The use of 5-aminolaevulinic acid (ALA)-induced endogenous
photosensitizers is a novel method currently
being investigated for PDT . 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 .
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.
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,
endometrial ablation, late-stage oesophageal cancer,
gastrointestinal cancer, Barrett’s oesophagus 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.