The use of 5-aminolaevulinic acid (ALA)-induced endogenous photosensitizers is a novel method currently being investigated for PDT [75]. The natural porphyrin, haem, is synthesized in every energy-producing cell and is the prosthetic group for haemoglobin, myoglobin and other haematoproteins.

The rate-limiting step in the synthetic pathway for haem is the conversion of glycine and succinyl coenzyme A to ALA, this step being under a negative feedback control by haem. However, the addition of excess exogenous ALA can bypass this negative feedback, leading to a build-up of protoporphyrin IX, an effective photosensitizer for PDT [76].

As such, ALA has been extensively studied as a prodrug for the endogenous production and accumulation of protoporphyrin IX in diseased tissue, especially in malignancies. The tumour selectivity of ALA is influenced by a number of factors, including increased permeability of abnormal keratin, increased levels of porphobilinogen deaminase, decreased levels of iron and decreased activity of ferrochelatase in the tumour cells. These conditions result in an accumulation of protoporphyrin IX in diseased cells, resulting in selectivity for the target tissue[77].

Marketed by DUSA Pharmaceuticals (Toronto, Canada) under the name Levulan®, ALA is the closest compound to being accepted into the clinic for photodynamic applications, with its New Drug Application (NDA) being almost accepted by the Food and Drug Administration (FDA) for the treatment of actinic keratoses, a common sun-induced precancerous skin lesion.

The company has also announced Phase I/II clinical trials involving Levulan as a treatment for acne, for the removal of unwanted hair, and for the photodetection of bladder cancer. Other clinical trials are under way using ALA as a therapy for non-melanoma skin cancer[78], endometrial ablation[79], late-stage oesophageal cancer, gastrointestinal cancer, Barrett’s oesophagus[80] and psoriasis.

Because of the low molecular weight and polar properties of ALA, it can also be used as a topical PDT agent against a number of dermatological conditions and has been shown to be effective against superficial basal cell carcinomas, Bowen’s disease, erythroplasia of Queyrat, cutaneous T-cell lymphoma and hirsutism.

One of the problems associated with ALA is that it does not penetrate the skin very deeply when used as a topical agent and in an attempt to overcome this, ALA esters are now being examined. PhotoCure AS (Oslo, Norway) is marketing the methyl ALA ester, P1202, and is studying its potential against basal cell carcinomas and other skin lesions together with several conditions that have been shown to be treated effectively by ALA.