Intraperitoneal photodynamic therapy in the Fischer 344 rat using 5-aminolevulinic acid and violet laser light: a toxicity study.
OBJECTIVE
Our study was designed to investigate 5-aminolevulinic acid (ALA) as a candidate for intraperitoneal photodynamic therapy (IP-PDT). The toxicity of IP-PDT and the effects of IP-PDT on abdominal and pelvic organs, particularly the small intestine, were investigated after ALA administration and illumination with violet laser light.


RESULTS
The toxicity of IP-PDT was evaluated in Fischer 344 rats in two ways. In the first part of the study local PDT effects on the intestine were analyzed histologically. Violet laser light (lambda: 406-415 nm) was applied as a 2 cm diameter spot on the intestine 3 h after intraperitoneal (i.p.) administration of 50 mg/kg ALA. (A) Histological tissue samples were taken 0 min, 6 h and 1, 2 and 3 days after treatment (optical dose 3.2 J/cm(2)). Immediately after local PDT (3.2 J/cm(2), 50 mg/kg ALA) showed no effect on the intestine. However, 6 h post PDT there was complete destruction of the mesothelial lining and the outer (longitudinal) smooth muscle. Ganglion cells of the myenteric (Auerbach) plexus were also destroyed. The inner circular smooth muscle, the muscularis mucosa and the lamina propria were unharmed. Marked lymphectasia was present at this time. (B) To determine the threshold light dose of tissue destruction caused by PDT, different optical doses (1.6, 3.2, 6.4 J/cm(2)) were administered and histologic analysis of tissue samples were obtained 1 day post treatment. Destruction of the entire external musculature, submucosal structures and muscularis mucosa of the intestine at the illumination site could be observed above 1.6 J/cm(2) (50 mg/kg ALA). In the second part of the study whole peritoneal cavity PDT (WPC-PDT) was performed by illumination of the whole peritoneal cavity with 1.6 J/cm(2) violet light 3 h after ALA administration using different drug doses (200, 100 and 50 mg/kg). WPC-PDT showed lethal toxicity with a drug dose above 50 mg/kg ALA at 1.6 J/cm(2). The probable cause of death in the first 3 days after IP-PDT was rhabdomyolysis, whereas when death occurred at longer time intervals, megaintestine associated with significant damage could be observed; however, without perforation of the intestinal wall.


CONCLUSIONS
In rats WPC-PDT with 50 mg/kg ALA, 1.6 J/cm2 at lambda=415 nm was the maximum tolerable light dose. This dose is likely to be above the threshold of destruction of ovarian cancer micrometastasis.
Major
Attila L
AL
Department of Obstetrics and Gynecology, University Hospital, 30 bld de la Cluse, 1211 Geneva 14, Switzerland.
Rose
G Scott
GS
Svaasand
Lars O
LO
Lüdicke
Frank
F
Campana
Aldo
A
van Gemert
Martin J C
MJ
D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007834:Lasers; D050356:Lipid Metabolism; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid