Protection of normal hematopoietic stem cells from the toxicity of purine base analogs: in vivo application.
Normal murine bone marrow cells were incubated with adenosine (100 microM) for 2 hrs followed by the addition of 6-thioguanine (6-TG) (0.3 and 1.0 microgram/ml) for 1, 24, and 48 hrs, and the survival of the committed stem cells (CFUc) and pluripotential stem cells (CFUs) was compared to the survival of CFUc and CFUs which were similarly incubated without adenosine. When 0.3 microgram/ml of 6-TG was used, preincubation with adenosine increased the survival of CFUc from 25% to 80% and from 14% to 36% for 24- and 48-hr incubations, respectively (P less than or equal to 0.005). For 1 microgram/ml of 6-TG, pretreatment with adenosine increased survival from from 11% to 69% and from 5% to 24%, respectively, for 24- and 48-hr incubations (P less than or equal to 0.0005). Adenosine had a similar effect on CFUs (P less than or equal to 0.03). This effect was not seen when equimolar concentrations of hypoxanthine, inosine, or adenine were substituted for adenosine. Inoculation of adenosine into mice (500 mg/kg of body weight) 1 hr prior to injection of lethal doses of 6-TG (50 mg/kg) increased the survival of the mice from 10% to 100% and from 20% to 80%, respectively, using two administration schedules. This effect of adenosine, which, as has been previously shown, is the result of the depletion of cellular phosphoribosyl pyrophosphate pools, is potentially useful for the selective protection of normal hematopoietic cells from the toxicity of purine analogs which require activation via a phosphoribosyl pyrophosphate-dependent reaction, while therapeutic effects are produced against malignant tissue.
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D051379:Mice; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011687:Purines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013866:Thioguanine / Q000037:antagonists & inhibitors / Q000633:toxicity; D014529:Uridine / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D011687:Purines; D010754:Phosphoribosyl Pyrophosphate; D013866:Thioguanine; D000241:Adenosine; D014529:Uridine