Thiothymidine plus low-dose UVA kills hyperproliferative human skin cells independently of their human papilloma virus status.
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.
Reelfs
Olivier
O
Cancer Research UK, Institute for Cell and Molecular Science, Skin Tumour Laboratory, 4, Newark Street, London E1 2AT, United Kingdom.
Xu
Yao-Zhong
YZ
Massey
Andrew
A
Karran
Peter
P
Storey
Alan
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects / Q000821:virology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology; D005434:Flow Cytometry; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000528:radiation effects / Q000821:virology; D051379:Mice; D008875:Middle Aged; D015282:Octreotide / Q000031:analogs & derivatives; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000821:virology*; D012867:Skin / Q000166:cytology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D014466:Ultraviolet Rays
C504257:177Lu-octreotide, DOTA(0)-Tyr(3)-; C414668:4-thiothymidine; D016159:Tumor Suppressor Protein p53; D015282:Octreotide; D013936:Thymidine