alpha-2--deoxythioguanosine and Neoplasms

Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells. Here, we show that treatment with a telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression through innate and adaptive immune-dependent responses in syngeneic and humanized mouse models of telomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8

Topics: Adaptive Immunity; Animals; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Deoxyguanosine; HCT116 Cells; Humans; Immunity, Innate; Membrane Proteins; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Neoplasms, Experimental; Signal Transduction; Telomerase; Telomere; Thionucleosides; Tumor Burden

alpha-2'-Deoxythioguanosine (alpha-TGdR) was administered as a single dose to 13 cancer patients in 18 experiments at dose levels of 150--1500 mg/m2 and as a daily dose to 22 patients in 42 experiments at dose levels of 100--4000 mg/m2/day X 5 days. No significant toxicity was observed. Blood levels and rates of excretion were determined with radiosulfur-labeled alpha-TGdR. Approximately 80% of the dose was excreted in the urine in 24 hours, initially as unchanged alpha-TGdR and increasingly as metabolites. Metabolites appear to be nucleosides and do not include 6-thioguanine, 6-thioxanthine, or 6-thiouric acid to any measurable extent. Small amounts of the alpha-TGdR in blood samples were bound to albumin and to erythrocyte membranes. Blood plasma levels of alpha-TGdR at the highest doses were in the range of 200--300 micrometer, declining in 24 hours to 67--124 micrometer.

Topics: Antineoplastic Agents; Biotransformation; Deoxyguanosine; Humans; Kinetics; Neoplasms; Thionucleosides