| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
We have previously reported that UVA-1 phototherapy induces apoptosis in skin-infiltrating T-cells and can thus be effectively used to treat patients with cutaneous T-cell lymphoma. Acutually, UVA-1 phototherapy was highly effective for cutaneous T-cell lymphoma (CTCL). Equivalent clinical responses could be achieved regardless of whether 130 Jcm^2 UVA-1 were given. We therefore speculated that which is the dose routinely used to treat atopic dermatitis, or 60 Jcm^2 UVA-1 were given. We therefore speculated that malignant T-cells might be more sensitive to UVA-1 phototherapy as compared with normal T-cells. CD4^+ T-cells were isolated using magnetic cell sorting either from a patient with Adult T-cell leukemia (ATL) or from normal healthy individuals and UVA-1 radiation-induced apoptosis was analyzed in these cells 24 hrs after in-vitro UVA-1 irradiation. In comparison with normal CD4^+ T-cells, malignant T-cells showed a higher susceptibility towards UVA-1 radiation-induced comparison
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with normal CD4^+ T-cells, malignant T-cells showed a higher susceptibility towards UVA-1 radiation-induced apoptosis. At a dose of 20 Jcm^2 UVA-1, 35 % of malignant, but only 16 % of normal T-cells were apoptotic. In addition, malignant T-cells exhibited a higher susceptibility to UVA-1 radiation-induced apoptosis than normal T-cells. In order to better understand this exquisite sensitivity of malignant T-cells, the photobiological and molecular mechanisms underlying UVA-1-induced apoptosis were further analyzed in malignant (Jurkat) versus normal T-cells. Treatment of malignant T-cells with FAS antibody or FASL-transfectant to downregulate FAS surface expression, however, decreased the susceptibility of Jurkat cells towards UVA1-induced apoptosis to normal levels, indicating the involvement of the FAS system. FAS-induced apoptosis is mediated further downstream by caspase-3. It was therefore of great interest that normal T-cells had significantly lower procaspase-3 levels as compared with malignant T-cells, and that addition of caspase-3 inhibitor completely prevented UVA-1-induced apoptosis in malignant cells. Finally, an increased sensitivity towards apoptosis was also observed in malignant cells in comparison with normals, when T-cells were left unirradiated but treated with singlet oxygen, which was generated through thermal decomposition of the endoperoxide of NDPO2. These findings indicate that upon singlet oxygen-induced activation the Fas signaling pathway determines the susceptibility of a given T cell towards UVA-1 induced apoptosis, possibly at the level of caspase-3 expression. In order to assess the clinical relevance of our findings, we have initiated a randomized, controlled multi-center trial in order to compare UVA1 phototherapy with UVB and PUVA in the treatment of patients with CTCL. Less
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