Light Dose Fractionation to Enhance Photodynamic Therapy Using 5‐Aminolevulinic Acid in the Normal Rat Colon

Abstract

5-Aminolevulinic acid (ALA) is an attractive photosensitizing agent for photodynamic therapy (PDT) as its photoactive derivative, protoporphyrin IX, is metabolized within 1-2 days, eliminating prolonged skin photosensitivity. However, at the maximum dose patients can tolerate by mouth, 60 mg/kg, only superficial effects are seen. This paper extends earlier studies on enhancing the effect by light fractionation. Experiments in the normal rat colon looked at the area of necrosis around a single light delivery fiber 3 days after PDT with a range of light-dose fractionation regimes. All animals were given 200 mg/kg ALA intravenously 2 h prior to light delivery (100 mW at 635 nm) and each interruption in illumination was for 150 s. The area of PDT necrosis (total dose 25 J) could be increased by a factor of 3 with a single interval after 5 J, compared with continuous illumination. Alternatively, with this single break, the total light dose could be reduced by 60% to achieve the same area of necrosis as with continuous illumination. This simple modification to PDT with ALA could markedly reduce current treatment times as well as increasing clinical efficacy.

The role of reperfusion injury in photodynamic therapy with 5-aminolaevulinic acid – a study on normal rat colon

“…These include using a low light fluence rate (Robinson et al, 1998), ALA esters (Peng et al, 1996), iron chelators (Ortel et al, 1993;Curnow et al, 1998) and light dose fractionation (Messmann et al, 1995). In our studies, temporarily interrupting the light administration for 150 s increased the area of tissue necrosis by a factor of 3 (Curnow et al, 1999). The precise mechanism of this is not fully understood.…”

The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy

“…Standardised topical PpIX-PDT protocols utilising both ALA (Ameluz, Spirit Healthcare, UK) and MAL (Metvix, Galderma, UK) have been implemented within dermatology to good effect when the disease remains superficial [18], but improvement is required to treat thicker or acrally located conditions [19]. Many adaptations to standard treatment have been considered to improve efficacy including skin pre-treatment with the malignant cell differentiation potentiator dimethyl sulfoxide [20], skin stripping with tape [21], light dose fractionation [22,23], low fluence rate light administration [24] as well as combinations with other techniques such as low-dose Photofrin ® [25], hyperthermia [26,27], iontophoresis [28] and bioreductive drugs [29]. Concurrent administration of an iron chelator, such as ethylenediamine tetraacetic acid (EDTA) [30][31][32][33], desferrioxamine (DFO) [30,[34][35][36][37] or the novel hydroxypyridinone iron chelator 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94) [38][39][40][41][42][43], during PpIX-PDT has also been demonstrated to increase cellular accumulation of PpIX by reducing its bioconversion to haem by ferrochelatase (an iron dependent process) thus increasing cell kill on subsequent irradiation.…”

Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94: an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma

“…Various adaptations to the standard treatment have 6 therefore been considered. These include skin pre-treatment with the malignant cell differentiation potentiator dimethyl sulfoxide (DMSO) [10], the use of iron chelators [11], skin stripping with tape [12], light dose fractionation [13,14], low fluence rate light administration [15] as well as combinations with other techniques such as low dose Photofrin [16], hyperthermia [17,18], iontophoresis [19] and bioreductive drugs [20].…”