Photoactivation of DNA thiobases as a potential novel therapeutic option

Curr Biol. 2001 Jul 24;11(14):1142-6. doi: 10.1016/s0960-9822(01)00272-x.

Abstract

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA / chemistry
  • DNA / radiation effects*
  • DNA Repair
  • Humans
  • Mercaptopurine / chemistry
  • Mercaptopurine / radiation effects
  • Phototherapy / methods*
  • Thioguanine / chemistry
  • Thioguanine / radiation effects
  • Thiouridine / analogs & derivatives*
  • Thiouridine / therapeutic use
  • Ultraviolet Therapy
  • Xeroderma Pigmentosum / drug therapy

Substances

  • Thiouridine
  • 4-thio-2'-deoxyuridine
  • DNA
  • Mercaptopurine
  • Thioguanine