The lack of efficacy of 4,6,6'-trimethylangelicin to induce immune suppression in an animal model for photopheresis: a comparison with 8-MOP.
Photopheresis is an extracorporeal form of photochemotherapy with 8-methoxypsoralen (8-MOP) and UVA (PUVA). Patients ingest 8-MOP and then a psoralen-rich buffy coat is obtained by centrifugation and mixed with saline. This mixture is recirculated through a UVA radiation field and then reinfused. Photopheresis appears to be effective for several T cell-mediated disorders, because the treatment results in a specific immune response against the pathogenic clone of T cells involved. With PUVA therapy, the whole body of the patient is exposed to UVA, after ingestion of 8-MOP. Upon UVA exposure 8-MOP binds to, amongst others, DNA and induces DNA monoadducts and interstrand cross-links. As a result of these photoadducts photocarcinogenicity is a risk in PUVA. In PUVA for psoriasis, it proved that angular furocoumarins, although almost incapable of inducing DNA cross-links (less carcinogenic), are still effective. In order to determine if monoadducts induced by photopheresis could also be effective we used, specifically, 4,6,4'-trimethylangelicin (TMA). In this report, we compare the photodegradation of both TMA and 8-MOP under conditions relevant to the in vivo situation, as well as the effect both compounds have on the viability of rat lymphocytes as measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. We show that TMA did not induce immunosuppression in vivo, even after extensive irradiation. In addition a dose dependency of 8-MOP/UVA versus the induced immune suppression was carried out. It was shown that there is a log dose/response correlation of r=0.9205.
van Iperen
H P
HP
Leiden/Amsterdam Center for Drug Research, Department of Medicinal Photochemistry, State University of Leiden, The Netherlands.
Brun
B M
BM
Caffieri
S
S
Dall'Acqua
F
F
Gasparro
F P
FP
Beijersbergen Henegouwen
G M
GM
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D011564:Furocoumarins / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D017893:Photopheresis; D017319:Photosensitizing Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014466:Ultraviolet Rays
D011564:Furocoumarins; D007166:Immunosuppressive Agents; D017319:Photosensitizing Agents; C041621:4,4',6-trimethylangelicin; D008730:Methoxsalen