The role of nitric oxide in the treatment of tumours with aminolaevulinic acid-induced photodynamic therapy.
Photodynamic therapy (PDT) is a local cancer treatment which induces cell death by the interaction of light with a photosensitizing drug. Previous studies indicate that nitric oxide (NO) plays a role in Photofrin-PDT, but this has not been investigated in aminolaevulinic acid (ALA)-PDT. The current study determines whether inhibition of nitric oxide synthase (NOS) activity modulates treatment responses to ALA-PDT, in tumours displaying differential levels of NO. Murine tumours with low (EMT6) or high (RIF-1) NO levels were implanted into the cremaster muscle of BALB/c or C3H/HeN mice respectively. Animals were prepared for in vivo microscopy 7-14days later. Mice received oral ALA (200mg/kg) 4h before PDT. l-NAME, l-NNA or 1400W (10mg/kg) were administered via the jugular vein 5min before PDT. NOS inhibition (l-NAME or l-NNA) combined with ALA-PDT in RIF-1 tumours demonstrated enhanced damage to both the tumour and normal microvasculature, with increased macromolecular leak and reduction in vessel diameter, whereas ALA-PDT alone had no effect. In contrast, EMT6 tumours responded to ALA-PDT alone but sensitivity was not enhanced in the presence of NOS inhibition. 1400 W combined with ALA-PDT induced similar microvascular effects to l-NAME in both tumours, but were less pronounced. The data demonstrates that NO has an important role in events likely to be critical for treatment response, sensitivity and therapeutic outcome of ALA-PDT.
Reeves
K J
KJ
School of Medicine & Biomedical Sciences, University of Sheffield, Sheffield S10 2RX, UK. k.j.reeves@sheffield.ac.uk
Reed
M W R
MW
Brown
N J
NJ
D000284:Administration, Oral; D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011524:Protoporphyrins / Q000378:metabolism
D017319:Photosensitizing Agents; D011524:Protoporphyrins; D019335:Nitroarginine; D009569:Nitric Oxide; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester