Mechanisms for optimising photodynamic therapy: second-generation photosensitisers in combination with mitomycin C

Geel, I. P. J. van; Oppelaar, Hugo; Oussoren, Y.; Schuitmaker, J. J.; Stewart, F. A.

doi:10.1038/bjc.1995.336

Cited by 37 publications

(35 citation statements)

References 12 publications

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“…The results from this study demonstrated that Foscan PDT was relatively ineffective at controlling the regrowth of H-MESO1 xenografts when illumination was given at intervals of 424 h. This is in agreement with several other studies in rodent tumours and human xenografts grown in nude mice (Ris et al, 1993;Morlet et al, 1995;Van Geel et al, 1995;Veenhuizen et al, 1997a) , but it differs from clinical experience. Standard clinical protocols for Foscan PDT involve illumination with 20 -30 J cm À2 at 4 days after a drug dose of 0.15 mg kg À1 .…”

Section: Discussionsupporting

confidence: 91%

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

et al. 2003

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Clinical photodynamic therapy (PDT) schedules are based on the assumption that optimum drug -light intervals are times at which there is a maximum differential between photosensitiser retention in the tumour and surrounding normal tissue. However, vascularmediated effects contribute to tumour destruction by PDT; therefore, plasma sensitiser levels and endothelial cell drug exposure could also be important determinants of PDT response. The purpose of this study was to investigate the influence of tumour, tissue and plasma concentrations of the photosensitiser Foscan s (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response. Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were injected (i.v.) with a single dose of 14 C-labelled mTHPC, or with two doses, separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured at 5 min to 120 h after drug administration. The PDT tumour and skin responses were evaluated by illuminating separate groups mice at intervals of 5 min to 120 h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin increased during the first 24 h after a single injection, and remained almost constant for at least 120 h. The second injection produced a further, rapid increase in mTHPC levels in tumours and skin, with steady state being maintained from 20 min to 120 h. By contrast, PDT response of both tumours and skin were maximal for illumination at 1 -3 h after drug, with very little response when illumination was given 48 -120 h after drug. There was no significant correlation between tumour or skin drug level and PDT response. There was, however, a significant correlation between plasma drug levels and tumour or skin response, excluding an initial distribution time of 20 min. These studies demonstrate a pronounced disassociation between tumour drug levels and optimum drug -light intervals for PDT response with Foscan. We suggest that the PDT effect, in both tumours and normal tissues, is largely mediated via vascular damage and that the selectivity of PDT is not based on differential tumour drug uptake.

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Section: Discussionsupporting

confidence: 91%

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

et al. 2003

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“…The partial and reversible reduction in tumor perfusion induced by 6 hr-interval PDT, due to the low drug level found in the tumor vasculature at this time, may account for the limited effect on the tumor eradication observed with this PDT regimen. Similar to the observations made with other vasculature-targeting photosensitizers, 19,22,23 our results indicate that, after tumor vasculature damage induced by PDT with hypericin, tumor cells are killed mainly by the resultant oxygen and nutrient deprivation, which leads to the delayed tumor cell death. Indeed, this PDT induced vascular damage can also be found histologically.…”

Section: Type Of Cell Death After Hypericin-mediated Pdtsupporting

confidence: 89%

“…19 Briefly, at various times after PDT, tumors were removed from surrounding normal tissues, weighed and minced under sterile and subdued light conditions. The minced tumor was disaggregated in 5 ml sterile PBS containing 0.05% protease (Sigma Type IX), 0.02% DNase (Sigma Type I) and 0.02% collagenase (Sigma Type IV) under continuous stirring at 37°C for 40 min.…”

Section: In Vivo/in Vitro Cell Survival Assaymentioning

confidence: 99%

“…This experiment allowed us to determine the following 3 parameters: 19 (i) the cell number recovered per g tumor tissue based on the cell counts after tissue digestion; (ii) the plating efficiency of recovered cells determined by the clonogenic assay; and (iii) the viable cells (clonogenic cells) per g tumor tissue obtained from the product of cell number and plating efficiency. Each data point represents the mean of at least 3 experiments (performed in duplicate) and is expressed as relative to untreated control tumors.…”

Section: In Vivo/in Vitro Cell Survival Assaymentioning

confidence: 99%

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Photodynamic therapy with hypericin induces vascular damage and apoptosis in the RIF‐1 mouse tumor model

Chen

Roskams

et al. 2001

Intl Journal of Cancer

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Hypericin, a polycyclic quinone obtained from plants of the genus Hypericum, has been proven to be a potent photosensitizer. The mechanism of tumor eradication and mode of cell death induced by in vivo photodynamic therapy (PDT) with hypericin were investigated in the present study using 2 therapeutic protocols. RIF-1 tumors were exposed to laser light at either 0.5 hr or 6 hr after hypericin administration (5 mg/kg, i.v.). A significant reduction in tumor perfusion, as determined by the retention of fluorescein in the tumor tissue, was detected immediately after both PDT treatments. Further decrease in tumor perfusion was observed in the hours after treatment. The re-establishment of tumor perfusion, however, occurred 24 hr after 6 hr-interval PDT, but not after 0.5 hr-interval PDT. The kinetics of tumor cell survival estimated by the in vivo/in vitro clonogenic assay revealed no or limited cell death when tumors were explanted immediately after irradiation, whereas a delayed but progressive cell death was detected when tumors remained in situ after both PDT treatments. The detection of nucleosomal DNA fragmentation by agarose gel electrophoresis or TUNEL assay and the assessment of cell morphology by light microscopy indicated that apoptosis was the most prominent tumor response to hypericin-mediated PDT. Furthermore, immunohistochemical analysis of the tumor tissue showed an increased expression of both Fas and Fas ligand after irradiation, suggesting that this cell death pathway might contribute to the overall PDT-induced apoptotic response. In conclusion, our results demonstrate that apoptosis, likely occurring as a result of vascular damage, is responsible for the tumor eradication by PDT with hypericin in this tumor model.

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“…Various laboratory investigators have therefore explored the approach of combining bioreductive drugs with photodynamic therapy in order to exploit the PDT-induced hypoxia and enhance the tumoricidal effect of the bioreductive drug (Evensen and Moan, 1988;Gonzalez et al, 1986;Winther et al, 1988;Bremner et al, 1992;Baas et al, 1994;Van Geel et al, 1995). In most cases an advantage was observed for the combination therapy although exact timing of the administration of the bioreductive drug appeared to be important (Evensen and Moan, 1988;Winther et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study

Baas

Geel²,

Oppelaar³

et al. 1996

Br J Cancer

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Summary Photodynamic therapy (PDT) using Photofrin was used in combination with a hypoxic toxin (mitomycin C, MMC) to treat four patients with recurrent skin metastasis of a mammary carcinoma. In precinical experiments an additive effect was found for the combination of MMC and PDT for treating subcutaneous RIFI tumours in mice. When interstitial PDT was combined with a low dose of MMC (administered 15 min before illumination), the Photofrin dose or light dose could be reduced by a factor of 2 in order to obtain equivalent cure rate or growth delay. In the clinical pilot study, a low dose of Photfrin (0.75 mg kg-') was used for PDT alone (superficial illumination) or combined with low-dose MMC (5 mg m-2). Different tumour areas were illuminated with or without a preceding infusion of MMC. Both tumour response and skin photosensitivity were scored. After 8-12 weeks of treatment, tumour cure could be achieved by administering light doses > 150 J cm-2 for PDT alone and similar effects were obtained when light doses of 75-87.5 J cm-2 were given after infusion with MMC. In all cases necrotic tissue of both tumour and surrounding skin was observed, which lasted for a mean of 5 months (range 2-20 months). Skin phototoxicity, tested by using a standardised illumination of skin patches on the back, lasted maximally 3 weeks. Three main conclusions could be drawn from these studies: (1) The enhanced effects of the combination of PDT and MMC observed in mouse tumours can be extrapolated to patients with mammary skin metastasis. (2) The combination of PDT and hypoxic toxins facilitates treatment by permitting lower doses of photosensitiser to be used (thereby reducing skin phototoxicity) or lower light doses (thereby reducing illumination times and allowing the possibility to treat larger tumour areas). (3) Restoration of skin after PDT in previously treated tumour areas (chemotherapy, radiation therapy and surgery) is very slow.

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Mechanisms for optimising photodynamic therapy: second-generation photosensitisers in combination with mitomycin C

Abstract: Summary Mechanisms for improving photodynamic therapy (PDT) were investigated in the murine RIFI tumour using meso-tetrahydroxyphenylchlorin (m-THPC)

Cited by 37 publications

References 12 publications

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

Photodynamic therapy with hypericin induces vascular damage and apoptosis in the RIF‐1 mouse tumor model

Enhancement of photodynamic therapy by mitomycin C: a preclinical and clinical study

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