Biomedical subjects

I Nathan

Publications and source records attributed to I Nathan.

75 records · Page 5Linked to original sources

PubMedDate not supplied

Non-steroidal antiestrogens induce apoptosis in HL60 and MOLT3 leukemic cells; involvement of reactive oxygen radicals and protein kinase C.

The antitumoral activity of non-steroidal antiestrogens on promyelocytic leukemia HL60 and T lymphoblastic MOLT3 cell lines was studied. Tamoxifen and its derivatives, clomiphene and nafoxidine, caused reduction of cell viability in a dose-dependent manner. These drugs showed differences in their potency following four days incubation, with nafoxidine being the most efficient inhibitor and tamoxifen the least active. Apoptosis was induced as assessed by the DNA ladder pattern and formation of pre G0/G1 population as detected by flow cytometry analysis of DNA. The effect of these drugs was abrogated by antioxidants: alpha-tocopherol was most effective in antagonizing the drugs' effect. N-acetyl L-cysteine reversed mainly the decrease in cell viability caused by the drugs, but was less active on induction of apoptosis. GF109203X, a protein kinase inhibitor, attenuated apoptosis induced by clomiphene in MOLT3 cells. The results suggest that the antileukemic activity of the antiestrogens is mediated by oxidative stress and protein kinase C (PKC) activation. Triphenylethylene antiestrogens and their derivatives may be used as antileukemic drugs which kill cells by apoptosis mediated by oxidative stress and activation of PKC.

Acetylcysteine↗

PubMedDate not supplied

New combination of 5-fluorouracil and interferon-gamma effective against human myeloid leukemia in vitro.

The therapeutic potential of recombinant interferon gamma (IFN gamma) alone or in combination with two cytotoxic drugs - 5-fluorouracil (5-FU) and cytosine arabinoside (Ara-C) - was studied in vitro on two myeloid leukemia systems: HL60 promyelocytic cell line and chronic granulocytic leukemia (CGL) progenitor cells. When applied individually, IFN gamma and the drugs inhibited in a dose-dependent manner HL60 cell colony formation in semisolid culture. Moreover, IFN gamma or the cytotoxic drugs dose-dependently reduced the colony formation of CGL progenitor cell in agar. When added in combination, IFN gamma potentiated synergistically the inhibitory action of 5-FU in both systems. The most pronounced potentiation was detected at concentrations of 0.5 microgram/ml 5-FU and 50 U/ml IFN gamma. On the contrary, the antiproliferative effect of Ara-C was enhanced only subadditively when combined with IFN gamma. In view of the present findings, which are supported by new evidence from the literature, the use of 5-FU in leukemia should be reconsidered. The results further imply the potential value of combined treatment of 5-FU and IFN gamma in leukemia.

Cell Line↗

PubMedDate not supplied

TPK inhibitors differentially affect IFN-gamma activities.

The effect of various tyrosine protein kinase inhibitors on processes involved in the antiproliferative effect of interferon-gamma on WISH cells was studied. Following 24 hr treatment interferon-gamma inhibited thymidine incorporation into DNA and thymidine kinase activity, but no significant effect on cell number was observed. The isoflavonoid, genistein, which is a specific inhibitor of tyrosine protein kinase, reversed the inhibition in thymidine incorporation caused by the cytokine in a dose dependent manner. Prunetin, a member of the same group, did not significantly antagonize this effect. N alpha-tosyl-L-lysyl-chloromethane, a serine protease inhibitor which also serves as a tyrosine protein kinase inhibitor, partially reversed the effect of interferon-gamma at a concentration of 100 microM. The bioflavonoid, quercetin, a non-specific tyrosine protein kinase inhibitor, at a concentration of 30 microM completely abolished the action of interferon-gamma on thymidine incorporation. Genistein completely reversed the inhibition of thymidine kinase exerted by interferon, while quercetin had only a slight effect. However, the drugs could not antagonize the antiproliferative effect of interferon following 48 hr incubation, as measured by reduction of cell number. The results indicate that tyrosine protein kinase may play a role in the effects of interferon on thymidine metabolism and thymidine kinase activity. The differential effects of the inhibitors on thymidine metabolism and cell proliferation could support dissociation between the effect of interferon-gamma on these processes. Alternatively, this dissociation of effects could point to the limited use of inhibitors in clarifying modes of action as described.

Cell Division↗