title: The combined use of known antiviral reverse transcriptase inhibitors AZT and DDI induce anticancer effects at low concentrations.
abstract: A hallmark of tumor cell survival is the maintenance of elongated telomeres. It is known that antiviral reverse transcriptase inhibitors (RTIs) such as azidothymidine (AZT) and didanosine (ddI) lead to telomere shortening at high, potentially toxic concentrations. We hypothesized that those drugs might have synergistic effects enabling successful therapy with low, nontoxic concentrations. Biologic effects of AZT and ddI were analyzed at concentrations that correspond to minimal plasma levels achieved during human immunodeficiency virus therapy. Long-term coapplication of low-dose AZT and ddI induced a significant shortening of telomeres in the tumor cell lines HCT-116, SkMel-28, MelJuso, and Jurkat. Treatment of cells with both RTI, but not with single RTI, led to a significant accumulation of γH2AX, to p53 phosphorylation, and to cell apoptosis in all cell lines. Oral low-dose dual RTI application but not low-dose single RTI application was associated with a significantly reduced tumor growth of HCT-116 cells in mice. This antiproliferative activity of the combined use of AZT and ddI at low, clinically applicable concentrations warrants clinical testing in human solid cancer.
authors.affiliation: Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aschacher
authors.forename: Sandra
authors.initials: S
authors.lastname: Sampl
authors.forename: Lisa
authors.initials: L
authors.lastname: Käser
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.forename: Michael
authors.initials: M
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015139:Blotting, Southern; D045744:Cell Line, Tumor; D016049:Didanosine / Q000008:administration & dosage*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D060888:Real-Time Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage; D016615:Telomere / Q000187:drug effects; D059506:Telomere Shortening / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D015215:Zidovudine / Q000008:administration & dosage*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016049:Didanosine