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A comparative experimental study of the specific activity of drugs based on 5-aminolevulinic acid (5-ALA) and its hexyl ester (5-ALA HE) was carried out. Their ability to induce the synthesis of photoactive protoporphyrin IX in the healthy tissues of the rabbit bladder when instilling the drug solutions at various concentrations has been estimated. It was shown that 5-ALA HE results in the induction and accumulation of PPIX in the rabbit bladder epithelium at much lower concentrations than 5-ALA. Thus, a significant increase in the fluorescence intensity in comparison with the control was achieved by instillation of 5-ALA HE solution in the rabbit’ bladder at a concentration of only 0.0001% (fluorescence intensity 2.20±0.60 a.u.), and for 5-ALA – only when using a solution at a concentration of 0.3% (fluorescence intensity 2.60±1.02 a.u.).

The use of synthetic lipophilic molecules derived from 5-aminolevulinic acid (ALA) is currently under investigation to enhance cellular ALA penetration. In this work we studied the effect of systemic administration to mice of the hexyl ester of ALA (He-ALA) on porphyrin tissue synthesis as compared to ALA. In most normal tissues as well as in tumour, He-ALA induced less porphyrin synthesis than ALA after its systemic administration either intravenous or intraperitoneal, although explant organ cultures exposed to either ALA or He-ALA revealed equally active esterases. The only tissue that accumulated higher porphyrin levels from He-ALA (seven times more than ALA) was the brain, and this correlated well with a rapid increase in ALA/He-ALA content in brain after administration of He-ALA. This may be ascribed to a differential permeability to lipophilic substances controlled by the blood–brain barrier, a feature which could be further exploited to treat brain tumours. British Journal of Cancer (2002) 87, 790–795. doi:10.1038/sj.bjc.6600559 www.bjcancer.com © 2002 Cancer Research UK

Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)-based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that in mice PpIX is not only produced in the application area but also in other organs including skin outside the application area, whereas esterified ALA does not. From these results, it was concluded that it is not redistribution of circulating PpIX that causes the fluorescence distant from the ALA application site, but rather, local PpIX production induced by circulating ALA. In the present study we investigate the effects of the ALA concentration in the cream, the application time, the presence of a penetration enhancer, the presence of the stratum corneum and esterification of ALA on the PpIX production in nude mouse skin outside the area where ALA is applied. For this purpose, ALA and ALA hexyl ester (ALAHE) were applied to one flank, and the PpIX fluorescence was measured in the contralateral flank. During a 24 h application of ALA, PpIX was produced in the contralateral flank. No PpIX could be detected in the contralateral flank after ALA application times ranging from 1 to 60 min. Tape-stripping the skin prior to short-term ALA application, but not the addition of a penetration enhancer, resulted in PpIX production in the contralateral flank. When ALAHE was applied, no PpIX fluorescence was measured in the contralateral flank under any application condition. The results suggest that the systemic component of PpIX production outside the ALA application area plays a minor or no role in relevant clinical situations, when the duration of ALA (ester) application is relatively short and a penetration enhancer is possibly added.

Summary Background Photodynamic therapy (PDT) using 5-aminolevulinic acid is considered to be ineffective in the treatment of tumors with progression to the deep layer. Therefore, for such tumors, a method is required which can enhance the effectiveness of this therapy. We examined the anti tumor effect of the combination of PDT with 5-aminolevulinic acid hexyl ester (hALA) and hyperthermia (HT) in a squamous cell carcinoma (SCC) tumor model. Methods A tumor model was prepared by subcutaneously implanting SCC into nude mice, and treated with HT, PDT with hALA (hALA-PDT), or hALA-PDT combined with HT (PDT + HT). The treatment was performed by remodeled near infra-red irradiator which allows the generation of two types of rays for PDT and HT. With HT, the tumor was irradiated for raising the temperature with a light dose of 437.5 J/cm 2 . With hALA-PDT, the tumor treated with 250 mg/kg hALA was irradiated with a light dose of 50 J/cm 2 . With PDT + HT, the tumor was treated as for hALA-PDT except that the temperature was raised during irradiation with a light dose of 437.5 J/cm 2 (including light dose of 50 J/cm 2 for PDT). Results The tumor growth rates on Day 12 were 97.10% in HT, 67.55% in hALA-PDT and 33.90% in PDT + HT, and PDT + HT showed significant inhibitory effects on tumor growth, although the anti-tumoral effects of HT and hALA-PDT were not seen. Conclusion hALA-PDT combined with HT demonstrated a significant inhibitory effect on the tumor growth of squamous cell carcinoma showing a progression in the deep layer. This suggests that this therapy is useful for tumors showing progression to the deep layer, which hALA-PDT alone is generally ineffective in treating.