Photodynamic therapy using a protoporphyrinogen oxidase inhibitor.
The use of endogenously created porphyrins as an alternative to photosensitizer injection for photodynamic therapy is a rapidly evolving area of study. One common method to induce porphyrin synthesis and accumulation in cells is the topical, oral, or parenteral administration of 5-aminolevulinic acid, a precursor for heme biosynthesis. Porphyrin accumulation may also be elicited by the use of enzyme inhibitors of the heme biosynthetic pathway. Groups of DBA/2 mice bearing SMT-F mammary tumors were placed on a diet containing 0-4000 ppm of a protoporphyrinogen oxidase inhibitor, FP-846. This agent blocks a critical step in porphyrin metabolism and results in elevated intracellular levels of protoporphyrin IX. Light treatment of tumors produced both initial and long-term regression that was dependent on the amount of inhibitor, the duration of inhibitor exposure to animals, and the amount of light used in PDT. Tumor regression occurred without significant destruction of normal tissues in the treatment field and without initial vascular constriction or blood flow stasis. Tumor cure in animals given 4000 ppm FP-846 in feed for 3 days and 300 J/cm2 602-670 nm light (23% cure) was similar to the response in animals given 10 mg/kg Photofrin and the same light dose (20%).
Fingar
V H
VH
Division of Surgical Oncology, Henry Vogt Cancer Institute, University of Louisville, Kentucky 40292, USA. vhfing01@pdt.bcc.louisville.edu
Wieman
T J
TJ
McMahon
K S
KS
Haydon
P S
PS
Halling
B P
BP
Yuhas
D A
DA
Winkelman
J W
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005420:Flavoproteins; D008027:Light; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D008833:Microcirculation / Q000187:drug effects; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000098:blood supply; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010778:Photochemotherapy; D050768:Protoporphyrinogen Oxidase; D013449:Sulfonamides; D013997:Time Factors; D014230:Triazoles
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D024101:Mitochondrial Proteins; D013449:Sulfonamides; D014230:Triazoles; C475571:N-(2,4-dichloro-5-(4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl)methanesulfonamide; D017323:Dihematoporphyrin Ether; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493979:Ppox protein, mouse; D050768:Protoporphyrinogen Oxidase