PRECLINICAL EXAMINATION OF FIRST and SECOND GENERATION PHOTOSENSITIZERS USED IN PHOTODYNAMIC THERAPY

Gomer, Charles J.

doi:10.1111/j.1751-1097.1991.tb02133.x

Cited by 327 publications

(152 citation statements)

References 158 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%

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%

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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“…However, prolonged skin photosensitivity due to non-specific localisation of the photosensitiser is associated with Photofrinmediated PDT (Benson, 1988). Therefore new photosensitisers and better methods of photosensitiser localisation are being investigated (Bachor et al, 1991;Goff et al, 1991;Gomer, 1991;Pandey et al, 1991;Hasan, 1992;Henderson & Dougherty, 1992). Other approaches for achieving better localisation include local administration of the photosensitiser (Amano et al, 1988;Bachor et al, 1992).…”

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confidence: 99%

A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin

Iinuma

Farshi²,

Ortel³

et al. 1994

Br J Cancer

237

122

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“…The treatment is based on a selective uptake of porphyrinbased photosensitizing chemical in tumor tissue relative to the surrounding normal tissue followed by irradiation of the tumor with light (visible or near infra-red), typically delivered through a laser. PDT is showing promise against a variety of solid tumors as well as against many non-malignant diseases (Dougherty et al, 1998;Pass, 1993;Tom, 1997;Gomer, 1991). PDT is known to result in a sequence of photochemical and photobiological events that leads to an oxidative damage to many of cellular targets, subsequently resulting in the killing of cancerous cells and thereby tumor ablation that often leads to a complete cure (Dougherty et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Involvement of retinoblastoma (Rb) and E2F transcription factors during photodynamic therapy of human epidermoid carcinoma cells A431

1999

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Photodynamic therapy (PDT), a promising new therapeutic modality for the management of a variety of solid malignancies and many non-malignant diseases, is a bimodal therapy using a porphyrin based photosensitizing chemical and visible light. The proper understanding of the mechanism of PDT-mediated cancer cell-kill may result in improving the e cacy of this treatment modality. Earlier we have shown (Proc. Natl. Acad. Sci. USA; 95: 6977-6982, 1998) that silicon phthalocyanine (Pc4)-PDT results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclins (E and D1) and cyclin dependent kinases (cdk2 and cdk6), results in a G0/G1-phase arrest followed by apoptosis in human epidermoid carcinoma cells A431. We have also demonstrated the generation of nitric oxide during PDT-mediated apoptosis (Cancer Res.; 58: 1785-1788. Retinoblastoma (pRb) and E2F family transcription factors are important proteins, which regulate the G1?S transition in the cell cycle. Here, we provide evidence for the involvement of pRb-E2F/DP machinery as an important contributor of PDT-mediated cell cycle arrest and apoptosis. Western blot analysis demonstrated a decrease in the hyper-phosphorylated form of pRb at 3, 6 and 12 h post-PDT with a relative increase in hypo-phosphorylated pRb. Western blot analysis also revealed that PDT-caused decrease in phosphorylation of pRb occurs at serine-780. The ELISA data demonstrated a time dependent accumulation of hypo-phosphorylated pRb by PDT. This response was accompanied with down-regulation in the protein expression of all ®ve E2F (1 ± 5) family transcription factors, and their heterodimeric partners DP1 and DP2. These results suggest that Pc4-PDT of A431 cells results in a down regulation of hyper-phosphorylated pRb protein with a relative increase in hypo-phosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that these events result in a stoppage of the cell cycle progression at G1?S transition thereby leading to a G0/G1 phase arrest and a subsequent apoptotic cell death. These data provide an evidence for the involvement of pRb-E2F/DP machinery in PDTmediated cell cycle arrest leading to apoptosis.

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PRECLINICAL EXAMINATION OF FIRST and SECOND GENERATION PHOTOSENSITIZERS USED IN PHOTODYNAMIC THERAPY

Cited by 327 publications

References 158 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?

A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin

Involvement of retinoblastoma (Rb) and E2F transcription factors during photodynamic therapy of human epidermoid carcinoma cells A431

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