Clinical and preclinical photodynamic therapy

Fisher, Anita M.; Murphree, A. Linn; Gomer, Charles J.

doi:10.1002/lsm.1900170103

Cited by 397 publications

(231 citation statements)

References 163 publications

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“…In the case of Photofrin, as well as photosensitizers designated as 'second generation', investigations of dosing have used traditional pharmacokinetics to define times of maximum sensitizer concentration in tumours, maximum tumournormal tissue ratios, toxicity, metabolism, etc., as well as exploration of irradiation schema related to total fluence and fluence rates (Gomer, 1991;Henderson and Dougherty, 1992;Fisher et al, 1995). Unlike systemic administration of a photosensitizer, optimization of 6-ALA induction of protoporphyrin IX represents a different challenge because the photosensitizer is a product of a biosynthetic pathway that evolved to form haem, a non-photosensitizing end product.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, malignant lesions are exposed to light of an appropriate wavelength and damage is usually the result of a photochemical reaction involving the conversion of oxygen to its highly toxic singlet state. However, prolonged skin photosensitivity and/or lack of specificity for malignant tissue are undesirable properties of many of the photosensitizers used in PDT (Dougherty et al, 1978;Bown, 1990;Overholt et al, 1993;Fisher et al, 1995). Recently, investigators have found that exogenous administration of 8-ALA to lesions can induce the accumulation of protoporphyrin IX (PPIX) (Malik and Laguci, 1987; Shoenfeld et al, 1994;Hua et al, 1995), an efficient photosensitizer (Kennedy et al, 1990).…”

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confidence: 99%

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A regulatory role for porphobilinogen deaminase (PBGD) in δ-aminolaevulinic acid (δ-ALA)-induced photosensitization?

Gibson

Cupriks²,

Havens³

et al. 1998

Br J Cancer

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Summary As an initial approach to optimize 8-aminolaevulinic acid (6-ALA)-induced photosensitization of tumours, we examined the response of three enzymes of the haem biosynthetic pathway: 8-ALA dehydratase, porphobilinogen deaminase (PBGD) and ferrochelatase. Only PBGD activity displayed a time-and dose-related increase in tumours after intravenous administration of 300 mg kg-1 6-ALA. The time course for porphyrin fluorescence changes, reflecting increased production of the penultimate porphyrin, protoporphyrin IX (PPIX), showed a similar pattern to PBGD. This apparent correlation between PBGD activity and porphyrin fluorescence was also observed in four cultured tumour cell lines exposed to 0.1-2.0 mm 6-ALA in vitro. The increase in PBGD activity and PPIX fluorescence was prevented by the protein synthesis inhibitor cycloheximide. As the apparent Km for PBGD was similar before and after 6-ALA, the increase in PBGD activity was attributed to induction of enzyme de novo. These observations of an associated response of PBGD and PPIX imply that PBGD may be a ratelimiting determinant for the efficacy of 6-ALA-induced photosensitization when used in photodynamic therapy.Keywords: 6-aminolaevulinic acid: photosensitization; porphobilinogen deaminase: haem biosynthesis; porphyrin fluorescence Haem is an essential prosthetic group in many critical cellular proteins such as haemoglobin, cytochrome P450 and cyclooxygenase (Abraham, 1991). Eight enzymes are involved in the biosynthesis of haem, a process that occurs in two subcellular compartments: the mitochondria and the cytosol. The first enzyme in the haem pathway, mitochondrial 8-aminolaevulinic acid synthase (8-ALA-S), forms 6-ALA from glycine and succinyl CoA and is a target for the regulation of haem biosynthesis. Feedback inhibition of 8-ALA-S occurs when intracellular haem is present in excess (Ade, 1990).The last step in the haem biosynthetic pathway, the insertion of iron into PPIX to form haem, is catalysed by the mitochondrial enzyme ferrochelatase (FC). In unperturbed systems, FC is regulated by the availability of iron and/or PPIX. Two of the metabolic events that occur between 8-ALA-S and FC are catalysed by the cytosolic enzymes 8-ALA dehydratase (8-ALA-D) and porphobilinogen deaminase (PBGD). The dehydratase enzyme catalyses the condensation of two 8-ALA molecules to form porphobilinogen (PBG). It is the first enzyme that will metabolize the administered 8-ALA. The next enzyme in haem biosynthesis, PBGD, forms the tetrapyrole ring from four porphobilinogen molecules (Abraham, 1991).By providing the 8-ALA-S product, 8-ALA, the initial feedback step has been circumvented and this approach has been exploited for use in photodynamic therapy (PDT) of cancer (Kennedy and Pottier, 1992;Grant et al, 1993; Cairnduff et al, 1994;Regula et al, 1995). Traditional PDT regimens consist of the systemic adminis- Accepted 13 June 1997 Correspondence to: R Hilf tration of a photosensitizer followed by an appropriate interval to allow for its maximal accumulation in ma...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A regulatory role for porphobilinogen deaminase (PBGD) in δ-aminolaevulinic acid (δ-ALA)-induced photosensitization?

Gibson

Cupriks²,

Havens³

et al. 1998

Br J Cancer

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“…Photodynamic therapy (PDT), also called photochemotherapy, is a new modality for the treatment of cancer [1][2][3] and a variety of nononcologic conditions [3][4][5][6][7]. PDT is based on administering a photosensitizer, which is preferentially retained in tumor (and other proliferating) tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, Photofrin absorbs weakly at 630 nm and, moreover, is characterized by prolonged cutaneous phototoxicity. Second-generation photosensitizers for improved photochemotherapy are under development and are in various stages of preclinical and clinical trials [1,3].…”

Section: Introductionmentioning

confidence: 99%

Photodynamic parameters in the chick chorioallantoic membrane (CAM) bioassay for topically applied photosensitizers

Hammer‐Wilson

Akian

Espinoza

et al. 1999

Journal of Photochemistry and Photobiology B: Biology

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“…Photodynamic therapy (PDT) has been used successfully to control the growth of a variety of human malignancies (Rosenthal and Glatstein, 1994;van Hillegersberg et al, 1994;Fisher et al, 1995;Kriegmeir et al, 1996;Peng et al, 1997). Based on these clinical trials, PDT has been approved as a treatment for various cancers in the US, Canada, France, The Netherlands and Japan.…”

mentioning

confidence: 99%

δ-Aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro

Havens

Nguyen

et al. 1999

Br J Cancer

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Summary Recently, considerable interest has been given to photodynamic therapy of cancer using δ-aminolaevulinic acid to induce protoporphyrin IX as the cell photosensitizer. One advantage of this modality is that protoporphyrin IX is cleared from tissue within 24 h after δ-aminolaevulinic acid administration. This could allow for multiple treatment regimens because of little concern regarding the accumulation of the photosensitizer in normal tissues. However, the haem biosynthetic pathway would have to be fully functional after the first course of therapy to allow for subsequent treatments. Photosensitization of cultured R3230AC rat mammary adenocarcinoma cells with δ-aminolaevulinic acid-induced protoporphyrin IX resulted in the inhibition of porphobilinogen deaminase, an enzyme in the haem biosynthetic pathway, and a concomitant decrease in protoporphyrin IX levels. Cultured R3230AC cells exposed to 0.5 mM δ-aminolaevulinic acid for 27 h accumulated 6.07 × 10 -16 mol of protoporphyrin IX per cell and had a porphobilinogen deaminase activity of 0.046 fmol uroporphyrin per 30 min per cell. Cells cultured under the same incubation conditions but exposed to 30 mJ cm -2 irradiation after a 3-h incubation with δ-aminolaevulinic acid showed a significant reduction in protoporphyrin IX, 2.28 × 10 -16 mol per cell, and an 80% reduction in porphobilinogen deaminase activity to 0.0088 fmol uroporphyrin per 30 min per cell. Similar effects were evident in irradiated cells incubated with δ-aminolaevulinic acid immediately after, or following a 24 h interval, post-irradiation. There was little gain in efficacy from a second treatment regimen applied within 24 h of the initial treatment, probably a result of initial metabolic damage leading to reduced levels of protoporphyrin IX. These findings suggest that a correlation may exist between the δ-aminolaevulinic acid induction of porphobilinogen deaminase activity and the increase in intracellular protoporphyrin IX accumulation.

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Clinical and preclinical photodynamic therapy

Cited by 397 publications

References 163 publications

A regulatory role for porphobilinogen deaminase (PBGD) in δ-aminolaevulinic acid (δ-ALA)-induced photosensitization?

A regulatory role for porphobilinogen deaminase (PBGD) in δ-aminolaevulinic acid (δ-ALA)-induced photosensitization?

Photodynamic parameters in the chick chorioallantoic membrane (CAM) bioassay for topically applied photosensitizers

δ-Aminolaevulinic acid-induced photodynamic therapy inhibits protoporphyrin IX biosynthesis and reduces subsequent treatment efficacy in vitro

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