Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma

Campbell, S.; Morton, C.A.; Alyahya, Reem; Horton, S. J.; Pye, A. Kenneth; Curnow, Alison

doi:10.1111/j.1365-2133.2008.08668.x

Cited by 46 publications

(41 citation statements)

References 28 publications

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“…[48,49]. Although these clinical investigations were only designed to assess safety, enhancements in tumour clearance were observed both clinically and histologically when CP94 was included within the photosensitising cream.…”

Section: Introductionmentioning

confidence: 99%

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

Curnow

Pye

2015

Photonics &Amp; Lasers in Medicine

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Section: Introductionmentioning

confidence: 99%

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

Curnow

Pye

2015

Photonics &Amp; Lasers in Medicine

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“…They also permit insight to the mechanisms that may explain the promising initial clinical results obtained with this enhanced treatment regime in the first clinical safety pilot studies [35][36], as the increased therapeutic effects are most likely being conveyed through the elevated dermal PpIX accumulation observed following effective iron chelation achieved via topical CP94 administration.…”

Section: Discussionmentioning

confidence: 99%

“…This experimentation has been extended here to consider the effect of topical CP94 administration in vivo in a normal rat skin model. In light of our previous findings with CP94 augmentation of PpIX-PDT demonstrated in epidermal squamous carcinoma cells (A431) [30][31], a colonic tumour model [33] and dermatological skin lesions [35][36], it was not deemed necessary to create a neoplastic skin model here when our main focus was to assess PpIX production/excised tissue fluorescence (which we have been unable to do clinically due to ethical constraints).…”

Section: Discussionmentioning

confidence: 99%

“…However because CP94 experiences rapid first pass glucuronidation when administered orally to humans [34], a topical administration route for a dermatological PDT application may be preferable. Two small clinical pilot studies of CP94 in combination with ALA or MAL-induced PDT have been conducted to date and have demonstrated the safety and feasibility of adding this iron chelator to the photosensitising cream [35][36]. Additionally, although these clinical investigations were only designed to assess safety, some promising initial enhancements in tumour clearance were observed when CP94 was included within the photosensitising cream.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing Protoporphyrin IX induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model

Curnow¹,

Macrobert²

2016

J Heavy Met Toxicity Dis

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Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of nonmelanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem.A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/-2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07).It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy.4

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“…In addition, the iron chelating capacity and toxicity of CP94 have been investigated in a number of iron overloaded and non-overloaded animal models including mice [21,22], rats [23,24], guinea pigs [23], rabbits [25] and Cebus monkeys [24]. Rat studies were found to be predictive of the iron chelating capacity recorded in primates [24] and the metabolism of CP94 in guinea pigs was noted to be more similar to that of humans [23] than studies undertaken in rats as this compound is glucuronidated by the liver and excreted in urine. Topical CP94 administration has been investigated in humans as way of improving PpIX-induced PDT for the treatment of certain non-melanoma skin cancers and precancers.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Iron Chelation and Hypoxic or Hyperoxic Oxygen Manipulation on the Accumulation/Photobleaching of Protoporphryin IX and Cytotoxcity in Human Glioma Cells

Blake¹,

Allen²,

Curnow³

2013

J Anal Bioanal Tech

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Background and objective: Gliomas remain the most common and problematic primary brain tumors to treat given their mobile and invasive characteristics, resulting in a 5 years survival rate of less than 5%. Recently the administration of photosensitive fluorescent drugs has been utilized to aid in the identification and resection of gliomas. In this experimental investigation of human glioma cells the effect of iron chelation and oxygenation manipulation, firstly on the accumulation of the clinically useful photosensitizer protoporphyrin IX (PpIX) and subsequently on PpIX photobleaching and cytotoxicity on irradiation, has been examined with the aim of improving fluorescence-guided resection/photodynamic therapy (PDT). Materials and methods:Cells were incubated at concentrations of 5%, 20% or 40% oxygen for 24 hours prior to and for 3 hours following the administration of the PpIX precursors aminolevulinic acid (ALA), methyl levulinate (MAL) or hexyl aminolevulinate (HAL) with or without the iron chelator 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94). PpIX levels were monitored using a fluorescence plate reader (excitation filter 400 ± 30 nm; emission filter 645 ± 40 nm). Cells were irradiated with 15 J/cm 2 red lights and viability measured using the neutral red uptake assay.Results: Manipulation of the oxygen environment and/or co administration of CP94 with PpIX precursors resulted in significant changes in both PpIX accumulation and photobleaching. Incubation with ALA/ MAL at 5% or 40% oxygen produced the greatest levels of PpIX and photobleaching respectively. Both these parameters were further elevated through co administration of CP94. The combination of hyperoxygenation and CP94 administration significantly increased photobleaching (a marker of PDT effect) but not cytotoxicity in this experimental system. Conclusions:PpIX accumulation was greatest when the cells were grown in hypoxic (5% oxygen) conditions (mimicking the in vivo situation) with ALA/MAL+CP94. Fluorescence-guided resection of glioma may therefore be improved through the addition of the iron chelating adjuvant CP94.

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Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma

Cited by 46 publications

References 28 publications

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

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

Enhancing Protoporphyrin IX induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model

The Effects of Iron Chelation and Hypoxic or Hyperoxic Oxygen Manipulation on the Accumulation/Photobleaching of Protoporphryin IX and Cytotoxcity in Human Glioma Cells

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