title: The influence of hypoxia and pH on aminolaevulinic acid-induced photodynamic therapy in bladder cancer cells in vitro.
abstract: Photodynamic therapy (PDT) is a cancer treatment based on the interaction of light and a photosensitizing chemical. The photosensitizer protoporphyrin IX (PpIX) is generated via the haem biosynthetic pathway after administration of aminolaevulinic acid (ALA). The cellular microenvironment of tumours is hypoxic and acidotic relative to normal tissue, which may influence PpIX generation and compromise PDT efficacy. This study used bladder cancer cells, incubated with ALA at various oxygen tensions and H+ ion concentrations, and assessed the effects on PpIX generation and PDT sensitivity. PpIX production was reduced at 0%, 2.5% (19 mmHg) and 5% (38 mmHg) oxygen compared with that at 21% (160 mmHg) oxygen (0.15, 0.28 and 0.398 ng microg(-1) protein compared with 0.68 ng microg(-1) respectively; P < 0.05). The response to PDT was abolished by hypoxia, as a result of both reduced PpIX synthesis and reduced PDT toxicity. PpIX production was greater at pH 7.0 and 6.5 (0.75 and 0.66 ng microg(-1)) compared with that at pH 7.4 and 5.5 (0.41 and 0.55 ng microg(-1) respectively). PDT cytotoxicity was enhanced at lower pH values. These results suggest that ALA-induced PDT may be inhibited by hypoxia due to reduced intrinsic PpIX synthesis. Acidosis may slightly enhance the efficacy of ALA-induced PDT.
authors.affiliation: The Department of Surgical and Anaesthetic Sciences, Sheffield University, Royal Hallamshire Hospital, UK.
authors.forename: L
authors.initials: L
authors.lastname: Wyld
authors.forename: M W
authors.initials: MW
authors.lastname: Reed
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000138:Acidosis; D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D015687:Cell Hypoxia; D002470:Cell Survival; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000378:metabolism; D011524:Protoporphyrins / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000628:therapy*
chemical_list: D017319:Photosensitizing Agents; D011524:Protoporphyrins; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX