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T J Dougherty

Publications and source records attributed to T J Dougherty.

At least 91 records · Page 5Linked to original sources
PubMed1990

Some components of the tumor-localizing fraction of hematoporphyrin derivative.

In continuation of the effort to delineate the structure of Photofrin, a chromatographically well separated component of the tumor-localizing fraction was isolated and purified using a combination of gel filtration chromatography and semi-preparative high-performance liquid chromatography. This component, the least hydrophobic of the tumor-localizing fraction, was deemed to be dihematoporphyrin ether, based on mass spectrometric analysis and its behavior toward base hydrolysis and lithium aluminum hydride reduction. Although less potent than Photofrin, the purified component was an active photosensitizer.

Animals↗
PubMed1989

Syntheses and photosensitizing activity of porphyrins joined with ester linkages.

In order to investigate the structure of hematoporphyrin derivative and its purified version, Photofrin-II, porphyrin dimers with ester linkage were synthesized. 2,4-Diacetyldeuteroporphyrin dimethyl ester and protoporphyrin IX dimethyl ester were used as starting materials. The methyl esters were replaced by trimethylsilylethyl esters to protect the carboxylic groups. Deprotection using tetra-n-butylammonium fluoride in tetrahydrofuran regenerated the carboxylic functions. Reversed phase high performance liquid chromatography was used to compare the synthetic dimers with components of Photofrin-II. Our data indicate that these dimers are not components of Photofrin-II. During the synthesis of a 13C-labeled dimer with an ester linkage, a small amount of trimer was also isolated. The structures of these compounds were confirmed by nuclear magnetic resonance and mass spectroscopy. Using a standard screening system with DBA/2 mice bearing transplanted SMT-F tumors, these dimers were found not to be as active as Photofrin-II.

Animals↗
PubMed1989

Photodynamic therapy--new approaches.

Photodynamic therapy (PDT) requires a photosensitizer within a target tissue and activation by proper-wavelength radiation at appropriate energy level to achieve complete eradication of that tissue. Whereas the first clinical results were reported nearly a decade ago, only in the past few years has the necessary technology been available for development of phase III controlled clinical trials. Photofrin II, the trade name for a mixture of oligomeric porphyrins, is effective in treatment of a wide variety of malignant tumors and is the subject of Phase III controlled trials in bladder and lung. New photosensitizers are being developed that may be both more efficient and less likely to cause the generalized cutaneous photosensitivity associated with Photofrin II. Further advances in light sources and delivery systems portend an even broader acceptance of PDT in medical and biological science.

Animals↗
PubMed1989

Photodynamic therapy in gynecologic malignancies.

Twenty-one patients with recurrent gynecologic malignancies were treated with photodynamic therapy using Photofrin II and argon dye laser. Seven of twenty-one patients with cutaneous lesions treated palliatively had a complete response and four of eleven patients with cervical and vaginal recurrences had an objective response to phototherapy. Two of the patients with complete response continued to be free of disease after 28 and 36 months of follow-up.

Dihematoporphyrin Ether↗
PubMed1989

Protection of murine foot tissue and transplantable tumor against Photofrin-II-mediated photodynamic sensitization with WR-2721.

Four thiol-containing compounds, WR-2721, WR-149024, WR-168643 and WR-361, were compared as photoprotectors of murine feet. The protector doses were the maximal tolerated intraperitoneal doses, administered 24 h after injection of Photofrin II and 15 min before illumination with 630-nm laser light. While all four compounds were effective, only WR-2721 demonstrated a statistically significant attenuation of phototoxicity. WR-2721 was found to protect SMT-F tumors in the same mouse strain, using tumor growth delay and short-term control as endpoints. A comparison of the dose modification factors for foot and tumor responses indicated no therapeutic advantage in using WR-2721 during photodynamic treatment of these two tissues.

Amifostine↗
PubMed1989

The time course of cutaneous porphyrin photosensitization in the murine ear.

This study was designed to investigate the time course of acute cutaneous photosensitivity following administration of Photofrin II using the murine ear swelling response (ESR) as an in vivo end-point. Ros:(ICR) mice were injected with 5 mg/kg Photofrin II and illuminated 7.5 h to 31 days later with 630-nm laser light; ESR was measured 24 h after illumination. There was a direct correlation between ESR and the concentration of [14C]Photofrin II in blood, while no relationship between ESR and the level of [14C]Photofrin II in the ear tissue of exsanguinated mice was evident. Photosensitivity in the mouse foot can be suppressed by preexposure to low doses of light via a photochemical destruction of tissue-bound sensitizer (Boyle and Potter, 1987, Photochem. Photobiol. 46, 997-1001). However, mouse ears pretreated with 84 J/cm2 of 630-nm light (28 J/cm2/day, given 2, 4 and 6 d after injection), a dose sufficient to reduce porphyrin fluorescence in ear tissue by about 75%, prior to the usual light dose (88.6 J/cm2, 630 nm, day 9 after injection) showed a mean ESR not significantly different (P less than 0.5) from that for ears which received only a single dose of 88.6 J/cm2 on day 9. It is concluded, for this animal model, that circulating porphyrin is the source of photoinduced ear-tissue edema and that photobleaching of tissue-bound sensitizer does not attenuate ear-tissue photosensitivity.

Animals↗
PubMed1989

Distribution and elimination of Photofrin II in mice.

The distribution and elimination of [14C]PII, the radioisotopically-labeled equivalent of the mixture of porphyrins known as Photofrin II used in the photodynamic treatment of solid tumors, were determined in tumor-free and SMT-F tumor-bearing DBA/2 Ha-DD mice. Following i.p. injection, drug was absorbed from the peritoneum with a half-life of about 1 h; elimination from plasma was rapid, declining about 1.4 logs in concentration over 48 h following i.v. administration. However, some [14C]-activity was still detectable after 75 days. Normal tissues take up the drug within about 7.5 h after administration, with peak concentrations distributed as follows: liver, adrenal gland, urinary bladder greater than pancreas, kidney, spleen greater than stomach, bone, lung, heart greater than muscle much greater than brain. Only skeletal muscle, brain, and skin located contralaterally to subcutaneously implanted SMT-F tumors had peak [14C]-activities lower than tumor tissue; skin overlying SMT-F tumors showed concentrations not significantly different (P greater than 0.3) from tumor. After 75 days all tissues examined retained some fraction of [14C]-activity, ranging from 16% for kidney to 61% for spleen, of the initial peak tissue levels. The primary route of elimination of Photofrin II was through the bile-gut pathway, with greater than 59% of the administered [14C]-activity recovered in the feces, and only about 6% in the urine, over 192 h. HPLC analyses of fecal extracts showed that mostly monomeric and other low molecular weight porphyrin components of Photofrin II were eliminated. The higher molecular weight oligomeric fractions of Photofrin II were retained in liver and spleen up to 14 days after injection.

Animals↗
PubMed1989

Activity of cefepime against ceftazidime- and cefotaxime-resistant gram-negative bacteria and its relationship to beta-lactamase levels.

One hundred clinical isolates resistant to ceftazidime and/or cefotaxime were examined for susceptibility to cefepime. The most frequently encountered ceftazidime-cefotaxime-resistant strains belonged to the genera Enterobacter, Pseudomonas, and Citrobacter. Among these strains, 92% were resistant to cefoperazone, 91% were resistant to cefotaxime, 84% were resistant to ceftazidime, and 6% were resistant to cefepime. Of the members of the family Enterobacteriaceae, 57% were resistant to ceftriaxone. The six strains resistant to cefepime were all Pseudomonas aeruginosa and were resistant to both cefotaxime and ceftazidime. Cefepime-resistant P. aeruginosa strains had exceptionally high levels of beta-lactamase activity, higher than the levels found in strains resistant to ceftazidime but susceptible to cefepime. The beta-lactamases from the cefepime-resistant strains were type I (Richmond-Sykes), were constitutively produced, and did not have increased affinity or hydrolytic activity for cefepime. Thus, cefepime was active against most gram-negative bacteria which have developed resistance to the broad-spectrum cephalosporins, and resistance to cefepime in P. aeruginosa appears to be associated with higher beta-lactamase levels than in cefepime-susceptible strains.

Bacterial Infections↗
PubMed1989

Photodynamic therapy: status and potential.

Photodynamic therapy (PDT) uses drugs which, while pharmacologically inactive, can be activated in vivo by visible or near infrared light to produce a local toxic reaction (photosensitizers). Photofrin II (PII) is a mixture of oligomeric porphyrins which accumulate and are retained over several days in all malignant tissue at levels generally higher than surrounding epithelial tissues. Following activation by red light, generally obtained from a laser and delivered by simple quartz fiber optics, PII produces a photochemical generation of cytotoxic singlet oxygen that destroys the tissue in which it resides. Several thousand cancer patients with both early and advanced tumors have been treated to date with encouraging results. Phase III comparative, controlled clinical trials are underway for photodynamic treatment of tumors of the bladder, esophagus, and bronchus.

Clinical Protocols↗
PubMed1988

Intraoperative photodynamic therapy for retroperitoneal sarcomas.

A pilot study was done to determine the feasibility of adjuvant photodynamic therapy (PDT) in recurrent retroperitoneal sarcomas. Ten patients, who had recurrences after conventional methods of treatment, had repeated resections of the tumor and intraoperative photodynamic treatment to the tumor bed. The methods and equipment used are detailed. In eight of ten patients, a complete resection was possible, and two patients are alive without recurrence at 28 and 24 months. There were no complications from the therapy. Tumors elicited red fluorescence, which helped in identifying residual tumor areas. Adjuvant PDT is a feasible alternative although its effectiveness should be evaluated further.

Adult↗
PubMed1988

Study of factors mediating effect of photodynamic therapy on bladder in canine bladder model.

The canine bladder model was employed to study the factors mediating the effect of photodynamic therapy (PDT) on the bladder. The recovery (time taken for the bladder volume to return to pre-PDT value), gross and microscopic findings, implicate both bladder high filling pressure (60 cm H2O) and high light dose as factors mediating the effect of photodynamic therapy on bladder capacity. We recommend that photodynamic therapy to the bladder be performed under a filling pressure of 30 cm H2O, which is physiologic, and whole bladder illumination at a light dose not greater than 30 J/cm2.

Animals↗
PubMed1988

Association between early inhibition of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12.

Quinolone antimicrobial agents are known to interact with DNA gyrase, but the mechanism by which bacterial cell death occurs is not fully understood. In order to determine whether there is a correlation between quinolone-induced inhibition of early (i.e., 10 to 15 min) DNA synthesis and potency (MICs and MBCs), we measured the rate of DNA synthesis in log-phase Escherichia coli K-12 by using [3H]thymidine incorporation. Three quinolones (ciprofloxacin, norfloxacin, and difloxacin) were selected based on their decreasing activity against reference strain KL16. All three quinolones caused an early 50% inhibition of DNA synthesis which was proportional to MICs and MBCs (r greater than 0.99). Furthermore, 50% inhibition of DNA synthesis and MICs were nearly identical for mutant strains with an altered quinolone target (gyrA) or with decreased [nfxB(ompF)] or increased (acrA) permeability. There were significant differences (P less than 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains. The comparison of the three mutants with the wild-type strain permitted an in vivo examination of the effects of alterations of the drug target or entry on the activity determined by DNA synthesis inhibition and MICs.

Anti-Infective Agents↗
PubMed1987

Photodynamic therapy in the management of resistant lower urinary tract carcinoma.

Twenty-three patients with resistant transitional cell carcinoma (TCC) of the bladder and posterior urethra had photodynamic therapy (PDT). Seventy-two hours after an intravenous injection with 2 mg/kg of the photosensitizer dihematoporphyrin ether (DHE) (Photofrin II, Photomedica, Raritan, NJ), each patient received cystoscopic light treatment. The light dose to the whole bladder using the bulb diffuser ranged from 5 to 60 J/cm2; power density ranged from 9 to 22 mW/cm2. The focal light dose ranged from 100 to 200 J/cm2 at a power density from 100 to 200 mW/cm2. To treat the urethra, a diffuser fiber was used to deliver 200 to 400 J/linear cm at a power of 110 to 300 mW/cm. In the 19 of 23 patients who were treated for resistant superficial TCC, 83.3% of the tumors had responded at the initial follow-up evaluation. Seven patients had a complete response and 10 had a partial response. Three of 19 patients who received inadequate light treatment failed to respond. Control of intractable gross hematuria was the only benefit for patients with locally invasive disease (greater than or equal to T2). Irritating lower urinary tract symptoms that varied in severity and duration occurred in all patients. Four patients experienced bladder shrinkage, which did not resolve. Although the light and drug doses remain to be determined, a whole bladder light dose of 15 to 20 J/cm2 with a drug dose of 2 mg/kg seems to be effective enough without producing permanent adverse effects in the bladder.

Aged↗
PubMed1987

Hyperthermic potentiation of photodynamic therapy employing Photofrin I and II: comparison of results using three animal tumor models.

Hyperthermia induced by a microwave source (2,450 MHz) was used alone and in combination with photodynamic therapy (PDT) to treat the SMT-F, EMT-6, and RIF animal tumors in vivo. PDT was administered using either Photofrin I or II as the photosensitizer and an argon-pumped tunable dye laser (630 nm) as the light source. Greater than additive increases in long-term tumor control were achieved when hyperthermia was given immediately post-PDT in the SMT-F and RIF tumor systems. Only additive (or independent) increases in tumor control were achieved when hyperthermia was given immediately before PDT in all these tumor systems and when heat was applied post-PDT using the EMT-6 tumor. In a series of experiments using the SMT-F tumor, it was observed that decreases in PDT drug or light doses could be offset (in terms of tumor control) by the addition of a subsequent heat treatment. This result, along with others presented, indicates the clinical potential of PDT and hyperthermia as adjuvant cancer modalities.

Animals↗
PubMed1987

Characterization of intra-tumoral porphyrin following injection of hematoporphyrin derivative or its purified component.

Photodynamic therapy (PDT) utilizes either hematoporphyrin derivative (Hpd) or a purified form of Hpd termed DHE, as photosensitizers for treatment of a variety of solid tumors in man. The reasons for long retention of these porphyrins in a wide range of histologically diverse tumors remain obscure. We have found that the RIF fibrosarcoma and SMT-F mammary carcinoma in mice, a intrapancreatic tumor in the hamster and a tumor removed from a patient with a myxoid sarcoma, make take up Hpd or DHE by endocytosis. On the other hand the RIF tumor cells in vitro show a tendency for selective uptake and retention of the more hydrophobic components of the mixture.

Animals↗