G. Wagnieres

Selectivity of the photosensitiser Tookad for photodynamic therapy evaluated in the Syrian golden hamster cheek pouch tumour model.

The response to photodynamic therapy (PDT) with the photosensitiser (PS) Tookad® was measured in the Syrian hamster cheek pouch model on normal mucosae and chemically induced squamous cell carcinoma. This PS is a palladium-bacteriopheophorbide presenting absorption peaks at 538 and 762 nm. The light dose, drug dose and drug injection-light irradiation times (DLI), ranging between 100 and 300 J cm−2, 1–5 mg kg−1 and 10–240 min respectively, were varied and the response to PDT was analysed by staging the macroscopic response and by the histological examination of the sections of the irradiated cheek pouch. A fast time decay of the tissular response with drug dose of 1–5 mg kg−1 was observed for DLI ranging from 10 to 240 min and for light doses of 100–300 J cm−2 delivered at a light dose rate of 150 mW cm−2. A significantly higher level of tissular response was observed for squamous cell carcinoma compared to normal tissue. Nevertheless, the threshold level of the drug–light dose for a detectable response was not significantly different in the tumoral vs normal tissue. The highest response at the shortest DLIs and the absence of measurable response at DLI larger than 240 min at light dose of 300 J cm−2 and drug dose of 5 mg kg−1 reveals the predominantly vascular effect of Tookad®. This observation suggests that Tookad® could be effective in PDT of vascularised lesions.

Uptake and localisation of mTHPC (Foscan) and its 14C-labelled form in normal and tumour tissues of the hamster squamous cell carcinoma model: a comparative study.

The aim of this study was to evaluate the pharmacokinetics of meta(tetrahydroxyphenyl)chlorin (mTHPC) on different tissues of interest in a hamster tumour model and to confirm our earlier animal studies on semi-quantitative fluorescence microscopy. The results obtained by three different evaluation methods were compared: in vivo spectrofluorometry, ex vivo fluorescence microscopy and chemical extraction of 14C-labelled mTHPC. Following intracardiac injection of 0.5 mg kg−1 mTHPC, groups of five tumour-bearing animals were used for in situ light-induced fluorescence spectroscopy. Afterwards, the biopsies were taken and snap frozen for fluorescence microscopy. The presence of radioactivity in serum and tissues was determined after chemical digestion in scintillation fluid using a scintillation counter. For each analysed tissue, a good correlation was observed between the three evaluation methods. The highest fluorescence intensity and quantities of mTHPC were observed between 12 and 24 h in liver, kidney, serum, vascular endothelium and advanced neoplasia. The majority of mTHPC was found at around 48 h in smooth muscle and at 96 h in healthy cheek pouch mucosa and early malignant lesions. The lowest level of mTHPC was noted in striated muscle at all times. No selectivity in dye localisation was observed between early squamous cell carcinoma and healthy mucosa. Soon after the injection, a significant selectivity was noted for advanced squamous cell carcinoma as compared to healthy cheek pouch mucosa or striated muscle. A significant difference in mTHPC localisation and quantity was also observed between striated and smooth muscle during the first 48 h following the injection. Finally, this study demonstrated the usefulness of non-invasive in situ spectroscopic measurements to be performed systematically prior to photodynamic therapy as a real-time monitoring for each treated patient in order to individualise and adapt the light dosimetry and avoid over or under treatments.

Preclinical evaluation of a novel water-soluble chlorin E6 derivative (BLC 1010) as photosensitizer for the closure of the neovessels.

Abstract In the present study, photodynamic activity of a novel photosensitizer (PS), Chlorin e6-2.5 N-methyl-d-glucamine (BLC 1010), was evaluated using the chorioallantoic membrane (CAM) as an in vivo model. After intravenous (i.v.) injection of BLC 1010 into the CAM vasculature, the applicability of this drug for photodynamic therapy (PDT) was assessed in terms of fluorescence pharmacokinetics, i.e. leakage from the CAM vessels, and photothrombic activity. The influence of different PDT parameters including drug and light doses on the photodynamic activity of BLC 1010 has been investigated. It was found that, irrespective of drug dose, an identical continuous decrease in fluorescence contrast between the drug inside and outside the blood vessels was observed. The optimal treatment conditions leading to desired vascular damage were obtained by varying drug and light doses. Indeed, observable damage was achieved when irradiation was performed at light doses up to 5 J/cm2 1 min after i.v. injection of drug doses up to 0.5 mg/kg body weight(b.w.). However, when irradiation with light doses of more than 10 J/cm2 was performed 1 min after injection of drug doses up to 2 mg/kg body weight, this led to occlusion of large blood vessels. It has been demonstrated that it is possible to obtain the desired vascular occlusion and stasis with BLC 1010 for different combinations of drug and/or light doses.

Possibilités et limites des traitements endoscopique et photodynamique pour le carcinome épidermoïde précoce des voies aérodigestives supérieures, des bronches et de ľœsophage

RésuméLe traitement photodynamique de 57 carcinomes épidermoïdes superficiels du pharynx [10], des bronches [21] et de ľœsophage [26] a été évalué chez 35 patients porteurs de polylocalisations carcinomateuses synchrones ou métachrones des voies aérodigestives supérieures.Ľirradiation laser a été effectuée 72 heures après injection intraveineuse du dérivé de ľhématoporphyrine (photofrin I ou II: 2 mg/kg ou lmg/kg), à une dose ďirradiation finalement fixée à 80-100 mWatt/cm2 pendant 20 minutes (100/120 joules/cm2) dans le rouge (630 nm) ou dans le vert (514 nm), en fonction du degré ďinfiltration carcinomateuse intra-pariétale.Les résultats obtenus sont bons pour les carcinomes in situ et micro-invasifs des bronches et de ľœsophage (3 récidives sur 37 lésions traitées). Dans le pharynx, où la géométrie est compliquée, et pour les carcinomes sous-muqueux, les résultats sont moins satisfaisants (6 récidives sur 17 lésions traitées). Le suivi des patients est supérieur à 3 ans pour plus de la moitié des cas (extrêmes: 6 à 82 mois).Les 6 complications observées ont eu lieu au début de notre expérience, lors des 29 premiers traitements jusqu’en 1987. Depuis lors, 28 nouvelles lésions ont été traitées sans complications, la maîtrise des doses ďirradiation, du choix de la longueur ďonde et de la quantité ďHpD injectée étant meilleure.SummaryThe photodynamic treatment of 57 squamous cell cancers of the pharynx [10], the bronchi [21] and the oesophagus [26] was assessed on 35 patients with synchronous or metachronous cancerous polylocalisations of the upper aero-digestive tract.Laser irradiation was carried out 72 hours after an intravenous injection of hematoporphyrine derivative (photofrin I or II: 2 mg/kg or 1mg/kg), to a dose of irradiation fixed at 80-100 m Watt/cm2 for a duration of 20 minutes (100/120 joules/cm2) in the red wavelength (630 nm) or in the green wavelength (514 nm), depending on the degree of intra-parietal penetration of the cancer.The tests carried out on the in situ and micro-invasive carcinomas of the bronchi and the oesophagus produced good results (for example, there were three relapses out of 37 treated lesions). However, for submucosal carcinoma and those in the pharynx where the geometry is more complicated, the results were less satisfying (6 relapses out of the 17 lesions that were treated). Patients are monitored for over 3 years in more than half of the cases (in more extreme cases: 6 to 82 months).The six complications observed here took place at the beginning of the experiment at the time of the first treatments up until 1987. Since then, however 28 new lesions have been treated without any further complications. This was due to an overall improvement in irradiation control, the choice of wavelength and the amount of HpD being injected.ResumenEl tratamiento fotodinámico de 57 carcinomas epidermoides superficiales de la faringe (10), de los bronquios (21) y del esófago (26) se han evaluado en 35 pacientes portadores de poli-localizaciones carcinomatosas sincronas o metacronas de las vías aéreo-digestivas superiores.La irradiación laser ha sido efectuada 72 horas después de la inyección intra-venosa de un derivado de la hematoporfirina (fotofrin 1 o 11: 2 mg/kg o 1 mglkg), a una dosis de irradiación finalmente fijada de 80-100 Watt/cm2 durante 20 minutos (100/ 120 joules/cm2) en el rojo (630 nm) o en el verde (514 nm), en función del grado de infiltración carcinomatosa intra-parietal.Los resultados obtenidos son buenos para los carcinomas in situ y microinvasivos de bronquios y del esofago (3 recidivas sobre 37 lesiones tratadas). En la faringe donde la geometría es complicada y para los carcinomas sub-mucosos, los resultados son menos satisfactorios (6 recidivas sobre 17 lesiones tratadas). El seguimiento de los pacientes es superior a 3 años para más de la mitad de los casos (extremos: 6 a 82 meses).Las 6 complicaciones observadas han tenido lugar al comienzo de nuestra experiencia, en los primeros 29 tratamientos hasta 1987. Después, las 28 nuevas lesiones han sido tratadas sin complicaciones; el dominio de las dosis de irradiación, la escogencia de la longitud de onda y de la cantidad de HpD han sido mejores.