Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of vesnarinone, an oral cardiotonic, on the growth and differentiation of human myeloid leukemia cells. Vesnarinone alone markedly induced erythroid differentiation of HEL cells. All-trans-retinoic acid also induced erythroid differentiation of the cells, and the differentiation was greatly enhanced by combined treatment with vesnarinone and retinoic acid. HEL cells are highly resistant to some anticancer drugs, including vincristine, but treatment with vesnarinone greatly increased the sensitivity of HEL cells to vincristine. Enhancement of vincristine sensitivity by vesnarinone was not as significant for other leukemia cells. Expression of P-glycoprotein in HEL cells was effectively inhibited by vesnarinone, suggesting that the restoration of vincristine sensitivity is associated with decrease of P-glycoprotein expression in HEL cells. The plasma level of vesnarinone required to induce differentiation of leukemia cells is 30 micrograms/mL, which could be achieved with oral administration. These results suggest that vesnarinone should be useful in differentiation therapy for some types of myelogenous leukemia.
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PMID:Induction of differentiation and enhancement of vincristine sensitivity of human erythroleukemia HEL cells by vesnarinone, a positive inotropic agent. 853 90

Vesnarinone is a positive inotropic agent used for treating congestive heart failure. We evaluated its ex vivo effects on myeloid leukemia cell lines and primary acute myelogenous leukemia cells. Vesnarinone inhibited the incorporation of radiolabeled thymidine by a myeloid cell line, HL60, in a dose-dependent manner at concentrations ranging from 0.1 to 30 microg/mL. A maximum 40% suppression was seen at a concentration of 10 microg/mL. Determination of viable cell counts by trypan blue dye exclusion method demonstrated vesnarinone to be cytocidal for HL60 cells. Vesnarinone induced DNA fragmentation as detected by electrophresis in HL60 cells after 72-hour culture; this effect was not inhibited by G-CSF. The apoptosis induced by vesnarinone was also detected by the in situ end-labeling method. Northern blot analysis showed a reduction of c-myc mRNA expression in HL60 cells by vesnarinone. However, immunostaining assay showed no change in the expression of Fas and Bcl-2 proteins. We next examined the effect of vesnarinone on primary myeloid leukemia cells derived from 10 patients: 3 cases of M1, 2 of M2, 3 of M3, 1 of M4, and 1 of M6, by the French-American-British classification. Vesnarinone inhibited the incorporation of thymidine in all cells, with a mean suppression of 58.1%. DNA electrophoresis showed induction of DNA fragmentation in cultured cells with vesnarinone for 72 hours in 8 of the 10 patients with primary leukemia. However, bone marrow mononuclear cells from healthy controls showed no growth suppression or DNA fragmentation in response to vesnarinone. These results suggest that vesnarinone may be useful in treating myeloid leukemia.
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PMID:Vesnarinone exhibits antitumor effect against myeloid leukemia cells via apoptosis. 932 55

Vesnarinone (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone), a quinolinone derivative, is an orally active inotropic agent used in Japan for the treatment of chronic heart failure. Recently, it has been reported that vesnarinone induces differentiation and apoptosis in certain types of leukaemia and solid tumour cells, and exhibits antitumour effect on several tumours xenografted in nude mice. In the present study, we examined the antitumour effect of vesnarinone in combination with radiation and conventional anticancer agents in nude mice xenografted with human gastric carcinoma, a poorly-differentiated adenocarcinoma, MKN-45 cell line which has a wild-type p53 gene. Vesnarinone treatment combined with radiation resulted in a higher antitumour activity compared with a single treatment with either vesnarinone or radiation alone. Further, vesnarinone treatment together with radiation and conventional anticancer agents including 5-FU and picibanil (an immunopotentiator) produced the highest antitumour effect compared with any other treatment. Additionally, the combination treatment induced marked differentiation and apoptosis of the tumour cells and an increase in the expression of p53 gene in the treated tumour cells. The results suggest that vesnarinone, in combination with radiation and the conventional antitumour agents, may be of clinical interest for treatment of certain types of gastric tumours.
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PMID:Enhancement of anticancer effects of radiation and conventional anticancer agents by a quinolinone derivative, vesnarinone: studies on human gastric cancer tissue xenografts in nude mice. 956 10

Vesnarinone has been shown to be a unique anti-proliferating, differentiation-inducing and apoptosis inducing drug against several human malignancies, including leukemia and several solid tumors. Furthermore, vesnarinone potentiates the effect of conventional cytotoxic chemotherapy or radiation therapy. Combination of differentiation-inducing therapy by vesnarinone with conventional chemotherapy or radiation therapy might be second- or third-line therapy in patients with advanced cancer. Analysis of the molecular mechanisms of the tumor differentiation therapy by vesnarinone might provide selective and targeted molecules for novel tumor dormancy therapy.
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PMID:Vesnarinone: a differentiation-inducing anti-cancer drug. 1285 78