Summary Selective sensitisation of malignant tumours to monochromatic light (photodynamic therapy, PDT) is a promising approach to cancer treatment, but current sensitisers are unsatisfactory and the parameters controlling effects produced in normal and neoplastic tissue are poorly understood. To quantify the effects in a relatively homogeneous organ, we carried out experiments in the livers of normal rats following systemic sensitisation with haematoporphyrin derivative (HpD) and a new sensitiser, a sulphonated aluminium phthalocyanine (AlSPc) using light from an Argon pumped tunable dye laser. Damage from PDT (dominant at lOOmW laser power) could be distinguished from that due to local hyperthermia (dominant at 400mW). For both sensitisers, the extent of PDT necrosis increased with the applied light energy and was abolished by occluding the hepatic blood flow during therapy. With HpD, the extent of PDT necrosis was maximum with only a few hours between sensitisation and therapy, and was not detectable when this interval was increased to a week. With AlSPc, the extent of necrosis in liver changed little with sensitisation times from 1 h to 1000 h (6 weeks), and declined slowly thereafter, matching the amount of AlSPc measurable by alkali extraction, although prolonged photosensitisation was not seen with AlSPc in muscle. Less cutaneous photosensitivity was seen with AlSPc than with HpD. AlSPc is easier to produce and handle than HpD, has a more appropriate strong absorption peak (at 675nm) and from these results, warrants further study as a photosensitiser for PDT.

The colon is protected from disruption and bursting pressures by the submucosal collagen layer. Photodynamic therapy with aluminium sulphonated phthalocyanine (AlSPc) does not cause perforation or reduction in the bursting strength of the rodent colon despite causing full thickness damage. Thermal injury also produces full thickness necrosis but causes perforation and considerably reduces the bursting strength of the colon. The differing mechanisms of damage were examined. Using transmission electron microscopy we examined collagen from undamaged normal rodent colon, colon damaged by photodynamic therapy and thermally injured colon. Following photodynamic therapy collagen maintained its architecture and periodicity. Thermally damaged collagen became grossly swollen and lost its fibrillary architecture. We have concluded that photodynamic therapy with AlSPc is collagen sparing.

Summary Photodynamic therapy (PDT) involves the interaction of light with an administered photosensitising agent to produce cellular destruction. It has promising potential for the local and endoscopic treatment of gastrointestinal cancer. There is however little data on the response of normal intestine to PDT.We have investigated the use of a new photosensitiser chloro aluminium sulphonated phthalocyanine (AlSPc) for colonic PDT. The peak concentration of AISPc in the colon measured by alkali extraction occurred 1 h after i.v. injection. The cellular uptake demonstrated by laser fluorescence microscopy was greater in the mucosa than in the muscle. AlSPc was activated in the tissues by light from an argon ion pumped dye laser at 675nm. The laser power was set at lOOmW and the fibre placed touching the mucosa. In control animals no macroscopic damage was seen. Temperature measurement using a microthermocouple array showed no temperature rise during light exposure. The energy (fluence), dose of sensitiser and time from sensitisation to phototherapy were altered and the area of necrosis measured. The geometry of the colon made theoretical analysis of the correlation between laser energy and size of lesion difficult. However, following direct measurement of the relative light intensity (fluence rate) in the colon we were able to confirm that there was a threshold fluence for colonic necrosis. The area of photodynamic damage seen 72h after phototherapy fell with the fall in tissue concentration of AISPc from I h to 1 month after i.v. injection. However, maximum tissue necrosis occurred when treatment was performed immediately after i.v. injection. In this situation, intense vascular spasm was seen and any light transmitted through the colon which fell on the small bowel mesentery caused a lethal ischaemic necrosis.The initial histological changes after PDT were vascular, followed by full thickness necrosis at 72 h. Healing by regeneration was complete by 2-3 weeks. Despite full thickness necrosis there was no reduction in the colonic bursting pressure at any time. Colon treated by hyperthermia had a reduced bursting pressure. Specific collagen stains showed that PDT did not alter the submucosal collagen architecture whereas hyperthermia did.Photodynamic therapy (PDT) offers the potential of selectively destroying malignant tumours. Several photosensitising agents are retained longer in tumours and rapidly growing tissues than in the surrounding normal tissue. Illumination of the tumour with light of wavelengths absorbed by these agents results in tumour cell destruction (Doiron & Gomer, 1984). In spite of the potential of this technique there are certain disadvantages in the presently most widely used photosensitiser, haematoporphyrin derivative (HpD). It is a complex mixture of porphyrins whose composition varies with differing preparations and time in storage. Efforts have been directed at identifying the active component and it has been variously described as dihaematoporphyrin ether (Dougherty et al., 1984) or...

The most widely discussed aspect of photodynamic therapy (PDT) is the preferential uptake and retention of sensitisers by malignant tissues. The sensitiser usually used is hematoporphyrin derivative (HPD) but this compound is not an ideal photosensitiser for this purpose and we have therefore studied an aluminum sulfonated phthalocyanine (AlSPc) as a possible alternative. Here we have studied the uptake and retention of this compound in a rat colon cancer, a hamster pancreatic cancer and a mouse glioma, using an alkali extraction technique to estimate tissue AlSPc and comparing the results with those from the corresponding normal tissues. All of the tumors studied reached accumulation peaks at 24‐48 h after intravenous administration of AlSPc compared with peaks at 1‐3 h in the normal tissues. The tumors outside the central nervous system (CNS) reached peak tumor : normal tissue ratios of 2‐3 : 1 and the tumor within the CNS, the malignant glioma, reached a far higher ratio of 28 : 1. These ratios are similar to those reported by others using HPD.

Summary Photodynamic therapy (PDT) is a promising approach to the local destruction of malignant tumours, but little work has been done to determine which factors control the extent of tissue necrosis produced. Using a new photosensitiser, a sulphonated aluminium phthalocyanine (AlSPc) and light from an argon ion pumped dye laser at 675 nm, we quantified the effects of interstitial PDT in a transplantable fibrosarcoma in rats. At lOOmW laser power, thermal effects were comparable to those of PDT, so subsequent studies were carried out at 50mW, where thermal effects were minimal. The depth of PDT necrosis increased with the logarithm of the applied energy. Tissue concentration of AlSPc was measured by alkali extraction and at all times after sensitisation, correlated well with the necrosis produced with a given light dose. Peak tumour concentration of AlSPc occurred 24-48h after sensitisation compared with a peak at 3h in muscle. The peak ratio tumour:muscle was 2:1 at 24h. Apart from a different time interval to reach the peak sensitiser concentration, the extent of tumour damage varied with the light and sensitiser parameters in a similar way to that found in normal liver, although the optical penetration depth was greater in the tumour (2.5mm vs. 1.8mm). At doses of AlSPc below 1 mg kg-the diameter of necrosis increased with the logarithm of the dose of sensitiser, and doubling the dose from 0.25 to 0.5 mg kg-increased the depth of necrosis by 50%. However, at higher doses, the changes were smaller and increasing the dose from 2.5 to 5mgkg-1 only increased the necrosis by 10% for the same light dose. In all dose ranges, a given percentage increase in the tissue concentration of AlSPc gave a much smaller percentage increase in the extent of necrosis for the same light dose, suggesting that selectivity of necrosis between tumour and normal tissue is likely to be much less than the selectivity of retention of the photosensitiser. From these results, the extent of PDT necrosis in this fibrosarcoma is as predictable as it is in normal liver if the light dose, tissue concentration of AlSPc and optical penetration depth of the tissue are known. Further studies are now required on different tumour models to establish how tumours respond compared with adjacent normal tissue when the tumour is growing in its organ of origin rather than the non-physiological situation using a transplantable tumour as in this study.