RESUMEN

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.

Asunto(s)

Ácido Aminolevulínico/farmacología , Carcinoma Basocelular/irrigación sanguínea , Fotoblanqueo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Neoplasias Cutáneas/irrigación sanguínea , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/terapia , Humanos , Modelos Cardiovasculares , Protoporfirinas/farmacocinética , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de la radiación , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/terapia , Espectrometría de Fluorescencia

RESUMEN

PURPOSE: Numerous preclinical studies have shown that local photodynamic therapy (PDT) of tumors enhances systemic antitumor immunity. However, other than single-case and anecdotal reports, this phenomenon has not been examined following clinical PDT. To determine whether PDT in a clinical setting enhances systemic recognition of tumor cells, we examined whether PDT of basal cell carcinoma resulted in an increased systemic immune response to Hip1, a tumor antigen associated with basal cell carcinoma. EXPERIMENTAL DESIGN: Basal cell carcinoma lesions were either treated with PDT or surgically removed. Blood was collected from patients immediately before or 7 to 10 days following treatment. Peripheral blood leukocytes were isolated from HLA-A2-expressing patients and reactivity to a HLA-A2-restricted Hip1 peptide was measured by INF-gamma ELISpot assay. RESULTS: Immune recognition of Hip1 increased in patients whose basal cell carcinoma lesions were treated with PDT. This increase in reactivity was significantly greater than reactivity observed in patients whose lesions were surgically removed. Patients with superficial lesions exhibited greater enhancement of reactivity compared with patients with nodular lesions. Immune reactivity following PDT was inversely correlated with treatment area and light dose. CONCLUSIONS: These findings show for the first time that local tumor PDT can enhance systemic immune responses to tumors in patients, and validate previous preclinical findings.

Asunto(s)

Antígenos de Neoplasias/inmunología , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/inmunología , Inmunidad Celular/fisiología , Fotoquimioterapia , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Niño , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Mapeo Epitopo , Femenino , Antígeno HLA-A2/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Unión Proteica/inmunología , Regulación hacia Arriba/inmunología , Adulto Joven

Asunto(s)

Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Carcinoma de Células de Merkel/patología , Humanos , Neoplasias Cutáneas/patología

RESUMEN

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.

Asunto(s)

Antraquinonas/uso terapéutico , Clorofila/uso terapéutico , Yodobencenos/química , Fotoquimioterapia , Animales , Antraquinonas/química , Antraquinonas/farmacocinética , Clorofila/química , Clorofila/farmacocinética , Clorofila A , Radioisótopos de Yodo/química , Isomerismo , Ratones , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Tomografía de Emisión de Positrones , Distribución Tisular

RESUMEN

BACKGROUND: Data suggest that photodynamic therapy using topical methyl aminolevulinate (MAL PDT) may be a noninvasive alternative to excisional surgery for nodular basal cell carcinoma (BCC). In the studies described here, we investigated the histologic response, tolerability, and cosmetic outcome with MAL PDT for primary nodular BCC (or= 50% reduction in greatest diameter) at 3 months were re-treated (21%). Treatment sites were excised at 3 months (clinical nonresponders) or 6 months (clinical responders) after the last treatment. RESULTS: Histologically verified lesion complete response rates were higher with MAL PDT than with placebo [73% (55/75) vs. 27% (20/75)]. Treatment was most effective for facial lesions (89% complete response). Cosmetic outcome was good or excellent in 98% of evaluable, completely responding lesions treated with MAL PDT. CONCLUSION: Although longer follow-up studies are required, these promising data indicate the potential of topical MAL PDT as a noninvasive treatment alternative for nodular BCC.

Asunto(s)

Ácido Aminolevulínico/análogos & derivados , Carcinoma Basocelular/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Ácido Aminolevulínico/efectos adversos , Ácido Aminolevulínico/uso terapéutico , Carcinoma Basocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/efectos adversos , Estudios Prospectivos , Neoplasias Cutáneas/patología , Resultado del Tratamiento

RESUMEN

In our present study, 3-(1(')-m-iodobenzyloxyethyl)pyropheophorbide-a methyl ester 1, 3-(1'-m-iodobenzyloxyethyl)-17(2)-{(2-deoxy)glucose}pyropheophorbide-a 2, and 3-(1'-m-iodobenzyloxyethyl)-17(2)-{(1-deoxy)galactose}pyropheophorbide-a 3 were synthesized and converted into the corresponding (124)I-labeled analogues by reacting the intermediate trimethyltin analogues with Na(124)I. Photosensitizers 1-3 were evaluated for the PDT efficacy in C3H mice bearing RIF tumors at variable doses and showed a significant long-term tumor cure. Among the compounds investigated, the non-carbohydrate analogue 1 was most effective. These results were in contrast to the in vitro data, where compared to the parent analogue the corresponding galactose and glucose derivatives showed enhanced cell kill. Among the corresponding (124)I-labeled analogues, excellent tumor images were obtained from compound 1 in both tumor models (RIF and Colon-26) and the best tumor contrast was observed at 72 h after injection. Conjugating a glucose moiety to photosensitizer 1 initially diminished its tumor uptake, whereas with time the corresponding galactose analogue showed improved tumor contrast.

Asunto(s)

Clorofila/análogos & derivados , Galactosa/química , Glucosa/química , Radioisótopos de Yodo/uso terapéutico , Fotoquimioterapia , Tomografía de Emisión de Positrones/métodos , Animales , Clorofila/química , Clorofila/farmacocinética , Clorofila/uso terapéutico , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Espectrofotometría Ultravioleta , Distribución Tisular

RESUMEN

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.

Asunto(s)

Ácido Aminolevulínico/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Fotoblanqueo , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Dimensión del Dolor , Fotoquimioterapia/efectos adversos , Protoporfirinas/metabolismo , Neoplasias Cutáneas/fisiopatología

RESUMEN

The photophysical, electrochemical and spectroscopic characteristics of a conjugate of 3-devinyl-3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) and a cyanine dye have been investigated both as a linked conjugate and as individual components. A photoexcitation of the HPPH moiety of the conjugate results in electron transfer from the singlet excited state of HPPH (1HPPH*) to the cyanine dye as well as that from the cyanine dye to 1HPPH* and is followed in both cases by facile back electron transfer to the ground state as indicated by time-resolved fluorescence and transient absorption measurements. Intersystem crossing to the triplet excited state (3HPPH*) competes with the electron transfer and 3HPPH* is quenched by oxygen to produce singlet oxygen (1O2), leading to specific covalent cross-linking of the nonactivated signal transducer and activator of transcription (STAT-3). In contrast to excitation of the HPPH moiety, photoexcitation of the cyanine dye unit results in a strong emission at 875 nm, which can be used for efficient tumor imaging. Compared to HPPH alone, the presence of the cyanine dye moiety in the conjugate produces a significantly higher uptake in tumors than in skin. Thus, the HPPH-cyanine dye conjugate can be used as a dual tumor imaging and photodynamic therapy agent.

Asunto(s)

Reactivos de Enlaces Cruzados/química , Fotoquimioterapia/métodos , Factor de Transcripción STAT3/química , Animales , Carbocianinas/química , Carbocianinas/farmacología , Clorofila/análogos & derivados , Clorofila/química , Clorofila/farmacología , Electroquímica , Fluorescencia , Glioma/diagnóstico , Glioma/tratamiento farmacológico , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Oxidación-Reducción , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Oxígeno Singlete/química

RESUMEN

We report a novel nanoformulation of a photosensitizer (PS), for photodynamic therapy (PDT) of cancer, where the PS molecules are covalently incorporated into organically modified silica (ORMOSIL) nanoparticles. We found that the covalently incorporated PS molecules retained their spectroscopic and functional properties and could robustly generate cytotoxic singlet oxygen molecules upon photoirradiation. The synthesized nanoparticles are of ultralow size ( approximately 20 nm) and are highly monodispersed and stable in aqueous suspension. The advantage offered by this covalently linked nanofabrication is that the drug is not released during systemic circulation, which is often a problem with physical encapsulation. These nanoparticles are also avidly uptaken by tumor cells in vitro and demonstrate phototoxic action, thereby highlighting their potential in diagnosis and PDT of cancer.

Asunto(s)

Portadores de Fármacos/química , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Dióxido de Silicio/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalización/métodos , Composición de Medicamentos/métodos , Humanos , Ensayo de Materiales , Conformación Molecular , Nanopartículas/ultraestructura , Nanotecnología/métodos , Compuestos Orgánicos/química , Tamaño de la Partícula , Fármacos Fotosensibilizantes/química

Asunto(s)

Carcinoma Basocelular/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Cutáneas/terapia , Carcinoma Basocelular/etiología , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Legrado , Desecación , Progresión de la Enfermedad , Humanos , Terapia de Inmunosupresión/efectos adversos , Periodo Intraoperatorio , Cirugía de Mohs , Ácidos Polimetacrílicos/uso terapéutico , Radioterapia/efectos adversos , Recurrencia , Factores de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Quistes de Tarlov/patología

RESUMEN

Photodynamic therapy (PDT) involves the administration of a photosensitizing drug and its subsequent activation by light at wavelengths matching the absorption spectrum of the photosensitizer. Because the skin is readily accessible to light-based therapies, PDT with systemic and particularly with topical agents has become important in treating cutaneous disorders. Topical PDT is indicated for treating actinic keratosis, superficial or thin non-melanoma skin cancer, including some cases of nodular basal cell carcinoma, and some cutaneous lymphomas. Advantages of aminolevulinic acid/methyl aminolevulinate PDT include the possibility of simultaneous treatment of multiple tumors and large surface areas, good cosmesis, and minimal morbidity, such as bleeding, scarring, or infection.

Asunto(s)

Carcinoma Basocelular/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Fotoquimioterapia/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Enfermedad de Bowen/tratamiento farmacológico , Humanos , Queratosis/tratamiento farmacológico , Luz , Linfoma de Células B/tratamiento farmacológico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico

Asunto(s)

Dermatofibrosarcoma/terapia , Neoplasias Cutáneas/terapia , Dermatofibrosarcoma/diagnóstico , Dermatofibrosarcoma/patología , Progresión de la Enfermedad , Humanos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología

RESUMEN

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.

Asunto(s)

Transportadoras de Casetes de Unión a ATP/fisiología , Proteínas de Neoplasias/fisiología , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antineoplásicos/uso terapéutico , Benzamidas , Carcinoma de Células Escamosas , Línea Celular Tumoral , Terapia Combinada , Humanos , Neoplasias Hipofaríngeas , Mesilato de Imatinib , Fármacos Fotosensibilizantes/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores

RESUMEN

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.

Asunto(s)

Flúor , Imidas/síntesis química , Fármacos Fotosensibilizantes/síntesis química , Porfirinas/síntesis química , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Imidas/química , Imidas/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Porfirinas/química , Porfirinas/farmacología , Rhodobacter sphaeroides/química , Solubilidad , Spirulina/química , Estereoisomerismo , Relación Estructura-Actividad , Agua

RESUMEN

A lactose moiety was regioselectively introduced at various positions of N-hexyl-mesopurpurinimide (a class of chlorin containing a fused six-membered imide ring system, lambda(max): 700 nm) to investigate the effect of its presence and position on photosensitizing efficacy. The resulting novel structures produced a significant difference in in vitro and in vivo efficacy. Among the positional isomers in which the lactose moiety was introduced at positions 3, 8, and 12, the 3-lactose purpurin-18-N-hexylimide produced the best efficacy. Compared to these analogues, the lactose moiety joined with an amide bond at position 17(2), and with an N-benzyl group bearing a -C[triple bond]C- linkage at position 13(2) showed reduced in vitro/in vivo photosensitivity. A noticeable difference between lactose conjugates in cell uptake (RIF tumor cells) was observed at 3 and 24 h postincubation. Replacing the lactose (Galbeta1 --> 4Glc) with beta-galactose and glucose moieties at position 3 of purpurinimide produced an increase in both cell uptake and in in vitro efficacy, but with reduced in vivo efficacy. Sites of intracellular localization differed among photosensitizers with and without carbohydrate moieties. Molecular modeling shows favorable interactions of 3- and 12-lactose-purpurinimide analogues with both galectin-1 and galectin-3, but clear contributions were not found for the conjugate containing lactose moiety at position 8. In a comparative ELISA study of the lactose conjugates with free lactose, all carbohydrate-purpurinimides showed binding to both galectins with a significant variation between the batches of galectins.

Asunto(s)

Carbohidratos/química , Carbohidratos/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Porfirinas/química , Porfirinas/farmacología , Animales , Transporte Biológico Activo , Carbohidratos/farmacocinética , Línea Celular Tumoral , Galectinas/química , Galectinas/metabolismo , Humanos , Técnicas In Vitro , Ratones , Ratones Endogámicos C3H , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Porfirinas/farmacocinética

RESUMEN

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.

Asunto(s)

Ácido Aminolevulínico/uso terapéutico , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Ácido Aminolevulínico/efectos adversos , Enfermedad de Bowen/tratamiento farmacológico , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Humanos , Fotoquimioterapia/efectos adversos

Asunto(s)

Carcinoma de Células de Merkel/terapia , Neoplasias Cutáneas/terapia , Algoritmos , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/radioterapia , Carcinoma de Células de Merkel/cirugía , Estudios de Seguimiento , Humanos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/radioterapia , Neoplasias Cutáneas/cirugía

RESUMEN

BACKGROUND AND OBJECTIVES: While basal cell carcinoma (BCC) is effectively treated by several methods, many patients with numerous or frequently occurring lesions seek alternatives that can treat multiple cancers, with improved cosmetic outcome. PDT for esophageal and lung carcinomas is approved at a porfimer sodium (Photofrin) dose of 2 mg/kg, but lower doses increase selectivity and decrease both cutaneous phototoxicity and cost. We evaluated low doses of porfimer sodium PDT for treatment of multiple BCC. MATERIALS AND METHODS: Seventy-seven patients with 2,041 BCC were injected with 0.75, 0.875, or 1.0 mg/kg porfimer sodium and treated 2 days later with 630-nm light. Clinical responses were determined at 6 months, then periodically to 5 years. RESULTS: Increasing porfimer sodium dose increased complete responses (CR), with initial CR rates of 72.7% (66-78%, 95% CI), 79.9% (73-86%, 95% CI), and 92.2% (91-93%, 95% CI), albeit with some lower selectivity at the highest dose. At 1 mg/kg, 5-year recurrence rates were 28% (21-35%, 95% CI) and 15% (11-18%, 95% CI) for sporadic and nevoid basal cell carcinoma syndrome (NBCCS) lesions, respectively. CONCLUSIONS: This is the largest dose-ranging study of porfimer sodium, and the largest number of lesions treated in a single study. We found that with 1 mg/kg porfimer sodium, PDT can be a selective and durable treatment for sporadic and NBCCS-associated BCC.

Asunto(s)

Carcinoma Basocelular/tratamiento farmacológico , Éter de Dihematoporfirina/administración & dosificación , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Resultado del Tratamiento

RESUMEN

The purpose of this review is to call attention in the use of chlorophyll-a and bacteriochlorophyll-a to develop more than 600 photosensitizers (lambda (max) 660 nm-800 nm) during the last 15 years (1990-2005) at the Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo. This article mainly includes the chemistry, preclinical results, and brief clinical data of some of the most effective photosensitizers. The utility of the tumor-avid photosensitizers in developing multimodality agents (imaging and therapy) is also presented.

Asunto(s)

Diagnóstico por Imagen , Neoplasias/patología , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Bacterioclorofila A/química , Bacterioclorofila A/farmacología , Clorofila/química , Clorofila/farmacología , Fulerenos , Humanos , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología

RESUMEN

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. STUDY DESIGN/MATERIALS AND METHODS: Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. RESULTS: Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. CONCLUSION: We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted.

Asunto(s)

Ácido Aminolevulínico/farmacocinética , Éter de Dihematoporfirina/farmacocinética , Fármacos Fotosensibilizantes/farmacocinética , Administración Tópica , Ácido Aminolevulínico/análisis , Clorofila/análogos & derivados , Clorofila/farmacocinética , Éter de Dihematoporfirina/análisis , Fluorometría , Semivida , Humanos , Infusiones Intravenosas , Neoplasias/química , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/análisis