Carcinogenic effects of monofunctional and bifunctional furocoumarins

We initiated these studies to determine whether bifunctional (interstrand cross-linking) psoralens, such as 8-methoxypsoralen (8-MOP), are more carcinogenic than are the monofunctional, such as angelicin or isopsoralen derivatives, and 3-carbethoxysporalen (3-CP). Hairless mice (Skh:hr-1) in groups of 40 were treated three times weekly for 12 to 15 months. There were 17 groups, and the photocarcinogenic effects of 5 psoralens [8-MOP, 3-CP, 5-methylangelicin, 4,5'-dimethylangelicin (4,5'-DMA), and angelicin] were investigated. Ethanolic solutions of 0.01-0.1% psoralens were topically applied at 5.0 or 50 micrograms/cm2 from cervical to lumbar regions 45 minutes before exposure to UVA (320-400 nm) radiation (0.1, 2.5, or 7.5 joules/cm2). Control groups received either the drug application or UVA exposure only. The study revealed that isopsoralens, such as 5-methylangelicin or 4,5'-DMA, that form monofunctional adducts are more carcinogenic than bifunctional psoralens. The latency and time required for 50% prevelance of tumors was much longer with 8-MOP than with 4,5'-DMA or 5-methylangelicin. Mice treated with the latter 2 compounds had a greater number and larger tumors than mice treated with 8-MOP. The monofunctional angelicin was weakly carcinogenic, whereas 3-CP, also a monofunctional psoralen, was noncarcinogenic. Histologic examination revealed that tumors induced by 8-MOP, 5-methylangelicin, or 4,5'-DMA were all squamous cell carcinomas. Because of their skin-photosensitizing property and their ability to induce interstrand cross-links and severe damage to DNA in replication, bifunctional psoralens apparently produce more lethal damage in cells than do monofunctional isopsoralens.(ABSTRACT TRUNCATED AT 250 WORDS)