deoxy-4-thiothymidine and Skin-Neoplasms

The nucleoside analogue 4-thiothymidine has shown great potential in vitro as a photosensitiser for the photodynamic therapy of numerous cancer cell lines. However, the limited penetrating power of UV-A radiation, to which it responds, raises doubts as to its practical usefulness in clinical applications. We addressed this issue by studying the penetration extent of topical thiothymidine and the antiproliferative effect of its combination with UV-A radiation on ex vivo basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) skin cancer biopsies, and normal skin. Our results show that both the intralesional concentration of the drug and the intensity of UV-A radiation are sufficient to activate the molecule and cause extensive death by apoptosis of the malignant cells. Normal skin biopsies were not significantly affected by the treatment.

Topics: Apoptosis; Biopsy; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Line, Tumor; Humans; Photochemotherapy; Photosensitizing Agents; Skin; Skin Absorption; Skin Neoplasms; Thymidine; Ultraviolet Rays

The thymidine analogue 4-thiothymidine (S(4)TdR) is a photosensitizer for UVA radiation. The UV absorbance spectrum of S(4)TdR and its incorporation into DNA suggests that it might act synergistically with nonlethal doses of UVA to selectively kill hyperproliferative or cancerous skin cells. We show here that nontoxic concentrations of S(4)TdR combine with nonlethal doses of UVA to kill proliferating cultured skin cells. Established cell lines with a high fraction of proliferating cells were more sensitive than primary keratinocytes or fibroblasts to apoptosis induction by S(4)TdR/UVA. Although S(4)TdR plus UVA treatment induces stabilization of p53, cell death, as measured by apoptosis or clonal survival, occurs to a similar extent in both p53 wild-type and p53-null backgrounds. Furthermore, different types of human papilloma virus E6 proteins, which protect against UVB-induced apoptosis, have little effect on killing by S(4)TdR/UVA. S(4)TdR/UVA offers a possible therapeutic intervention strategy that seems to be applicable to human papilloma virus-associated skin lesions.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Combined Modality Therapy; DNA Damage; Female; Fibroblasts; Fibrosarcoma; Flow Cytometry; Humans; Keratinocytes; Mice; Middle Aged; Octreotide; Papillomaviridae; Papillomavirus Infections; Skin; Skin Neoplasms; Thymidine; Tumor Suppressor Protein p53; Ultraviolet Rays