Currently, HpD, and its purified versions, porfimer sodium (Photofrin) and dihematoporphyrin ether (Photofrin II) are used for photoirradiation therapy in combination with laser light in the range of 630 to 635 nm. These sensitizers, however, have the profound disadvantage of causing prolonged skin sensitization. Patients treated with these drugs are required to stay out of direct and indirect sunlight for as long as 2 months. Furthermore, damage to normal brain tissue has been reported in preclinical studies3,5,44 and local treatment selectivity may be limited, because these sensitizers appear to participate in edema bulk flow and thus may be transported into brain regions devoid of tumor.34
Recently, we investigated a novel substance, 5-ALA, for use in intraoperative fluorescence-guided resection of malignant gliomas.36–39 The substance 5-ALA is a naturally occurring metabolite in the heme biosynthesis pathway. Excess exogenous 5-ALA leads to accumulation of highly fluorescent heme precursor porphyrins, such as PPIX, in a number of malignant tissues,16,24 including malignant gliomas.36,38,39 Accumulation is highly specific and does not appear to occur in normal brain; however, apart from their strong fluorescence, endogenous porphyrins such as PPIX are also efficient photosensitizers.16,20 In contrast to hematoprophyrin derivatives, side-effects of 5-ALA in patients are negligible and include mild elevation of liver enzymes and a period of skin sensitization limited to fewer than 48 hours.7,19,27,36,39 Consequently, photoirradiation therapy with 5-ALA—induced porphyrins may be a modality worth investigating, especially as an adjuvant treatment after 5-ALA fluorescence-guided resection of malignant gliomas and for direct treatment of residual tumor areas for which the use of conventional surgical techniques may prove too dangerous.
To qualify as a photosensitizer, 5-ALA must fulfill a number of prerequisites. Its accumulation should be specific for malignant glioma tissue. It should not propagate or diffuse with cerebral edema to sensitize adjacent normal brain tissue while exerting sufficient phototoxic effects on tumor tissue.
The present investigation seeks to elucidate whether the photosensitizing effects of 5-ALA—induced porphyrins are sufficient for photoirradiation therapy in an animal model of glioma. Magnetic resonance imaging was used to determine tumor size prior to therapy and to compare it with the extent of phototoxic tumor damage. To determine the degree of unwanted sensitization of perifocal edematous tissue, a brain edema model was used.17,34 This edema model allowed assessment of any damage related to edema alone, thus allowing us to rule out interference from sensitized infiltrating tumor cells. Finally, 5-ALA was compared with a traditional sensitizer, Photofrin II, with regard to unwanted sensitization of normal brain.
We gratefully acknowledge ongoing technical support and advice from Reinhold Baumgartner, Ph.D., and Herbert Stepp, Ph.D., Laser Research Laboratory, Ludwig-Maximilians-University.
This work was supported by grants from the Curt-Bohnewand-Fonds, the K.L. Weigand'sche Stiftung and the Gravenhorst estate to W. Stummer.