Detail of "3868-32-4"

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Characterization of the metabolic forms of 6-thioguanine responsible for cytotoxicity and induction of differentiation of HL-60 acute promyelocytic leukemia cells

Characterization of the metabolic forms of 6-thioguanine responsible for cytotoxicity and induction of differentiation of HL-60 acute promyelocytic leukemia cells. Ishiguro, Kimiko; Schwartz, Edward L.; Sartorelli, Alan C. (Sch. Med., Yale Univ., New Haven, CT 06510, USA). J. Cell. Physiol., 121(2), 383-90 (English) 1984. CODEN: JCLLAX. ISSN: 0021-9541. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) HL-60 human acute promyelocytic leukemia cells that lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity were developed by mutagenization and selection. These cells exhibited markedly decreased sensitivity to the cytotoxic action of 6-thioguanine (TG) [154-42-7] and, in contrast to parental HL-60 cells, had the capacity to undergo terminal granulocytic differentiation after treatment with this purine antimetabolite. Anal. of extracellular and intracellular metabolites of TG revealed negligible metab. of TG in these HGPRT-deficient (HGPRT-) HL-60 cells. These findings are consistent with the concept that inhibition of cellular replication requires generation of analog nucleoitde and suggest that TG itself is capable of initiation of differentiation. 6-Thioguanosine (TGuo) [85-31-4] had limited activity, whereas b-2'-deoxythioguanosine (dTGuo) [789-61-7] was inactive, as an inducer of maturation of HGPRT- HL-60 cells. These cells converted relatively large amts. of the nucleosides to the free base TG; the simultaneous exposure of cells to 8-aminoguanosine (AGuo) [3868-32-4], an inhibitor of purine nucleoside phosphorylase activity, decreased the degrdn. of TGuo and dTGuo to TG and promoted the intracellular accumulation of TG nucleotides, presumably through the action of nucleoside kinase activities. In a double mutant deficient in both HGPRT and deoxycytidine kinase (DCK) activities, dTGuo was devoid of cytotoxicity and was an effective inducer of maturation. The potency of dTGuo as an inducer in this system was not significantly affected by the presence of AGuo. These results suggested that dTGuo itself was also an active initiator of maturation. Thus, induction of differentiation appeared to be due to the free base, TG, as well as its deoxynucleoside form, dTGuo, whereas the formation of TG nucleotides appeared to antagonize maturation and produce cytotoxicity.

Differential cytotoxicity of deoxyguanosine and 8-aminoguanosine for human leukemic cell lines and normal bone marrow progenitor cells

Differential cytotoxicity of deoxyguanosine and 8-aminoguanosine for human leukemic cell lines and normal bone marrow progenitor cells. De Fouw, Nanneke J.; Ma, David D. F.; Michalevicz, Rita; Gray, Douglas A.; Hoffbrand, A. Victor (Dep. Haematol., R. Free Hosp., London NW3 2QG, UK). Hematol. Oncol., 2(2), 189-97 (English) 1984. CODEN: HAONDL. ISSN: 0278-0232. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The inhibitory effect of deoxyguanosine (GdR) [961-07-9] alone or in combination with the purine nucleoside phosphorylase (PNP) [9030-21-1] inhibitor 8-aminoguanosine (AG) [3868-32-4] was tested on human T, B, cALL and myeloid leukemia cell lines and on normal human bone marrow hemopoietic progenitor cells. GdR was found to be toxic by T-leukemia cells. AG (100mM) alone did not have any inhibitory effect, but when used with GdR (2.5 ′ 10-5M) a synergistic effect was seen towards T cells. Incubation with GdR and AG resulted in a marked decrease in cell viability (>90% in 3 and >75% in four of 5 T leukemic cell lines tested at 72 h). This drug combination did not inhibit the growth of non-T leukemic cells and was also non-toxic to normal bone marrow multipotent progenitor cells in vitro. Adenosine deaminase (ADA) [9026-93-1] acts consecutively with PNP in purine degrdn. The addn. of an ADA inhibitor, deoxycoformycin [53910-25-1] and deoxyadenosine [958-09-8], however, did not enhance the toxicity of GdR and AG for T cell leukemia. The possibility of using GdR and AG for in vitro removal of residual T leukemic blasts with the sparing of normal bone marrow cells, prior to autologous bone marrow transplantation, should be further explored.