Topical protoporphyrin IX (PPIX) induced photodynamic therapy (PDT) of basal cell carcinoma (BCC) produces good
clinical outcomes with excellent cosmesis as long as the disease remains superficial. Efficacy for nodular BCC however
appears inferior to standard treatment unless repeat treatments are performed. Enhancement is therefore required and is
possible by employing iron chelating agents to temporarily increase PPIX accumulation above the levels normally
obtained using aminolevulinic acid (ALA) or the methyl ester of ALA (MAL) alone. In vitro studies investigated the
effect of the novel iron chelator, CP94 on necrotic or apoptotic cell death in cultured human skin fibroblasts and
epidermal carcinoma cells incubated with MAL. Furthermore, following a dose escalating safety study conducted with
ALA in patients, an additional twelve nodular BCCs were recruited for topical treatment with standard MAL-PDT +/-
increasing doses of CP94. Six weeks later following clinical assessment, the whole treatment site was excised for
histological analysis. CP94 produced greater cell death in vitro when administered in conjunction with MAL than this
porphyrin precursor could produce when administered alone. Clinically, PDT treatment using Metvix + CP94 was a
simple and safe modification associated with a trend of reduced tumor thickness with increasing CP94 dose.
Photodynamic therapy (PDT) using porphyrin precursors is commonly used in dermatology. Evidence indicates that
good clinical outcomes (associated with excellent cosmesis) can be achieved in superficial precancers and basal cell
carcinoma (BCC), however, efficacy appears less favorable for thicker nodular BCC (nBCC) unless multiple PDT
treatment cycles are performed. Enhancement is therefore required if nBCC lesions are to be treated effectively with a
single PDT treatment. The most common technique currently being routinely employed clinically is the use of
aminolevulinic acid (ALA) esters (usually methyl (MAL) or hexyl (HAL)). Standard dermatological PDT employing
these porphyrin precursors already manipulates the normal heme biosynthesis pathway resulting in a temporary
accumulation of the natural photosensitizer, protoporphyrin IX (PpIX). Further manipulation using iron chelating agents
is possible however. In normal and malignant human cells in vitro, the novel iron chelating agent CP94 produced greater
PPIX fluorescence when administered with ALA or MAL than either congener produced alone. CP94 was also
significantly more effective than the clinically established iron chelating agent desferrioxamine (DFO). Topical
application of ALA+CP94 to clinical nBCC lesions was a simple and safe treatment modification which produced a
significant increase in clinical clearance when CP94 was included in the cream.
This study employed a commercially available, non-invasive, fluorescence imaging system (Dyaderm, Biocam,
Germany), to measure protoporphyrin IX (PpIX) concentration at several different stages during clinical dermatological
methyl aminolevulinate photodynamic therapy (MAL-PDT). We validated the system prior to use to ensure that the
PpIX changes witnessed were accurate and not due to environmental or user induced artifacts. The system was then
employed to acquire color (morphological) and fluorescent (physiological) images simultaneously during dermatological
PDT. Clinical data was collected from a range of licensed dermatological conditions (actinic keratosis, Bowen's disease
and superficial basal cell carcinoma) during initial and subsequent PDT treatment cycles. The initial clinical data
indicated that each type of licensed lesion considered responded in a similar manner following the application of
Metvix (Galderma, U.K.) and the subsequent light irradiation (Aktilite, Galderma, U.K.). Images acquired three
hours after Metvix application showed a significant increase in PpIX concentration within the lesion (P < 0.05), whilst
PpIX levels in the surrounding normal tissue remained unaltered. After irradiation, the PpIX concentration was
significantly decreased and returned to a level similar to the initial concentration originally observed. Lesions that
received subsequent treatment cycles accumulated significantly less PpIX (P < 0.05) prior to irradiation.
Visual systems that have evolved in nature appear to exercise a mechanism that places emphasis upon areas in a scene without necessarily recognising objects that lie in those areas. This paper describes the application of a new model of visual attention to the automatic assessment of the degree of damage in cultured human lung fibroblasts. The visual attention estimator measures the dissimilarity between neighbourhoods in the image giving higher visual attention values to neighbouring pixel configurations that do not match identical positional arrangements in other randomly selected neighbourhoods in the image. A set of tools has been implemented that processes images and produces corresponding arrays of attention values. Additional functionality has been added that provides a measure of DNA damage to images of treated lung cells affected by ultraviolet light. The unpredictability of the image attracts visual attention with the result that greater damage is reflected by higher attention values. Results are presented that indicate that the ranking provided by the visual attention estimates compare favourably with an 'experts' visual assessment of the degree of damage. Potentially, visual attention estimates may provide an alternative method of calculating the efficacy of genotoxins or modulators of DNA damage in treated human cells.
Preliminary clinical studies of 5-aminolaevulinic acid (ALA) induced photodynamic therapy (PDT) with the maximum tolerated oral dose (60 mg/kg), currently appear to only produce limited amounts of necrosis. We have studied ways of increasing this effect without increasing the drug dose. In normal, female, Wistar rats we have found it possible to increase the area of necrosis produced in the colon substantially by simply interrupting the light dose (25 J, 635 nm, 100 mW) for a short period of time, while all other variables are kept constant. It is possible to cause up to four times more necrosis with a dose of 200 mg/kg ALA i.v. by introducing a single 150 second interval which splits the light dose into two fractions after 5 J has been delivered. We have found these parameters to be optimal for this dose. Likewise, in the same model, the effect of the iron chelating agent, CP94, was also investigated and we have found it possible to produce three times the area of necrosis with the simultaneous administration of 100 mg/kg CP94 i.v. and 50 mg/kg ALA i.v. We have therefore shown, that it is possible to significantly increase the effects of ALA induced PDT without increasing the administered dose of ALA by utilizing these techniques.
Conference Committee Involvement (1)
17th International Photodynamic Association World Congress
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