Biomedical subjects

Ronald B Moore

Publications and source records attributed to Ronald B Moore.

7 recordsLinked to original sources

PubMed2005

Distribution of photosensitizers in bladder cancer spheroids: implications for intravesical instillation of photosensitizers for photodynamic therapy of bladder cancer.

PURPOSE: Uniform intratumor distribution of sufficient photosensitizer is one of the important aspects of photodynamic therapy for solid tumors. METHODS: Multicellular spheroids derived from a human transitional cell carcinoma cell line (MGHU3) were used as a surrogate system of tiny solid tumors to study intratumor distribution of photosensitizers. Photosensitizers included Photofrin, hypocrellins (HBEA-R1/R2, HBBA-R2), aluminum phthalocyanine chloride (AlPC), benzoporphyrin derivative monoacid ring A (BPD-MA), protoporphyrin-IX (PpIX), and liposomal formulations of HBBA-R2 and BPD-MA. Spheroids were incubated with various doses of the above drugs for 1-4 hours, and were examined by confocal microscopy. RESULTS: Histology showed all cells were healthy in spheroids less than 400 microm in diameter. Scanning electron microscopy showed tight cell-to-cell interdigitation in spheroids. HBEA-R1/R2 distributed more uniformly in spheroids than other drugs. Free hypocrellins and BPD-MA penetrated spheroids centripetally deeper than AlPC, Photofrin, and PpIX. Liposomal HBBA-R2 and BPD-MA penetrated less than their free formulations. CONCLUSIONS: The spheroids mimic solid tumors prior to neovascularization. Based on drug distribution in spheroids, hypocrellins and BPD-MA appear superior to Photofrin, AlPC and PpIX for intravesical administration for bladder cancer phototherapy.

Administration, Intravesical↗

PubMed2004

Light dosimetry for multiple cylindrical diffusing sources for use in photodynamic therapy.

Since prostatic carcinoma is usually multifocal within the prostate, effective photodynamic therapy (PDT) of prostatic carcinoma is expected to require the photochemical destruction of the entire organ. Accurate light dosimetry will be essential to avoid damage to proximal sensitive tissue such as the rectum. The prostate will be illuminated using interstitial cylindrical fibreoptic light sources and, because of the limited transparency of prostate tissue, these sources will be mounted in a parallel array analogous to the source array used in brachytherapy. Both source spacing and the light delivered to each source will control light dosimetry from a parallel array of fibreoptic sources implanted into tissue. Clinical PDT will require dose planning in order to determine the position and illumination of each source prior to treatment, but unfortunately few methods of predicting light fluence from cylindrical interstitial sources currently exist. In this paper, a novel light fluence model is used to predict tissue transillumination resulting from cylindrical interstitial sources. The cylindrical source is modelled as a finite array of infinitesimal small sources using Christian Huygens' famous single-slit diffraction model. We show that this source model when combined with a robust derivation of fluence in a spherical geometry using diffusion theory, accurately predicts fluence levels from a single cylindrical source in a variety of media. This method is found to retain its accuracy near the sources. With a simple extension, this fluence model is used to predict the light fluence levels from an array of three sources and the predicted fluence is found to compare favourably with experimental data.

Diffusion↗

PubMed2004

A novel intravesical therapy for superficial bladder cancer in an orthotopic model: oncolytic reovirus therapy.

PURPOSE: To our knowledge this is the first report of intravesical oncolytic reovirus for therapy of superficial bladder cancer in an orthotopic bladder tumor model. Superficial bladder carcinomas are often multifocal and have high recurrences after surgical resection. In 20% of cases intravesical immunotherapy fails to prevent recurrence and complications from bacillus Calmette-Guerin (BCG) are common. Human reovirus is an oncolytic virus that selectively destroys cancer cells with an activated Ras pathway. We examined the ability of this virus to kill bladder cancer cells in vitro and inhibit tumor growth in vivo. MATERIALS AND METHODS: Following cytotoxicity assays in vitro dose escalation of intravesical reovirus was tested for tumor control and toxicity in a rat model. Treatments were done twice weekly for 3 weeks. In parallel intravesical BCG was studied. Animals were monitored on a daily basis for health status and by routine urine cytology. Animals underwent necropsy at study end point and appropriate tissues were taken for histology. RESULTS: Side effects in reovirus groups were minor compared with BCG complications. Tumor response (animal survival) was 90% 100 days after tumor implantation in reovirus treated animals, whereas the highest survival in BCG treated groups was 50%. Animals treated with reovirus had significantly higher tumor-free survival than those treated with immunotherapy or normal saline (log rank test p = 0.0002 and 0.04, respectively). CONCLUSIONS: Intravesical reovirus is safe and effective in this animal model and it may have clinical applications for bladder cancer treatment.

Animals↗

PubMed2003

Whole bladder photodynamic therapy for orthotopic superficial bladder cancer in rats: a study of intravenous and intravesical administration of photosensitizers.

PURPOSE: Photodynamic therapy after intravenous injection of Photofrin (QLT Phototherapeutics, Vancouver, British Columbia, Canada) results in a contracted bladder and skin photosensitivity, which limits its clinical application. In an attempt to overcome these limitations photodynamic therapy after intravesical instillation of Photofrin or 5-aminolevulinic acid (ALA) in an orthotopic rat bladder tumor model was explored and compared with intravenous Photofrin for photodynamic therapy efficacy and phototoxicity. MATERIALS AND METHODS: At 2 weeks after bladder implantation of 1.5 x 10(6) AY-27 tumor cells animals were randomly grouped. Photofrin was administered (5 mg./kg. intravenously and 2 mg./ml. intravesically). The ALA concentration for intravesical instillation was 300 mM. Whole bladder photodynamic therapy with graded doses of light (lambda = 630 nm.) was performed 4 hours after drug administration. Tumor control and complications were evaluated. RESULTS: Photodynamic therapy with intravenous Photofrin plus 100 J./cm.(2) light resulted in severe bladder damage. Of 10 rats 6 died and 2 of the 10 that received 50 J./cm.(2) died. There were no photodynamic therapy related deaths in groups receiving intravesical instillation of Photofrin or ALA that also received 50 to 100 J./cm.(2) Median survival in rats treated with ALA intravesically plus 75 J./cm.(2) (77 days), Photofrin intravesically plus 50 (67) or 100 J./cm.(2) (76) and Photofrin intravenously plus 50 J./cm.(2) (60) were significantly different from that in controls (44). CONCLUSIONS: Intravesical instillation of Photofrin or ALA can achieve the same photodynamic therapy efficacy as intravenous Photofrin in this orthotopic rat bladder tumor model with less phototoxicity to normal tissues.

Administration, Intravesical↗

PubMed2003

Selective reovirus killing of bladder cancer in a co-culture spheroid model.

Up to 50% of the transitional cell carcinomas (TCC) express an activated EGF pathway involving MAP/MEK and RAF kinase thus providing a novel means to selectively eliminate transformed cells expressing such proteins. This EGF pathway expression phenotype was also confirmed in our MGH-U3 and room temperature-112 human TCC cell lines, which makes them a suitable model target for the reovirus oncolysis. We report here on an in vitro assay of co-culture spheroids using either human or rat TCC cells with their corresponding fibroblasts to examine the potential of viral selective lysis for TCC. Reovirus, a respiratory enteric orphan virus, which mammals are exposed to early in life, was used in this study. Selective killing of transformed versus normal cells was assayed by time-lapse photography, vital dye staining, immunohistochemistry, and MTT assay. In this in vitro bladder cancer model, reovirus selectively destroyed the transformed cells by lysis or induction of apoptosis. Based on these findings we have initiated an in vivo pre-clinical study on intravesical administration of reovirus in an animal model to further explore the effect of reovirus-mediated oncolysis of TCC.

Carcinoma, Transitional Cell↗

PubMed2003

Leiomyosarcoma of the bladder in a retinoblastoma patient.

We report a rare case of leiomyosarcoma in the bladder which occurred in an 18-year-old female with a prior history of retinoblastoma (RB). Molecular characterization of this tumor displayed a homozygous RB deletion and a reduced P53 expression. These results suggest that the loss of RB and P53 may have contributed to the initiation and/or progression of the leiomyosarcoma of the bladder in this patient.

Adolescent↗

PubMed2002

The fluorescence biodistribution and kinetics of aminolevulinic acid induced protoporphyrin IX in the bladder of a rat model with orthotopic urothelial carcinoma.

PURPOSE: Photodynamic therapy is an alternative intravesical therapy modality for superficial bladder cancer. Aminolevulinic acid (ALA) induces the production of the endogenous photosensitizer protoporphyrin IX (PpIX). We compared intravenous versus intravesical administration of ALA and established the proper timing and dose of ALA for photodynamic therapy. To characterize the distribution of ALA in rat bladder tumor and normal bladder layers a cooled charge coupled device camera was used. MATERIALS AND METHODS: A total of 40 female Fisher F344 rats were used as test animals, including 36 inoculated with AY-27 tumor cells intravesically. PpIX accumulation was investigated by fluorescence microscopy comparing 100 and 300 mg./kg. intravenous administration with a 100 mg./ml. intravesical dose of ALA. Three areas of urothelium, submucosa and muscularis of the bladder wall were chosen for analysis. The software used allowed semiquantitative analysis by calculating the mean fluorescence count plus or minus standard error of mean within any chosen area on the fluorescence image. RESULTS: In this study the highest fluorescence difference in PpIX accumulation in tumor and the normal epithelium to the muscularis layer was achieved at 2 hours with intravenous administration (7:1 to 50:1). The highest absolute fluorescence levels were observed at 2 hours with the 100 mg./kg. intravenous dose and at 4 hours with the higher 300 mg./kg. dose. The difference in fluorescence intensity in tumor tissue to normal urothelium was 2:1 to 3:1 at 2 hours. At 4 hours it was less than 2:1. After intravesical administration no difference in PpIX accumulation in tumor and normal urothelium was observed. However, there was a 7:1 ratio in regard to the muscularis layer at 4 hours. CONCLUSIONS: According to the results of this study a difference in PpIX accumulation in urothelial carcinoma or normal urothelium and the muscular layer of the bladder can be achieved by each route of ALA administration. Although intravesical installation provided tumor and normal urothelium labeling comparable to the intravenous route, it lost the selectivity of PpIX accumulation in tumor and normal urothelium. The effect of this finding on clinical therapy results remains to be resolved in the future.

Administration, Intravesical↗