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T Hasan

Publications and source records attributed to T Hasan.

At least 73 records · Page 4Linked to original sources
PubMed1996

Spectral characterization of the benzoporphyrin derivative monoacid ring-A photoproduct formed in fetal calf solutions during irradiation with 694 nm continuous-wave radiation.

Benzoporphyrin derivative monoacid ring A (BPD-MA) is a second-generation photosensitizer for photodynamic therapy (PDT) that has shown good results in phase I clinical trials. Similar to other porphyrin derivatives, BPD-MA readily photobleaches during in-vivo PDT treatment. This study investigated the photodegradation of BPD-MA in fetal calf serum (FCS) solutions in vitro. Absorption and fluorescence spectra from dilute solutions of BPD-MA in 10% FCS were recorded before and immediately after irradiation with light at 694 nm. After irradiation, the appearance of a new fluorescence emission band at 650 nm and changes in the fluorescence excitation spectra indicate the formation of a photoproduct. Photoproduct formation was observed only when BPD-MA was bound to FCS and in oxygenated solutions. The spectroscopy of the photoproduct is consistent with the reaction of an oxygen species with the ring B vinyl group, forming a hydroxyaldehyde photoproduct. Monitoring the increase in photoproduct fluorescence during treatment may provide an in-vivo dosimeter to measure PDT efficacy.

Animals↗
PubMed1996

Liposomal benzoporphyrin derivative verteporfin photodynamic therapy. Selective treatment of choroidal neovascularization in monkeys.

PURPOSE: The authors have previously shown that photodynamic therapy (PDT) using lipoprotein-delivered benzoporphyrin derivative mono-acid (BPD) effectively closed experimental choroidal neovascularization (CNV). In the current study, the authors used a clinical preparation, liposomal BPD verteporfin in the same model, with experiments designed to establish optimal dye and light doses, and the timing of laser light irradiation after dye injection, for effective and selective closure of CNV. METHODS: Experimental CNV was induced in the maculae of cynomolgus monkeys. Liposomal BPD verteporfin was injected intravenously at doses of 1.0, 0.5, 0.375, and 0.25 mg/kg. Laser light at 692 nm then was applied to CNV, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2, at various times after dye injection, ranging from 5 to 120 minutes. Treatment effect was assessed by fundus photography and fluorescein angiography and confirmed by light and electron microscopy. The PDT of experimental CNV was studied to assess efficacy; PDT performance on normal eyes was studied to investigate selectivity. RESULTS: The CNV closure was demonstrated by fluorescein angiography and histopathologic findings at all tested dye doses. A dye dose of 0.375 mg/kg, with laser light irradiation applied 20 to 50 minutes after dye injection, optimized CNV closure with minimal retinal and choroidal damage. No major local adverse effects were noted, and the drug was well tolerated systematically. CONCLUSIONS: Liposomal BPD verteporfin is a potent photosensitizer, and PDT using this dye is a potentially effective and selective treatment for CNV.

Animals↗
PubMed1996

Perspectives in cutaneous photodynamic sensitization.

The photodynamic therapy of cutaneous disease is developing more rapidly than that of other organs due to the accessibility of the skin to photosensitizers and light. The use of hematoporphyrin derivative, with its prolonged photosensitivity of normal skin, is gradually being replaced by a new generation of tetrapyrrolic photosensitizers. These are designed to absorb at longer wavelengths for deeper tissue penetration. Many also feature a greatly reduced photosensitizing potential of uninvolved skin. Another major development is the topical and systemic use of aminolevulinic acid for inducing the formation of endogenous porphyrins in cells which result in photosensitivity. This regimen is currently used quite extensively due to the easy availability of both drug and suitable light sources. However, continued investigation of the underlying mechanisms and their regulation will help to improve this specific photodynamic regimen. Currently, researchers use a whole array of therapeutic regimens and schedules for the evaluation of treatment efficacy. A certain uniformity of both treatment parameters and evaluation criteria will help to improve more rapidly our understanding of photodynamic sensitization in skin disease. This will also help us to define the right place and targeting strategies for photodynamic therapy in dermatology.

Hematoporphyrin Derivative↗
PubMed1996

Treatment of ovarian cancer with photodynamic therapy and immunoconjugates in a murine ovarian cancer model.

In photodynamic therapy (PDT), photosensitisers accumulate somewhat preferentially in malignant tissues; photoactivation with appropriate wavelength of light release toxic molecular species which lead to tumour tissue death. In order to target ovarian cancer with increased specificity, a chlorin-based photosensitiser (chlorin e6 monoethylendiamine monoamide) was conjugated to OC125, a monoclonal antibody recognising an antigen expressed in 80% of non-mucinous ovarian cancers. In previous work, this immunoconjugate (IC) was shown to be selectively phototoxic to cancer cells from ovarian cancer patients ex vivo and to localise preferentially in ovarian cancer tissue in vivo. In this study we report results from in vivo phototoxicology and photodynamic treatment studies using this IC in a murine model for ovarian cancer. A comparison of single vs multiple treatments was also made. For in vivo experimentation, Balb C nude mice were injected with 30 x 10(6) NIH:OVCAR 3 cancer cells to create an ascitic tumour model. Animals were then given intraperitoneal injections of the immunoconjugate (0.5 mg kg-1). Twenty-four hours later the intraperitoneal surfaces were exposed to 656 nm light from an argon-ion pumped-dye laser (50 mW, 656 nm), using a cylindrical diffusing tip fibre. The overall treatment was given either once or multiply. No animals died from treatment complications. Twenty-four hours following one and three PDT treatments, the percentage of viable tumour cells in the ascites of the treated animals analysed ex vivo was 34% and 5% of control for one and three treatments respectively. With respect to survival, all control mice (n = 18) died between 30 and 50 days. However, for those treated three times (n = 10), 40% were still alive after 50 days, and for those treated four times (n = 12) 58% were alive after 50 days. Evaluation with log-rank test revealed a significant survival with intraperitoneal PDT compared with controls (P = 0.0006). These preliminary results suggest that PDT with an OC125 immunoconjugate may be an effective therapy for the management of advanced ovarian cancer. Clinical application of this therapy needs to be further optimised and may require multiple treatments, similar to fractionated radiation therapy and cyclic chemotherapy, in order to control malignant disease with acceptable toxicity to normal tissue.

Animals↗
PubMed1996

Photopatch test reactivity: effect of photoallergen concentration and UVA dosaging.

We have studied the influence of variations in allergen concentration and UVA dosaging on the results of photopatch testing with the Scandinavian standard photopatch series in 29 patients with photocontact and/or contact allergy to 1 or several of the allergens in that series. Photocontact test reactions were more sensitive to allergen dilution than plain contact test reactions. Even dilution from the standard 5% to 2.5% significantly reduced para-aminobenzoic acid photocontact test reactions. Reducing the UVA dose from the standard 5 J/cm2 to 2.5 or 1 J/cm2 in 2 out of 5 cases turned a significant (++) reaction into a doubtful one (+). Increasing the standard UVA dose of 5 J/ cm2 to 20-40 J/cm2 turned a single + photocontact reaction to trichlorcarbanilide and a single 1 + plain contact reaction to chlorhexidine into ++ reactions. In the majority of cases, however, neither photocontact nor plain contact test reactions were augemented by UVA doses up to 80 J/cm2. We conclude that a UVA dose of 5 J/cm2 is sufficient for eliciting photocontact allergic test reactions, and that a reduction of either the UVA dose level or the standard allergen concentrations of the Scandinavian photopatch test guidelines may cause loss of significant photocontact test reactions in a proportion of the cases.

4-Aminobenzoic Acid↗
PubMed1996

Benzophenothiazine and benzoporphyrin derivative combination phototherapy effectively eradicates large murine sarcomas.

The tumoricidal effects of photochemotherapy with two photosensitizers, 5-ethylamino-9-diethylaminobenzo[a] phenothiazinium chloride (EtNBS) and benzoporphyrin derivative monoacid ring A (BPD-MA), were evaluated separately and in combination against the EMT-6 fibrosarcoma implanted subcutaneously in BALB/c mice. Animals carrying tumors 8-10 mm in diameter were divided into eight different groups (approximately 20/group) and subjected to various photoirradiation and drug conditions. The tumor response to photodynamic therapy (PDT) was measured as the mean tumor wet weight 2 weeks post-PDT. The combination treatment with 5.25 mg/kg EtNBS and 2.5 mg/kg BPD-MA followed by photoirradiation with 100 J/cm2 at 652 nm and then by 100 J/cm2 at 690 nm resulted in a 95% reduction in the average tumor weights compared to controls (no light, no drugs) with 76% of the mice being tumor free 2 weeks post-PDT. Because treatment with EtNBS or BPD-MA at twice the light dose and drug concentration resulted in either no significant reduction in tumor weights or increased the lethality of treatment, respectively, the data suggest that the enhanced PDT effect observed with the combination of drugs is synergistic rather than additive. Histology of tumors 24 h post-PDT with the combination of drugs showed nearly complete destruction of the tumor mass with little or no damage to the vasculature and no extravasation of red blood cells. There was no damage to the normal skin adjacent to the tumor. Fluorescence microscopy of EMT-6 cells incubated in vitro with the two photosensitizers revealed that they were localized to different intracellular compartments. The fluorescence pattern from frozen tumor tissue slices following the in vivo administration of the photosensitizers indicated a greater intracellular localization for EtNBS vs BPD-MA.

Animals↗
PubMed1995

Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin.

OBJECTIVE: To investigate photodynamic therapy of experimental choroidal neovascularization using benzoporphyrin derivative monoacid (Verteporfin). METHODS: Photodynamic therapy using benzoporphyrin derivative monoacid was investigated in cynomolgus monkeys. Following intravenous injection of benzoporphyrin derivative monoacid (1 to 2 mg/kg) complexed with low-density lipoprotein, the eyes were irradiated with 692-nm light at a fluence of 50 to 150 J/cm2 and irradiance of 150 to 600 mW/cm2. Choroidal neovascularization was documented before photodynamic therapy and closure was demonstrated by fundus photography, fluorescein angiography, and light and electron microscopic examination. RESULTS: Following photodynamic therapy, vessels within choroidal neovascularization were occluded, and there was damage to the choroidal neovascularization endothelium and the subjacent choriocapillaris. Damage to the retinal pigment epithelium and photoreceptors was also observed. CONCLUSION: Photodynamic therapy with lipoprotein-delivered benzoporphyrin derivative monoacid was effective in this animal model of choroidal neovascularization and may be a promising, potentially selective, therapy for choroidal neovascularization.

Animals↗
PubMed1995

In vivo uptake of liposomal benzoporphyrin derivative and photothrombosis in experimental corneal neovascularization.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) has been used successfully to occlude neovascularizations experimentally. We evaluated the vasoocclusive potential of benzoporphyrin derivative (BPD), a new photosensitizer currently in clinical trials. Since liposomally formulated BPD strongly binds to endogenous low density lipoproteins (LDL) after i.v. injection, LDL act as carrier to deliver BPD preferentially to proliferating endothelial cells. STUDY DESIGN/MATERIALS AND METHODS: Corneal neovascularizations in rabbits were used as model. Time-dependent uptake and retention of liposomal BPD were measured in vivo by monitoring the laser-induced fluorescence (LIF). Photothrombosis was induced using a dye laser emitting at 692 nm. RESULTS: A maximal BPD concentration was measured at 60-90 minutes postinjection determining the optimal time interval for treatment. Exposures as low as 10 J/cm2 allowed complete and irreversible neovascular occlusion as documented angiographically. Histology revealed selective endothelial damage, adjacent corneal stroma, or iris vessels, remained intact. Identical results were obtained using BPD directly complexed with LDL suggesting use of a LDL-mediated pathway. CONCLUSION: We suggest BPD-PDT for a selective treatment of neovascular diseases.

Animals↗
PubMed1995

The effects of aggregation, protein binding and cellular incorporation on the photophysical properties of benzoporphyrin derivative monoacid ring A (BPDMA).

Absorption, fluorescence and laser flash photolysis spectroscopies were used to investigate the effects of self-aggregation, binding to human serum albumin and incorporation in cancer cells on the photophysics of benzoporphyrin derivative monoacid ring A (BPDMA). Aggregation of BPDMA has been studied in mixtures of methanol and phosphate-buffered saline (PBS). The extent of aggregation was dependent on dye concentration and solvent composition, becoming particularly marked in mixtures containing less than 30% methanol. A dimerization constant Kd or 9 x 10(6) M-1 was determined by fluorescence experiments for BPDMA in pure PBS. In addition to spectral modifications, aggregation induces a lowering of the fluorescence and intersystem crossing quantum yields. Human serum albumin binds BPDMA with an association constant Kb of 5.2 x 10(5) M-1 in PBS. When bound to HSA, BPDMA displays photophysical properties very similar to the monomer in organic solvents. The molar ratio [HSA]/[BPDMA] corresponding to complete binding of the dye was determined to be approximately 10. Efficient generation of the triplet state of BPDMA was also observed from aqueous cellular suspensions containing incorporated photosensitizer.

Animals↗
PubMed1995

Photoimmunotherapy of human uveal melanoma cells.

To examine whether tumor-reactive monoclonal antibodies can be used to enhance photodestruction of human uveal melanoma cells, we conjugated photosensitizer chlorin e6 monoethylenediamine monoamide (CMA) with a melanoma-reactive monoclonal antibody IG12 and evaluated the effectiveness of this immunoconjugate (IC) in the destruction of OCM431 human uveal melanoma cells in vitro. RPMI1846 melanoma cells do not react with IC and were used as non-target cells. For control, target and non-target cells were treated with IC or light alone. The effects of IC and free CMA in the destruction of melanoma cells were compared. Cell survival was assessed by a colorimetric assay using tetrazolium salt MTT. Target (OCM431) cells preincubated with IC and irradiated with 5-40 J cm-2 showed light dose-dependent decrease in cell survival. At 40 J cm-2, OCM431 cells preincubated with IC showed only 6 +/- 1.4% viability. Under same treatment, non-target (RPMI1846) cells showed much less phototoxicity; cell survival was 54 +/- 2.1%. Treatment with free CMA and light at 40 J cm-2 showed similar phototoxicity to both target and non-target cells, with cell survival being 24.3 +/- 3.5% and 23.7 +/- 1.5%, respectively. These results show that our IC is effective in causing photodestruction of human uveal melanoma cells in vitro. The phototoxicity is selective and more potent than free CMA.

Antibodies, Monoclonal↗
PubMed1995

Biodistribution and phototoxicity of 5-aminolevulinic acid-induced PpIX in an orthotopic rat bladder tumor model.

5-Aminolevulinic acid (ALA) is a precursor of heme biosynthesis. In the penultimate step of this biosynthesis, protoporphyrin IX (PpIX), an effective photosensitizer, is generated. In this study, the biodistribution and photodynamic effect of ALA-induced PpIX were investigated in an orthotopic rat bladder tumor model. A quantitative comparison of PpIX biodistribution by extraction and fluorescence spectroscopy following intravenous and intravesical administration of ALA was made. The tumor to normal bladder wall ratio was 2:1 at 4 hours for both delivery modes. Fluorescence microscopy demonstrated predominantly cellular rather than stromal PpIX fluorescence. Phototoxicity, evaluated 4 hours after ALA administration, was light dose-dependent with the most efficient tumor necrosis being observed upon 150 J/cm.2 of 630 nm. irradiation. These data suggest that optimized photodynamic therapy with ALA-induced PpIX may be an alternative treatment for superficial bladder carcinoma.

Aminolevulinic Acid↗
PubMed1994

Comparison of two routes of photosensitizer administration for photodynamic therapy of bladder cancer.

Photodynamic therapy (PDT) consists in administration of a photosensitizer and subsequent irradiation of the tumor with visible light. Routinely the photosensitizer is given intravenously (i.v.). The goal of our study was to examine whether intravesical (i.b.) instillation of the photosensitizer for PDT of bladder cancer might be feasible. Therefore, the uptake of chlor-aluminum-sulfonated phthalocyanine (CASPc) in bladder, bladder tumor, skin, and muscle in a rat bladder cancer model after i.v. injection and i.b. instillation was compared. The efficacy of PDT after either method of administration was also evaluated. The CASPc concentration in bladder tumor after i.v. injection was approximately 1.5-fold that after i.b. instillation. The ratio of CASPc concentration between bladder tumor and normal bladder was approximately 2:1 after administration by either route. There was no systemic absorption of CASPc after i.b. instillation; hence no systemic side effects are expected. PDT showed similar effects on bladder tumor after either method of administration, but less side effects on normal bladder wall after i.b. instillation. Our results demonstrate that i.b. instillation of CASPc for PDT of superficial bladder cancer seems to have advantages over i.v. injection.

Administration, Intravesical↗
PubMed1994

Vascular targeting in photodynamic occlusion of subretinal vessels.

PURPOSE: To evaluate the potential of photodynamic therapy (PDT) using benzoporphyrin derivative (BPD) for occlusion of subretinal neovascular membranes, the authors studied efficiency and collateral damage of PDT-induced photothrombosis in the rabbit choriocapillary layer. METHOD: Benzoporphyrin derivative, a new photosensitizer, currently in clinical trials for tumor therapy, was used. Low-density lipoprotein served as a carrier to enhance selective targeting of vascular endothelial cells. RESULTS: Complete choriocapillary occlusion was achieved at a BPD dose of 2 mg/kg and a radiant exposure as low as 10 J/cm2. When PDT was performed 3 hours after BPD application, damage to the neural retina was minimal. Only inner photoreceptor segments showed mitochondrial swelling probably secondary to choroidal ischemia. Bruch's membrane remained intact. Retinal pigment epithelium was invariably damaged as seen with other photosensitizers. CONCLUSION: Compared with photocoagulation BPD-PDT allows endothelial-bound intraluminal photothrombosis, sparing important structures such as neural retina and Bruch's membrane. It may thus provide a more selective treatment of juxtafoveal and subfoveal neovascular membranes.

Animals↗
PubMed1994

Photodynamic therapy of experimental choroidal melanoma using lipoprotein-delivered benzoporphyrin.

BACKGROUND: Benzoporphyrin derivative monoacid (BPD) is a new photosensitizer currently undergoing clinical trial for cutaneous malignancies. Compared with the clinically most frequently used sensitizer, Photofrin, BPD may offer higher tumor phototoxicity, better tissue penetration, and absence of significant skin sensitization. Low-density lipoprotein (LDL) carriers heighten efficiency and selectivity of BPD because neovascular and tumor cells express an increased number of LDL receptors. Hence, in addition to the vaso-occlusive effects similar to most other photosensitizers, LDL-BPD also has been shown to cause direct tumor cell damage. METHODS: Benzoporphyrin derivative monoacid was complexed with human LDL and used in photodynamic treatment of choroidal melanomas experimentally induced in eight albino rabbits. Five rabbits served as controls. Three hours after intravenous injection of 2 mg/kg body weight of LDL-BPD, eight tumors were irradiated at 692 nm and 100 J/cm2 via an argon-pumped dye laser coupled into a slit lamp. RESULTS: Angiography and histologic findings showed immediate photothrombosis after disintegration of endothelial membranes. After complete necrosis of tumor cells within 24 hours, a small fibrotic scar slowly developed. No tumor regrowth was noted up to 6 weeks when animals were killed. CONCLUSION: These data suggest that photodynamic treatment with LDL-BPD may be a promising modality for multiple clinical applications, including tumors and neovascularizations II.

Animals↗
PubMed1994

Photodynamic therapy inhibition of experimental intimal hyperplasia: acute and chronic effects.

PURPOSE: Intimal hyperplasia (IH) is a focal arterial problem that still eludes successful therapy. We have previously demonstrated the feasibility of use of photodynamic therapy (PDT) for the acute treatment of experimental IH with light to activate an otherwise biologically inert photosensitizer. The purpose of this study was to determine the acute and long-term effects of PDT inhibition of IH on the artery wall. METHODS: Segmental IH was induced by balloon injury localized to the cervical common carotid artery of 33 rats. The photosensitizer chloroaluminum sulfonated phthalocyanine (5 mg/kg) for the experimental group or saline solution for the control group was administered intravenously. Twenty-four hours later, all instrumented portions of arteries were irradiated at 675 nm to induce cytotoxic injury in the PDT-treated arteries as compared with laser only-treated arteries for controls. Animals were killed at 1, 2, 4, and 16 weeks. RESULTS: There were no untoward side effects in either group. All PDT-treated arteries were devoid of smooth muscle or inflammatory cells in the treated media. There was no evidence of arterial degeneration of PDT-treated arteries. Only three arteries in the PDT group developed IH, whereas it was universal in all controls. In control arteries, immunocytochemistry with bromodeoxyuridine revealed maximal intimal and medial cell proliferation at 1 week, and morphometric analysis demonstrated a maximal IH at 2 weeks. Immunocytochemistry staining for smooth muscle cell actin was positive for the IH in control and when present in PDT-treated arteries, whereas the adventitia of PDT-treated arteries were positive after 2 weeks. Electron microscopy demonstrated early myofibroblast migration to the adventitia, and at 16 weeks occasional myofibroblasts were noted in the media of PDT-treated arteries. There was complete reendothelial cell covering of the intima by 4 weeks. CONCLUSIONS: These in vivo data demonstrate that PDT is an effective local method for the treatment of experimental IH. There is no evidence of significant recurrence of IH or arterial degeneration. Further studies with PDT may provide novel approaches to the understanding and treatment of arterial IH.

Animals↗
PubMed1994

A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin.

5-Aminolaevulinic acid (ALA)-induced porphyrin biosynthesis and phototoxicity in vitro was investigated in five malignant and two normal cell lines. Intracellular protoporphyrin IX (PpIX) content was quantified by extraction and fluorescence spectroscopy. Cellular PpIX content did not always correlate with cell proliferation rate as measured by the doubling times of cell lines. Cellular efflux of PpIX was also investigated. In a bladder carcinoma cell line, the observed rapid efflux was not blocked by verapamil, an inhibitor of the P-glycoprotein efflux pump. These data support the view that cellular PpIX accumulation is a dynamic process that is determined by both the efflux of PpIX from the cells and enzyme activities in the haem biosynthesis pathway. Desferrioxamine (desferal), a modulator of PpIX biosynthesis, enhanced ALA-induced cellular PpIX content significantly in all carcinoma cell lines but not in non-malignant cell lines. The enhanced PpIX cellular accumulation is attributed to inhibition of ferrochelatase activity, the enzyme responsible for the conversion of PpIX to haem. PpIX-mediated cellular photodestruction following irradiation with an argon ion laser at 514.5 nm was determined by the 'MTT assay'. There appeared to be a 'threshold' effect of cellular PpIX content; cells that synthesised less than 140 ng/mg-1 protein exhibited very little phototoxic damage, while cell lines having greater than 140 ng PpIX/mg-1 protein [corrected] exhibited a consistent phototoxic response. Among the cell lines which did undergo phototoxic damage, there was not a strict correlation between PpIX cellular content and ALA-induced phototoxicity. Desferal enhanced the PpIX content and phototoxic effect in the responsive cells. Fluorescence microscopy of the ALA-treated cells revealed marked accumulation of PpIX in mitochondria (rhodamine 123 co-staining). That the primary site of phototoxic damage is also the mitochondria was confirmed by electron micrographs of cells photosensitised with ALA-induced PpIX, which showed swelling of mitochondria within minutes after irradiation while other suborganelles appeared to be unaffected. The repair or further destruction of the mitochondria was fluence and cell-type dependent. The data from this study suggest that the basis of increased ALA-induced PpIX accumulation in tumours is a combination of various aspects of the metabolic process and pharmacokinetics and that the efficacy of photodestruction of malignancy will be determined not only by the rate of PpIX synthesis but also by specific cellular and tissue characteristics.

Aminolevulinic Acid↗
PubMed1994

Photoimmunotherapy and biodistribution with an OC125-chlorin immunoconjugate in an in vivo murine ovarian cancer model.

Photodynamic therapy (PDT) is an experimental approach to the treatment of neoplasms in which photosensitisers (PSs) accumulated in malignant tissues are photoactivated with appropriate wavelengths of light. The target specificity of PSs may be improved by linking them with carrier macromolecules such as monoclonal antibodies (MAbs). OC125 is a murine MAb that recognises the antigen CA 125, which is expressed on 80% of non-mucinous ovarian tumours. A chlorin derivative conjugated to OC125 was shown to be selectively phototoxic to ovarian cancer and other CA 125-positive cells in vitro and ex vivo. We now report in vivo studies using an ascitic Balb/c nude mouse ovarian cancer model. Ascites was induced by intraperitoneal injection of cells from the human ovarian cancer cell line NIH:OVCAR3. Six weeks after injection, when the animals had developed ascites, biodistribution studies were carried out by injecting the immunoconjugate (IC) or free PS intraperitoneally and sacrificing the animals at 3, 6, 12, 24, 48, 72 and 168 h later. The PS was quantitated by extraction and fluorescence spectroscopy. For both the IC and free PS, peak tumour concentrations were reached at 24 h; however, the absolute concentrations for the IC were always higher (2- to 3-fold) than the free PS. Tumour to non-tumour ratios at 24 h for the IC were 6.8 for blood, 6.5 for liver, 7.2 for kidney, 5.7 for skin and 3.5 for intestine. Evaluation of viable tumour cells in ascites following in vivo PDT with a single light exposure demonstrated a dose-dependent relationship with fluence and IC concentration. However, there was significant treatment-related toxicity at all fluences. With multiple low-dose treatments, the percentage of viable tumour cells was also significantly reduced and there were no treatment-related deaths. These data suggest that, while photoimmunotherapy remains promising as a new treatment modality for ovarian cancers, careful quantitative dosimetry of both IC and light may need to be combined with multiple treatments (as with radiation therapy and chemotherapy) to control malignant disease yet maintain acceptable toxicity in vivo.

Animals↗