cell clonogenicity following PDT in vivo was assessed using the in vitro colony formation assay. In both tumors, it was found to be nearly unaffected by PDT if the tumor tissue was excised and explanted immediately following completion of treatment. This indicates that the effect of PDT on tumor cells directly was not sufficient to decrease tumor clonogenicity even at doses which led to total macroscopic tumor destruction. Where the tumors remained in situ following PDT and explantation was delayed for varying lengths of time (1 to 24 hr), tumor cell death occurred rapidly and progressively, indicating that tumor cell damage was expressed only if the cells remained exposed to the in situ environment after treatment. The kinetics and extent of tumor cell death were very similar for both tumor types despite their difference in cure rates. The reduction in tumor clonogenicity at 4 hr post-PDT closely matched that of tumor deprived of oxygen for the same period of time, implying that one of the major factors contributing to tumor destruction may be damage of the tumor circulation and the consequences of treatment-induced changes in tumor physiology.

Animals↗
PubMed1985

Interaction of photodynamic therapy and hyperthermia: tumor response and cell survival studies after treatment of mice in vivo.

The interaction of photodynamic therapy (PDT) and hyperthermia was studied in the radiation-induced-fibrosarcoma experimental mouse tumor system by tumor regrowth experiments as well as in vivo to in vitro cloning assays. In vivo, PDT (Photofrin II, 10 mg/kg i.p.), followed 24 h later by light (135 J/cm2, 630 nm) and/or heat (44 degrees C, 30 min) caused severe vascular damage (congestion of tumor vessels and hemorrhage) and subsequent disappearance of palpable tumor mass. While heat-treated tumors always started to regrow within 2 days of treatment, regrowth if it occurred was delayed to 4-5 days after PDT and 6-7 days following combined treatments. Only PDT followed by heat cured a considerable number of animals (45%), while PDT alone and heat followed by PDT cured less than 10% of animals, and heat alone caused no tumor cures. The various treatments differed in their immediate as well as their delayed effects on tumor clonogenicity when observed over a 24-h period. Tumors treated with PDT showed no immediate changes in clonogenicity, but progressive delayed cell death occurred if tumors remained in situ. Heat alone led to an immediate reduction in the number of clonogenic tumor cells, followed by some additional cell death for 4 h and subsequent recovery of clonogenicity. PDT followed by heat caused markedly potentiated immediate reduction in cell survival which may be the result of direct interaction of heat and PDT damage affecting the tumor cells. Some tumors rapidly progressed to total eradication, whereas others showed delayed survival values similar to those for tumor having received PDT only. In the reverse sequence, heat before PDT, the tumor cell survival kinetics resembled those following heat treatment alone. The comparative lack of effectiveness of this treatment regimen can be explained by the severe tumor hemorrhage caused by the initial heat treatment which reduces the transmission of light essential for the subsequent PDT treatment. This study shows that despite pronounced similarities in the microscopic and macroscopic appearance shortly after treatment by PDT or hyperthermia, these two modalities lead to tumor destruction by different mechanisms. Furthermore the combination of these two modalities in the proper sequence leads to potentiated cytocidal effects on the tumor cells in vivo.

Animals↗
PubMed1984

Enhanced tumor control following sequential treatments of photodynamic therapy (PDT) and localized microwave hyperthermia in vivo.

Photodynamic therapy (PDT), or photoradiation therapy (PRT), utilizing hematoporphyrin derivative (HPD) as photosensitizer and an argon-dye laser system as the light source, was used alone and in combination with localized microwave hyperthermia (2450 MHz) to treat axillary tumors of the SMT-F mammary carcinoma in mice. Thirty-minute heat treatments were applied either immediately before or immediately after a standard PDT treatment of 630 nm light at 75 mW/cm2 for 30 min (135 J/cm2) given 24 hr post-7.5 mg/kg HPD, intraperitoneally (i.p.). Tumor control as judged by lack of tumor regrowth 35 days or longer after the combined treatments was compared to that following each treatment when given alone. Little or no enhancement of tumor control was seen when sublethal temperatures of 37.5, 38.5, and 39.5 degrees C were applied for 30 min immediately following the PDT treatment. However, increasing levels of enhancement were seen when heat treatments of 40.5 and 41.5 degrees C or 44.5 degrees C, given for 30 min, were applied immediately before or after the photodynamic treatment.

Animals↗
PubMed1984

Photodynamic therapy (PDT) of malignant tumors.

Photodynamic therapy (PDT) is finding increasing application to a number of malignant tumors. It is based on the specific photosensitization of malignant tissue by a particular porphyrin derived from hematoporphyrin, known as Photofrin II. The exact structure at present is unknown. However this material, following systemic injection, is retained longer in malignant tissue than in many normal tissues and can be activated by visible light, usually red, to initiate a lethal phototoxic effect on the tumor. It is a particularly useful treatment when specificity is necessary in treatment, for example in treatment of widespread chest wall metastasis, bladder cancer and early lesions of the bronchus, trachea and esophagus, including CIS.

Animals↗
PubMed1984

Photoradiation therapy in advanced carcinoma of the trachea and bronchus.

Photoradiation therapy is a new technique being investigated for the treatment of solid malignant tumors. In this study, 17 patients with advanced, recurrent, biopsy-proven malignant lesions of the trachea or main-stem bronchus were treated by photoradiation therapy. Patients received hematoporphyrin derivative intravenously three days prior to light therapy. The light was delivered from a fiberoptic fiber attached to the output beam of a dye laser (633 +/- 3 nm). The fiber was passed through the large channel of a bronchoscope (Olympus BF 2T). Of the 17 patients, two had no measurable response to the photoradiation therapy, six had partial necrosis of the tumor, seven patients had a greater than 50 percent reduction in the intraluminal volume of tumor, and two were lost to follow-up. Survival ranged from 5 to 210 days (median survival, 40 days). Complications of the treatment were significant in this group of advanced-stage patients and included excessive secretions, fever, pneumonia, and abscess formation.

Adenocarcinoma↗
PubMed1984

Photoradiation of rabbit ocular malignant melanoma sensitized with hematoporphyrin derivative.

Photoradiation therapy (PRT) against the Greene-Harvey amelanotic malignant melanoma on the rabbit iris was effectively used to cause tumor regression. A dose of 2.5 mg/kg of hematoporphyrin derivative (HPD) given intravenously, followed by photoradiation at a wavelength of 632 nm and a power density as low as 71 mW/cm2 for 24 minutes (102 J/cm2) was found to be lethal for tumors 4 mm in diameter with an acceptable level of reversible toxicity to the surrounding tissues. This was best accomplished with a dye laser as the source of light because of its very narrow expanding cone of light, as emitted from a fiber optic. A 1000 Watt xenon arc lamp was also effective but not as efficient. Because of this tumor's exceptionally rapid growth rate, it was necessary to compromise one important variable - the 3 to 4 day period between injection of HPD and photoradiation to allow for HPD depletion from normal tissues. Thus, the best tumor death responses were achieved when the light was given 1 to 16 hours after administering HPD. It is surmised that with this rapidly growing tumor, new cell progeny possess insufficient concentrations of HPD to be killed by the radiant energy. At such a short delay period, toxicity to normal tissues was observed mainly as conjunctivitis and conjunctival chemosis. A dose level of HPD at 5 mg/kg was very close to the threshold where minor increases in light intensity would cause strong inflammatory reactions. Higher doses, at 7.5 and 10 mg/kg were excessive. A dose of 23 mg/kg accompanied by mild light energy exposures, even after 30 days, caused massive damage to normal tissues.

Animals↗
PubMed1984

Interaction of hyperthermia and photoradiation therapy.

Local microwave hyperthermia (2450 MHz) was applied to axillary implants of the SMT-F mammary carcinoma in mice in combination with photoradiation therapy (PRT) in an attempt to determine if the two modalities interact. When 40.5 degrees C was applied for 30 min immediately prior to or immediately following PRT (630-nm light, 30 min, at 75 mW/cm2, 20-24 hr post 7.5 mg/kg hematoporphyrin derivative), enhancement of tumor response over that of PRT alone was seen as judged by lack of tumor regrowth (35 days or longer after treatment). A temperature of 41.5 degrees C applied for 30 min immediately following the 30-min PRT treatment produced a result slightly greater than that seen at 40.5 degrees C. When a temperature of 44.5 degrees C for 30 min was applied immediately following PRT, a substantial enhancement of tumor control at 35 days post-treatment was found (53% versus 19 and 4%, respectively, for hyperthermia and PRT alone). These results suggest that tumor response to PRT is enhanced by both a sublethal hyperthermic treatment (40.5 degrees C, 41.5 degrees C) and a moderately lethal heat treatment (44.5 degrees C) given for a short duration, when applied immediately before or after photoradiation.

Animals↗
PubMed1983

Peptidoglycan biosynthesis in Neisseria gonorrhoeae strains sensitive and intrinsically resistant to beta-lactam antibiotics.

Treatment of penicillin-sensitive and intrinsically resistant Neisseria gonorrhoeae strains with their respective inhibitory concentrations of penicillin caused rapid cell death. When the peptidoglycan syntheses of these two strains were examined in the presence of penicillin, the sensitive strain continued to make this cell wall polymer for an extended time, whereas the resistant strain underwent a rapid and marked depression in synthesis. Examination of the labeled sodium dodecyl sulfate-insoluble peptidoglycan made in the presence of inhibitory concentrations of penicillin revealed further differences. The primary effect on the penicillin-sensitive gonococcus was a slight change in peptide cross-linking and a sharp decline in the degree of O-acetylation. In contrast, the resistant strain exhibited a substantial decline in cross-linking, with a very moderate change in O-acetylation. The degree of saturation of the individual penicillin-binding proteins (PBPs) was assessed under these conditions. PBP 2, which exhibits a reduced affinity for penicillin in the resistant strain, appeared to be related to O-acetylation, whereas PBP 1 was implicated in the transpeptidation reaction.

Acetylation↗