PUVA treatment selectively induces a cell cycle block and subsequent apoptosis in human T-lymphocytes.
Psoralen plus UVA (320-400 nm radiation; PUVA) is a highly effective therapy for cutaneous diseases caused by skin infiltration with normal or neoplastic T-lymphocytes. In comparing the effects of pharmacologically relevant, low-dose PUVA treatment on growth of human keratinocytes, peripheral blood leukocytes (PBMC), and T-lymphocyte cell lines, we determined that PBMC or T-lymphocytes were > 50-fold more sensitive to cytotoxic effects of PUVA, while antiproliferative effects were produced by similar PUVA levels in all cell types. Low doses of PUVA (10 ng/mL 8-methoxypsoralen and 1-2 J/cm2) were highly cytotoxic for phytohemagglutinin-activated normal lymphocytes or transformed T-lymphocytes as assessed by two viability assays and by flow cytofluorometry. Altered lymphocyte morphology, nuclear fragmentation, TUNEL+ nuclei or nuclear fragments, and the appearance of a sub-G1 DNA peak indicated that cell death occurred by apoptosis, beginning about 1 day after PUVA treatment and continuing for several days thereafter. From assessment of cell cycle progression in mimosine-synchronized cells, PUVA treatment markedly slowed cell cycle progression, eventually producing cell cycle arrest and apoptotic entry. We propose that the probable basis for disease remissions (psoriasis, cutaneous T-cell lymphoma) produced by PUVA treatment is through selective cytotoxic effects on clonal T-lymphocyte populations that are concentrated in diseased skin.
Johnson
R
R
Laboratory for Investigative dermatology, Rockefeller University, New York, NY 10021-6399, USA.
Staiano-Coico
L
L
Austin
L
L
Cardinale
I
I
Nabeya-Tsukifuji
R
R
Krueger
J G
JG
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects*; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008730:Methoxsalen / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D014466:Ultraviolet Rays
D017319:Photosensitizing Agents; D008730:Methoxsalen