RESUMO
Two positional isomers of purpurinimide, 3-[1'-(3-iodobenzyloxyethyl)] purpurin-18-N-hexylimide methyl ester 4, in which the iodobenzyl group is present at the top half of the molecule (position-3), and a 3-(1'-hexyloxyethy)purpurin-18-N-(3-iodo-benzylimide)] methyl ester 5, where the iodobenzyl group is introduced at the bottom half (N-substitued cyclicimide) of the molecule, were derived from chlorophyll-a. The tumor uptake and phototherapeutic abilities of these isomers were compared with the pyropheophorbide analogue 1 (lead compound). These compounds were then converted into the corresponding 124I-labeled PET imaging agents with specific activity >1 Ci/micromol. Among the positional isomers 4 and 5, purpurinimide 5 showed enhanced imaging and therapeutic potential. However, the lead compound 1 derived from pyropheophorbide-a exhibited the best PET imaging and PDT efficacy. For investigating the overall lipophilicity of the molecule, the 3-O-hexyl ether group present at position-3 of purpurinimide 5 was replaced with a methyl ether substituent, and the resulting product 10 showed improved tumor uptake, but due to its significantly higher uptake in the liver, spleen, and other organs, a poor tumor contrast in whole-body tumor imaging was observed.
Assuntos
Antraquinonas/uso terapêutico , Clorofila/uso terapêutico , Iodobenzenos/química , Fotoquimioterapia , Animais , Antraquinonas/química , Antraquinonas/farmacocinética , Clorofila/química , Clorofila/farmacocinética , Clorofila A , Radioisótopos do Iodo/química , Isomerismo , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Tomografia por Emissão de Pósitrons , Distribuição TecidualRESUMO
PURPOSE: In superficial basal cell carcinomas treated with photodynamic therapy with topical delta-aminolevulinic acid, we examined effects of light irradiance on photodynamic efficiency and pain. The rate of singlet-oxygen production depends on the product of irradiance and photosensitizer and oxygen concentrations. High irradiance and/or photosensitizer levels cause inefficient treatment from oxygen depletion in preclinical models. EXPERIMENTAL DESIGN: Self-sensitized photobleaching of protoporphyrin IX (PpIX) fluorescence was used as a surrogate metric for photodynamic dose. We developed instrumentation measuring fluorescence and reflectance from lesions and margins during treatment at 633 nm with various irradiances. When PpIX was 90% bleached, irradiance was increased to 150 mW/cm(2) until 200 J/cm(2) were delivered. Pain was monitored. RESULTS: In 33 superficial basal cell carcinomas in 26 patients, photobleaching efficiency decreased with increasing irradiance above 20 mW/cm(2), consistent with oxygen depletion. Fluences bleaching PpIX fluorescence 80% (D80) were 5.7 +/- 1.6, 4.5 +/- 0.3, 7.5 +/- 0.8, 7.4 +/- 0.3, 12.4 +/- 0.3, and 28.7 +/- 7.1 J/cm(2), respectively, at 10, 20, 40, 50, 60 and 150 mW/cm(2). At 20-150 mW/cm(2), D80 doses required 2.5-3.5 min; times for the total 200 J/cm(2) were 22.2-25.3 min. No significant pain occurred up to 50 mW/cm(2); pain was not significant when irradiance then increased. Clinical responses were comparable to continuous 150 mW/cm(2) treatment. CONCLUSIONS: Photodynamic therapy with topical delta-aminolevulinic acid using approximately 40 mW/cm(2) at 633 nm is photodynamically efficient with minimum pain. Once PpIX is largely photobleached, higher irradiances allow efficient, rapid delivery of additional light. Optimal fluence at a single low irradiance is yet to be determined.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Fotodegradação , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Medição da Dor , Fotoquimioterapia/efeitos adversos , Protoporfirinas/metabolismo , Neoplasias Cutâneas/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: In a recently completed pilot clinical study at Roswell Park Cancer Institute, patients with superficial basal cell carcinoma (sBCC) received topical application of 20% 5-aminolevulinic acid (ALA) and were irradiated with 633 nm light at 10-150 mW cm(-2). Protoporphyrin IX (PpIX) photobleaching in the lesion and the adjacent perilesion normal margin was monitored by fluorescence spectroscopy. In most cases, the rate of bleaching slowed as treatment progressed, leaving a fraction of the PpIX unbleached despite sustained irradiation. To account for this feature, we hypothesized a decrease in blood flow during ALA-photodynamic therapy (PDT) that reduced the rate of oxygen transported to the tissue and therefore attenuated the photobleaching process. We have performed a detailed analysis of this hypothesis. STUDY DESIGN/MATERIALS AND METHODS: We used a comprehensive, previously published mathematical model to simulate the effects of therapy-induced blood flow reduction on the measured PpIX photobleaching. This mathematical model of PDT in vivo incorporates a singlet-oxygen-mediated photobleaching mechanism, dynamic unloading of oxygen from hemoglobin, and provides for blood flow velocity changes. It permits simulation of the in vivo photobleaching of PpIX in this patient population over the full range of irradiances and fluences. RESULTS: The results suggest that the physiological equivalent of discrete blood flow reductions is necessary to simulate successfully the features of the bleaching data over the entire treatment fluence regime. Furthermore, the magnitude of the blood flow changes in the normal tissue margin and lesion for a wide range of irradiances is consistent with a nitric-oxide-mediated mechanism of vasoconstriction. CONCLUSION: A detailed numerical study using a comprehensive PDT dosimetry model is consistent with the hypothesis that the observed trends in the in vivo PpIX photobleaching data from patients may be explained on the basis of therapy-induced blood flow reductions at specific fluences.
Assuntos
Ácido Aminolevulínico/farmacologia , Carcinoma Basocelular/irrigação sanguínea , Fotodegradação , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Neoplasias Cutâneas/irrigação sanguínea , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/terapia , Humanos , Modelos Cardiovasculares , Protoporfirinas/farmacocinética , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos da radiação , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/terapia , Espectrometria de FluorescênciaRESUMO
PURPOSE: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDT efficacy. EXPERIMENTAL DESIGN: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second- and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1 tumor model. RESULTS: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3- to 6-fold in ABCG2+ cells, but not in ABCG2- cells, and enhanced PDT efficacy both in vitro and in vivo. CONCLUSIONS: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Proteínas de Neoplasias/fisiologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/uso terapêutico , Benzamidas , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Terapia Combinada , Humanos , Neoplasias Hipofaríngeas , Mesilato de Imatinib , Fármacos Fotossensibilizantes/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
At similar lipophilicity, compared to the nonfluorinated purpurinimide 11, the corresponding fluorinated analog 8 with a trifluoromethyl substituent at the lower half (position-132) of the molecule showed enhanced photosensitizing efficacy. The structural parameters established in purpurinimides (lambdamax: 700 nm) were successfully translated to the bacteriopurpurin imide system 19 (lambdamax: 792 nm) and within both series, a monotonic relationship between the lipophilicity and the in vivo PDT activity was observed. For preparing water-soluble compounds, the photosensitizers 8 and 19 were converted into the corresponding aminobenzyl-diethylenetriamine pentaacetate conjugates 23 and 26. Acid treatment of purpurinimide 23 produced the corresponding water-soluble analog 24. Bacteriochlorin 26 under acidic or basic conditions mainly gave the decomposition products. At similar in vivo treatment conditions (C3H mice with RIF tumors and BALB-C mice with colon-26 tumors) the water-soluble purpurinimide 24 was found to be more effective than the methyl ester analog 8. These results suggest that besides overall lipophilicity the inherent charge of the photosensitizer also influences the PDT efficacy.
Assuntos
Flúor , Imidas/síntese química , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Imidas/química , Imidas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Rhodobacter sphaeroides/química , Solubilidade , Spirulina/química , Estereoisomerismo , Relação Estrutura-Atividade , ÁguaRESUMO
Aminolevulinic acid photodynamic therapy (ALA-PDT) is an effective and noninvasive therapy for superficial basal cell carcinoma (BCC) and Bowen's disease. It also may have a role in the treatment of nodular BCC and other cutaneous malignancies, including localized cutaneous lymphomas. ALA-PDT offers multiple advantages over traditional treatments, including little to no scarring, excellent cosmetic results, and the ability to treat multiple lesions simultaneously. It is not an effective therapy for aggressive subtypes of BCC or for invasive squamous cell carcinoma. Finally, ALA-PDT may be a useful way to prevent new skin cancers in certain high-risk patients.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Ácido Aminolevulínico/efeitos adversos , Doença de Bowen/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Fotoquimioterapia/efeitos adversosRESUMO
PDT acts as a biological response modifier in addition to directly damaging target cells and their blood supply. The reduced efficacy of PDT in immunosuppressed patients demonstrates the importance of immune mechanisms in this therapy, and transplant recipients require aggressive optimization of direct cytotoxic pathways. However, immunocompetent individuals can benefit from PDT's effects on innate and adaptive immune responses, including the possibility of generating in situ anti-tumor vaccines.
Assuntos
Carcinoma de Células Escamosas/prevenção & controle , Fatores Imunológicos/uso terapêutico , Transplante de Órgãos/efeitos adversos , Fotoquimioterapia , Neoplasias Cutâneas/prevenção & controle , Ácido Aminolevulínico/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Humanos , Imunocompetência , Terapia de Imunossupressão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
The stable bacteriopurpurinimide (788 nm, epsilon: 38,600 in CH2Cl2), obtained by reducing the corresponding unstable Schiff base (803 nm, epsilon: 50,900 in CH2Cl2) that was isolated by reacting bacteriopurpurin methyl ester with 3,5-bis-(trifluoromethyl)benzylamine, produced promising photosensitizing efficacy. 1H NMR, mass spectrometry, and HPLC analyses confirmed the structures of new bacteriopurpurinimides and the metabolic product. The preliminary in vivo photosensitizing efficacy of this stable bacteriopurpurinimide was determined in C3H mice bearing radiation induced fibrosarcoma tumors as a function of variable drug doses. A drug dose of 1.0 micromol/kg and light exposure of 135 J/cm2 (75 mW/cm2; 24 h postinjection) at 796 nm for 30 min produced a 60% long-term tumor cure (3/5 mice were tumor-free on day 90). Colocalization study of the stable bacteriopurpurinimide with MitoTracker Green confirmed some mitochondrial localization. The fluorescein-exclusion assay and histological staining of CD31 confirmed vascular stasis at various time points post-PDT (post photodynamic therapy). The treatment parameters (time for maximum drug uptake and wavelength for light irradiation) were determined by in vivo reflectance spectroscopy.
Assuntos
Bacterioclorofila A/química , Flúor , Imidas/síntese química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Animais , Benzilaminas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Feminino , Fibrossarcoma/tratamento farmacológico , Imidas/farmacologia , Camundongos , Neoplasias Induzidas por Radiação/tratamento farmacológico , Oxirredução , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacocinética , Porfirinas/farmacologia , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/efeitos da radiaçãoRESUMO
PURPOSE: To measure skin photosensitivity in cancer patients infused with the new second-generation photodynamic sensitizer Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a). A major disadvantage of using the clinically approved photosensitizer Photofrin is potentially prolonged and sometimes severe cutaneous phototoxicity. PATIENTS AND METHODS: Forty-eight patients enrolled in Phases 1 and 2 clinical trials underwent two or more exposures to four graded doses (44.4, 66.6, 88.8 or 133.2 J/cm2) of artificial solar-spectrum light (SSL) before and after administration of Photochlor at a dose of 2.5, 3, 4, 5 or 6 mg/m2 . RESULTS: The most severe skin response, experienced by only six of the subjects, was limited to erythema without edema and could only be elicited by exposure to the highest light dose. Conversely, eight subjects had no discernible reaction to SSL at any light dose. For nearly all the patients, the peak skin response was obtained when the interval between sensitizer injection and exposure to SSL was 1 day and, generally, their sensitivity to SSL decreased with increasing sensitizer-light interval. For example, a 2-day sensitizer-SSL interval resulted in less severe reactions than those obtained with the 1-day interval in 79% of the subjects, while 90% of the subjects exposed to SSL 3 days after Photochlor infusion had responses that were less severe than those obtained with either the 1- or 2-day sensitizer-SSL interval. CONCLUSIONS: Photochlor, at clinically effective antitumor doses, causes only mild skin photosensitivity that declines rapidly over a few days.
Assuntos
Éter de Diematoporfirina/efeitos adversos , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Transtornos de Fotossensibilidade/induzido quimicamente , Fármacos Fotossensibilizantes/efeitos adversos , Éter de Diematoporfirina/uso terapêutico , Feminino , Humanos , Masculino , Fármacos Fotossensibilizantes/uso terapêutico , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Raios UltravioletaRESUMO
The effects of an additional keto group on absorption wavelength and the corresponding metal complexes Zn(II), Cu(II) In(III) on singlet oxygen production and photodynamic efficacy were examined among the alkyl ether analogs of pyropheophorbide-a. For the preparation of the desired photosensitizers, the methyl 13(2)-oxo-pyropheophorbide-a obtained by reacting methyl pyropheophorbide-a with aqueous LiOH-THF was converted into a series of alkyl ether analogs. These compounds were evaluated for photophysical properties and in vitro (by means of the MTT assay and intracellular localization in RIF cells) and in vivo (in C3H mice implanted with RIF tumors) photosensitizing efficacy. Among the alkyl ether derivatives, the methyl 3-decyloxyethyl-3-devinyl-13(2)-oxo-pyropheophorbide-a was found to be most effective and the insertion of In(III) into this analog further enhanced its in vitro and in vivo photosensitizing efficacy. Fluorescence microscopy showed that, in contrast to the hexyl and dodecyl ether derivatives of HPPH (which localize in mitochondria and lysosomes, respectively), the diketo-analogs and their In(III) complexes localized in Golgi bodies. The preliminary in vitro and in vivo results suggest that, in both free-base and metalated analogs, the introduction of an additional keto group at the five-member exocyclic ring in pyropheophorbide-a diminishes its photosensitizing efficacy. This may be due to a shift in subcellular localization from mitochondria to the Golgi bodies. The further introduction of In(III) enhances photoactivity, but not by shifting the localization of the photosensitizer.
Assuntos
Fármacos Fotossensibilizantes/química , Animais , Clorofila/análogos & derivados , Complexo de Golgi/metabolismo , Índio , Metais , Camundongos , Camundongos Endogâmicos , Mitocôndrias/metabolismo , Fármacos Fotossensibilizantes/metabolismo , Relação Estrutura-AtividadeRESUMO
PURPOSE: Photodynamic therapy (PDT) is a clinically approved treatment for a variety of solid malignancies. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a potent vascular targeting agent that has been shown to be effective against a variety of experimental rodent tumors and xenografts and is currently undergoing clinical evaluation. We have previously reported that the activity of PDT against transplanted mouse tumors is selectively enhanced by DMXAA. In the present study, we investigated the in vivo tumor vascular responses to the two treatments given alone and in combination. EXPERIMENTAL DESIGN: Vascular responses to (i) four different PDT regimens using the photosensitizer 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) at two different fluences (128 and 48 J/cm(2)) and fluence rates (112 and 14 mW/cm(2)), (ii) 5-aminolevulinic acid (ALA)-sensitized PDT (135 J/cm(2) at 75 mW/cm(2)), (iii) DMXAA at a high (30 mg/kg) and low dose (25 mg/kg), and (iv) the combination of HPPH-PDT (48 J/cm(2) at 112 mW/cm(2)) and low-dose DMXAA were studied in BALB/c mice bearing Colon-26 tumors. RESULTS: PDT-induced changes in vascular permeability, determined using noninvasive magnetic resonance imaging with a macromolecular contrast agent, were regimen dependent and did not predict tumor curability. However, a pattern of increasing (4 hours after treatment) and then decreasing (24 hours after) contrast agent concentrations in tumors, seen after high-dose DMXAA or the combination of PDT and low-dose DMXAA, was associated with long-term cure rates of >70%. This pattern was attributed to an initial increase in vessel permeability followed by substantial endothelial cell damage (CD31 immunohistochemistry) and loss of blood flow (fluorescein exclusion assay). Low dose-rate PDT, regardless of the delivered dose, increased the level of magnetic resonance contrast agent in peritumoral tissue, whereas treatment with either DMXAA alone, or PDT and DMXAA in combination resulted in a more selective tumor vascular response. CONCLUSIONS: The observed temporal and spatial differences in the response of tumor vessels to PDT and DMXAA treatments could provide valuable assistance in the optimization of scheduling when combining these therapies. The combination of PDT and DMXAA provides therapeutically synergistic and selective antitumor activity. Clinical evaluation of this combination is warranted.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Neoplasias Experimentais/tratamento farmacológico , Fotoquimioterapia , Xantonas/farmacologia , Ácido Aminolevulínico/administração & dosagem , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Clorofila/administração & dosagem , Clorofila/análogos & derivados , Terapia Combinada , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Resultado do Tratamento , Xantonas/uso terapêuticoRESUMO
Photodynamic therapy (PDT) is a local treatment of cancers. The principle of PDT is the production of reactive oxygen species, in particular singlet oxygen, by light activation of a photosensitizer introduced into the target cells. The direct photochemical and subsequent redox reactions can lead to cell death. This study sought to identify effects occurring during PDT and some of their consequences in surviving cells. Using epithelial cells in tissue culture and in tumors, several distinct PDT-mediated reactions were found, including global dephosphorylation of proteins, induced phosphorylation of a 71-kDa protein, initiation of cellular stress responses, structural modification and loss of epidermal growth factor receptor, and cross-linking of proteins. Specific covalent cross-linking of nonactivated signal transducer and activator of transcription (STAT)-3, and to a lesser extent of STAT1 and STAT4, correlated with PDT dose. Cross-linked STAT3 was primarily localized to the cytoplasm and failed to bind to DNA. The combination of STAT cross-linking and inactivation of receptor functions rendered PDT-treated cells refractory for at least 24 hours to interleukin-6 and oncostatin M, cytokines known to be elevated at site of tissue damage and inflammation. It is suggested that the loss of responsiveness to these inflammatory cytokines in the PDT-treated field assists tumor cells in evading the growth-suppressive activity of these mediators expected to be present at tissue sites after PDT.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Interleucina-6/antagonistas & inibidores , Fotoquimioterapia , Transativadores/metabolismo , Animais , Células COS , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Citoplasma/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-6/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Ratos , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Fator de Transcrição STAT4 , Transplante HeterólogoRESUMO
Photodynamic therapy (PDT) is a minimally invasive procedure with increasing promise in treatment of malignant and nonmalignant diseases. Most PDT studies have focused on issues of how to enhance the photocytotoxic reaction leading to apoptosis and/or necrosis of targeted tumor cells. However, the reactions of surviving cancer cells, as well as normal host cells, are important elements that contribute to the outcome. Little is known about how these cells at sites of treatment react to inflammatory cytokines and growth factors that are elicited by PDT. To answer this question, we treated several epithelial cancer cell lines and normal epithelial and stromal cells with membrane- and mitochondria-damaging PDT. At different time points after PDT, cells were stimulated with interleukin 6 class cytokines or epidermal growth factor (EGF). Cellular responsiveness was determined by the activation of signaling proteins. We found that within the time period of PDT reaction, both normal and malignant cells lost their responsiveness to the cytokines and growth factor in a PDT dose-dependent manner. Photosensitizers targeted to the plasma membrane or mitochondria had similar effects. The recovery of responsiveness required 48-72 h and was accompanied by resumption of cell proliferation. Although the loss of EGF response could be explained by the immediate degradation of EGF receptor, the loss of cytokine response was only, in part, correlated with a reduction in cytokine receptor proteins. A PDT-mediated reduction of Janus protein tyrosine kinase-1 was also observed in HeLa cells. Our results demonstrate that PDT alters the regulatory capability of normal and tumor cells by lowering the responsiveness to factors that are known to assist in tissue repair and immune response. This effect of PDT has to be considered when predicting outcome of PDT.
Assuntos
Ácido Aminolevulínico/farmacologia , Citocinas/farmacologia , Substâncias de Crescimento/farmacologia , Fotoquimioterapia , Escuridão , Éter de Diematoporfirina/farmacologia , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/fisiologia , Humanos , Cinética , Luz , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores de Citocinas/efeitos dos fármacos , Receptores de Citocinas/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais CultivadasRESUMO
Photodynamic therapy is an effective and often curative treatment for certain solid tumors. The porphyrin-based photosensitizer Photofrin, the only Food and Drug Administration-approved drug for this therapy, suffers from certain disadvantages: its complex chemical nature; retention by skin (leading to protracted cutaneous photosensitivity); and less than optimal photophysical properties. In this study, we examine the population pharmacokinetics and cutaneous phototoxicity of 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-type photosensitizer with more favorable photophysical properties. HPPH plasma concentration-time data were obtained in 25 patients enrolled in Phase I-II clinical trials for the treatment of partially obstructive esophageal carcinoma, high-grade dysplasia associated with Barrett's esophagus, carcinoma of the lung, or multiple basal cell carcinomas. Doses of 3, 4, 5, or 6 mg/m(2) were administered as 1-h i.v. infusions. The pharmacokinetic data for each patient were fitted with a standard two-compartment (biexponential) model with continuous infusion. The model fitting approach was iteratively reweighted nonlinear regression, with weights equal to the reciprocal of the square of the predicted HPPH plasma concentrations. The complete set of data for all 25 patients was then fitted simultaneously with nonlinear mixed effects modeling. Cutaneous phototoxicity responses were determined, as a function of time after HPPH infusion, following exposure to various doses of light from a solar simulator. The estimates of the population mean (variance) for each parameter were as follows: volume of distribution (V(C)), 2.40 liters/m(2) (0.259); steady-state volume (V(SS)), 9.58 liters/m(2) (11.6); systemic clearance (CL), 0.0296 liter/h/m(2) (0.000094); and distributional clearance (CL(D)), 0.144 liter/h/m(2) (0.00166). These parameters were independent of dose. Clearance increased with age. A relative error model was used for the difference in the raw and fitted data, and the overall coefficient of variation estimate across all of the data was 14.5%. The estimated mean population alpha and beta half-lives (95% confidence interval) were 7.77 h (3.46-17.6 h) and 596 h (120-2951 h), respectively. High-performance liquid chromatography analysis of serum showed no circulating HPPH metabolites, and in vitro incubation of HPPH with human liver microsomal preparations resulted in no metabolite or glucuronic acid-HPPH conjugate production. A minimal skin response to the solar simulator was observed, mostly in patients treated with the highest dose of HPPH, 6 mg/m(2). All of the HPPH pharmacokinetic parameters were consistent with a highly lipophilic agent that is concentrated in plasma and is nearly 100% bound to plasma proteins; this was verified by plasma protein binding studies. Whereas low concentrations of HPPH can be detected in plasma several months after a single infusion, no instances of cutaneous photosensitivity have been noted in these patients. In general, HPPH pharmacokinetic profiles are readily predictable from the global population model. This is the first comprehensive human population pharmacokinetic/pharmacodynamic study of a clinical anticancer photodynamic therapy agent.
Assuntos
Clorofila/análogos & derivados , Clorofila/farmacocinética , Neoplasias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/sangue , Esôfago de Barrett/tratamento farmacológico , Esôfago de Barrett/metabolismo , Proteínas Sanguíneas/metabolismo , Carcinoma Basocelular/sangue , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/metabolismo , Clorofila/efeitos adversos , Clorofila/sangue , Clorofila/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/efeitos adversos , Fármacos Fotossensibilizantes/sangue , Fármacos Fotossensibilizantes/uso terapêutico , Pele/efeitos dos fármacos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismoRESUMO
Pyropheophorbides and their metal complexes were synthesized to investigate their applications as nonradioactive peripheral benzodiazepine receptor (PBR) binding probes and photosensitizers for use in photodynamic therapy. They were found to be localized in mitochondria and showed significant binding to PBR. In some cases, the PBR binding values were similar to that for 17 (PK11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)isoquinoline-3-carboxamide). However, no direct correlation between 17 displacement ability and photosensitizing efficacy of photosensitizers was observed.
Assuntos
Índio , Níquel , Compostos Organometálicos/síntese química , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Receptores de GABA-A/metabolismo , Zinco , Animais , Isoquinolinas/farmacologia , Ligantes , Camundongos , Mitocôndrias/metabolismo , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Methyl 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a derivative), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophilic aromatic iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addition to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analogue of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 micromol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (lambda(max) 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.
Assuntos
Clorofila/análogos & derivados , Radioisótopos do Iodo , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/tratamento farmacológico , Fármacos Fotossensibilizantes/síntese química , Animais , Linhagem Celular Tumoral , Clorofila/síntese química , Clorofila/química , Clorofila/farmacologia , Feminino , Fluorescência , Meia-Vida , Camundongos , Camundongos Endogâmicos C3H , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Tomografia por Emissão de Pósitrons , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Distribuição TecidualRESUMO
OBJECTIVE: To report the use of wide-area 5-aminolevulinic acid photodynamic therapy to treat numerous basal cell carcinomas (BCCs) and basaloid follicular hamartomas (BFHs). DESIGN: Report of cases. SETTING: Roswell Park Cancer Institute. Patients Three children with BCCs and BFHs involving 12% to 25% of their body surface areas. Interventions Twenty percent 5-aminolevulinic acid was applied to up to 22% of the body surface for 24 hours under occlusion. A dye laser and a lamp illuminated fields up to 7 cm and 16 cm in diameter, respectively; up to 36 fields were treated per session. MAIN OUTCOME MEASURES: Morbidity, patient response, and light dose-photodynamic therapy response relationship and durability. RESULTS: Morbidity was minimal, with selective phototoxicity and rapid healing. After 4 to 7 sessions, with individual areas receiving 1 to 3 treatments, the patients had 85% to 98% overall clearance and excellent cosmetic outcomes without scarring. For laser treatments, a sigmoidal light dose-response relationship predicted more than 85% initial response rates for light doses 150 J/cm(2) or more. Responses were durable up to 6 years. Conclusion 5-Aminolevulinic acid photodynamic therapy is safe, well tolerated, and effective for extensive areas of diffuse BCCs and BFHs and appears to be the treatment of choice in children.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Hamartoma Múltiplo/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Ácido Aminolevulínico/efeitos adversos , Síndrome do Nevo Basocelular/patologia , Criança , Feminino , Síndrome do Hamartoma Múltiplo/patologia , Humanos , Masculino , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Photodynamic therapy (PDT) is a therapeutic modality involving the use of a photosensitizing agent activated by light to destroy tumor cells. Over the past 25 years, PDT has been shown useful in the treatment of actinic keratoses and certain nonmelanoma skin cancers, such as Bowen's disease and basal cell carcinoma. We review the current data available for PDT with systemic photofrin and topical 5-aminolevulinic acid (ALA). PDT offers many advantages including its non-invasiveness and its ability to treat multiple lesions simultaneously and is, therefore, an interesting alternative for treating certain skin malignancies.
Assuntos
Fotoquimioterapia , Neoplasias Cutâneas/tratamento farmacológico , Ácido Aminolevulínico/uso terapêutico , Doença de Bowen/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Éter de Diematoporfirina/uso terapêutico , Humanos , Ceratose/tratamento farmacológico , Fotoquimioterapia/métodos , Fotoquimioterapia/tendênciasRESUMO
Water soluble, core-modified porphyrins 1-5 bearing 1-4 carboxylic acid groups were prepared and evaluated in vitro as photosensitizers for photodynamic therapy. The 21,23-core-modified porphyrins 1-5 gave band I absorption maxima with lambda(max) of 695-701 nm. The number of carboxylic acid groups in the dithiaporphyrins 1-4 had little effect on either absorption maxima (lambda(max) of 696-701 nm for band I) or quantum yields of singlet oxygen generation [phi((1)O(2)) of 0.74-0.80]. Substituting two Se atoms for S gave a shorter band I absorption maximum (lambda(max) of 695 nm) and a smaller value for the quantum yield for generation of singlet oxygen [phi((1)O(2)) of 0.30]. The phototoxicity of 1-5 was evaluated against R3230AC cells. The phototoxicities of dithiaporphyrin 2, sulfonated thiaporphyrin 30, HPPH, and Photofrin were also evaluated against Colo-26 cells in culture using 4 J cm(-2) of 570-800 nm light. Compound 2 was significantly more phototoxic than sulfonated dithiaporphyrin 30, HPPH, or Photofrin. Cellular uptake was much greater for compounds 1, 2, and 5 relative to compounds 3 and 4. Confocal scanning laser microscopy and double labeling experiments with rhodamine 123 suggested that the mitochondria were an important target for dithiaporphyrins 1 and 2. Inhibition of mitochondrial cytochrome c oxidase activity in whole R3230AC cells was observed in the dark with compounds 1 and 30 and both in the dark and in the light with core-modified porphyrin 2.
Assuntos
Antineoplásicos/síntese química , Ácidos Carboxílicos/síntese química , Clorofila/análogos & derivados , Fármacos Fotossensibilizantes/síntese química , Porfirinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Clorofila/farmacologia , Escuridão , Éter de Diematoporfirina/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Fluorescência , Luz , Camundongos , Microscopia Confocal , Mitocôndrias/enzimologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Ratos , Oxigênio Singlete/química , Solubilidade , Espectrofotometria , Células Tumorais CultivadasRESUMO
In a sequence of reactions, methyl mesopyropheophorbide a, mesochlorin e(6) trimethyl ester, mesochlorin p(6) trimethyl ester, mesopurpurin-18-N-hexylimide methyl ester, and mesopurpurin-18-N-3,5-bis(trifluoromethyl)benzylimide methyl ester were synthesized from chlorophyll-a. These chlorins on reacting with osmium tetraoxide produced the corresponding vic-dihydroxybacteriochlorins. The 8-vinylchlorins obtained by refluxing the related vic-dihydroxybacteriochlorins in o-dichlorobenzene were individually treated with dimethylacetylenedicarboxylate (DMAD) under Diels-Alder reaction conditions. The intermediate adducts on 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) treatment rearranged to the corresponding stable benzobacteriochlorins, exhibiting the longest wavelength absorption in the range of 737 to 805 nm. In preliminary in vitro (RIF tumor cells) and in vivo screening (C3H/HeJ mice bearing RIF tumors), some of these compounds were found to be quite effective. Under similar treatment conditions (drug dose: 5.0 micromol/kg; light dose: 135 J/cm(2), tumors were exposed to light for 30 min at 24 h postinjection), the benzobacteriochlorins containing N-substituted-imide ring system produced enhanced photosensitizing efficacy with limited skin phototoxicity. These compounds were also found to bind to site II of human serum albumin (HSA). However, no correlation between the binding constant values and photosensitizing efficacy was observed. A competitive intracellular localization study of these novel structures with Rhodamine-123 (a mitochondrial probe) indicated their preferential localization in mitochondria, without producing any specific displacement of (3)H-PK11195 (PBR probe, (3)H-labeled 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide). These results suggest that the mitochondrial peripheral benzodiazepine receptor (PBR) is not the cellular binding site for this class of compounds.