Mechanisms of lymphocytotoxicity induced by extracorporeal photochemotherapy for cutaneous T cell lymphoma.
Extracorporeal photochemotherapy is an effective treatment for cutaneous T cell lymphoma but its mode of action is uncertain. The reduction in viability of patients' photoirradiated buffy coat lymphocytes was correlated with a 35% increase in DNA single-strand breaks and marked decreases in cellular ATP and NAD levels (to 58 and 34% of control, respectively) immediately after photoirradiation. Complementary in vitro studies were conducted with normal human peripheral blood lymphocytes using a Therakos ultraviolet A (UVA) light box. UVA light was cytotoxic on its own but was potentiated by 8-methoxysporalen. 3-aminobenzamide, a poly (ADP-ribose) synthetase inhibitor, mitigated the cytotoxic effect of ultraviolet A light in the presence of 8-methoxypsoralen in lymphocytes and reduced the amount of nucleotide depletion they caused. 10 J/cm2 of UVA light in the presence of 300 ng/ml 8-methoxypsoralen increased the poly (ADP-ribose) synthetase activity of peripheral blood lymphocytes. Exposing lymphocytes to deoxycoformycin and deoxyadenosine was found to induce biochemical and physical effects similar to those of photochemotherapy. In summary, we have shown that the lymphocytotoxic effect of extracorporeal photochemotherapy for cutaneous T cell lymphoma is apparently mediated by DNA damage, subsequent poly (ADP-ribosyl)ation and adenine nucleotide depletion. It is not known how the DNA damage and resultant biochemical effects relate to the possible immunological mechanism of extracorporeal photochemotherapy; however, it is possible that its effects can be mimicked by other DNA-damaging agents.
Marks
D I
DI
Department of Haematology and Medical Oncology, Royal Melbourne Hospital, Victoria, Australia.
Rockman
S P
SP
Oziemski
M A
MA
Fox
R M
RM
D000227:Adenine Nucleotides / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000528:radiation effects; D004249:DNA Damage; D003839:Deoxyadenosines / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007937:Leukapheresis / Q000379:methods; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects*; D016410:Lymphoma, T-Cell, Cutaneous / Q000628:therapy*; D008730:Methoxsalen / Q000378:metabolism / Q000633:toxicity; D009243:NAD / Q000378:metabolism; D011701:PUVA Therapy / Q000379:methods*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D000227:Adenine Nucleotides; D003839:Deoxyadenosines; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D000255:Adenosine Triphosphate; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D008730:Methoxsalen