Photodynamic therapy of a mouse glioma: intracranial tumours are resistant while subcutaneous tumours are sensitive

Abstract

Summary Subcutaneous and intracranial VMDk tumours were treated with photodynamic therapy (PDT) using a new sensitiser, m-THPP. Subcutaneous tumours were highly sensitive to PDT but intracranial tumours were much more resistant, requiring a 30-fold increase in sensitiser dose to produce equivalent levels of necrosis. Resistance of intracerebral tumours was not due to failure of the sensitiser to enter tumours. Necrosis of intracranial tumours was increased when mice breathed 100% oxygen during PDT while subcutaneous tumour necrosis was unaffected.Malignant astrocytic tumours, glioblastoma multiforme and malignant astrocytoma, run a particularly aggressive course; median survival after surgery being less than 1 year (Walker et al., 1980;Salcman, 1980). They do not metastasise and death is most commonly due to local recurrence of the tumour. Therefore, any improvement in local control would be expected to prolong survival. Photodynamic therapy (PDT) was proposed as an adjuvant therapy for the treatment of human brain tumours, after removal of the bulk of the tumour by radical surgery. PDT relies on the fact that certain systemically administered photosensitisers localise in and are retained by tumours (and also normal tissues). Exposure of the tumour to light which activates the photosensitiser leads to rapid necrosis, which is probably due to cell membrane damage by singlet oxygen (Moan et al., 1979). Brain tumours may be good candidates for PDT as photosensitisers so far investigated do not cross the blood brain barrier (BBB), but accumulate in brain tumours, which lack an effective barrier. Thus, administration of a photosensitiser before surgical debulking of the tumour, followed by illumination of the tumour bed to destroy remaining tumour cells, may conceivably eradicate the tumour.Initial applications of PDT to brain tumours in man produced equivocal results (Perria et al., 1980; Laws et al., 1981;McCulloch et al., 1984). Treatment protocols varied widely and, though there were some remissions, rapid tumour regrowth often occurred. Recent trials using more intensive PDT regimens have produced more promising results (Kaye & Morstyn, 1987;Muller & Wilson, 1987;Kaye, 1989), and have stimulated renewed interest in this treatment.Animal experiments have shown that, with the photosensitisers available for clinical use, haematoporphyrin derivative (HpD) and Photofrin II, PDT treatments which produce tumour kill also cause severe cerebral oedema and necrosis of normal brain (Rounds et al., 1982;Bonnett et al., 1984), which is probably due to damage to the endothelium of small blood vessels . Cerebral oedema resulting from PDT has been reported in man (Muller & Wilson, 1987;McCulloch et al., 1984). It has been successfully controlled with intra/post-operative steroids (Kaye & Morstyn, 1987) have therefore used the meta-isomer m-THPP in the treatment of subcutaneously and intracranially transplanted VMDk mouse gliomas (Bradford et al., 1987;Bradford et al., 1989). Further, in view of the evidence for oxygen dependenc...

Temoporfin (Foscan®, 5,10,15,20‐Tetra(m‐hydroxyphenyl)chlorin)—A Second‐generation Photosensitizer†,‡

“…The only significant drawback of these porphyrins was their weak absorption in the area of 630 nm which meant nothing was gained in this regard compared to Photofrin Ò . Nevertheless, a number of in vitro and in vivo tests established the basic PDT properties and advantage of the mTHPP porphyrin (33)(34)(35)(36)(37)(38)(39)(40)(41).…”

Photodynamic therapy of cancer — Challenges of multidrug resistance

“…23 However, the heterogeneity of PS uptake has been demonstrated in various in vitro and in vivo models. 24,25 The mechanisms of resistance to PDT ascribed to the PS may be shared with the general mechanisms of MDR, and are related to altered PS uptake and e®lux rates or altered intracellular tra±cking within cancer cells. 26 …”

Photodynamic Therapy for Malignant Mesothelioma: Preclinical Studies for Optimization of Treatment Protocols¶

“…Despite the lack of evidence for a PDT-induced oxygen deficit in the current studies, tumor response was significantly improved by providing external carbogen and/or nicotinamide at the time of PDT. Other studies using the porphyrin sensitizer meta-tetrahydroxyphenylporphyrin also demonstrated that the response of intracranial mouse gliomas to PDT increased when the mice were given 100% oxygen during treatment (51). Another small preclinical study demonstrated improved tumor response for human rectal-carcinoma xenografts treated with PDT under hyperbaric oxygen (28).…”