The effect of Gö6976 on chronic myeloid leukemia in vitro and in vivo.

Objectives: Chronic myeloid leukemia (CML) is a malignant tumor of the blood system. Gö6976, as a type of indolocarbazole and shows strong antitumor effects, but there have been no reports on the effect of Gö6976 on CML. The objectives of this research were: (1) to explore the impact of Gö6976 on CML in vitro and in vivo; and (2) to explore the drug toxicity of Gö6976 to normal cells and animals.Methods:K562 cells and CML mice were used to explore the effect of Gö6976 on CML. Peripheral blood mononuclear cells (PBMCs), CD34+ cells, and healthy mice were used to explore the drug toxicity of Gö6976.Results: Cell experiments showed that Gö6976 could inhibit the proliferation of K562 cells and enhance the inhibitory effects of imatinib at 5 µM and 10 µM, but it had little effect on CD34+ cells or PBMCs at concentrations less than 5 µM. Animal experiments showed that 2.5 mg/kg Gö6976 could effectively inhibit the development of CML in mice, and it had almost no effects on healthy mice at 2.5 mg/kg and 10 mg/kg.Discussion: Because of the direct inhibitory effect of Gö6976 on CML and its pharmacological enhancement effect on imatinib, it is foreseeable that Gö6976 could become a new type of anti-CML medicine. And the further research is needed.Conclusion: Our findings verified that Gö6976 could effectively inhibit CML in vitro and in vivo, and it is almost nontoxic to hematopoietic cells, immune cells, and healthy mice.

Behavioral effects of rimcazole analogues alone and in combination with cocaine.

Several sigma receptor ligands have been reported to also have affinity for the dopamine transporter, among them rimcazole (9-[3-(cis-3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride). However, rimcazole lacks behavioral effects like those of other dopamine uptake inhibitors, such as cocaine and GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride). Because of this profile, the interactions with cocaine of rimcazole and several of its novel analogues were assessed. The compounds studied were rimcazole, its N-methyl analogue, SH 1-73 (9-[3-(cis-3,5-dimethyl-4-methyl-1-piperazinyl)-propyl]carbazole hydrobromide), the dibrominated analogue, SH 1-76 (3,6-dibromo-9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole hydrochloride), and the N-propylphenyl analogues, SH 3-24 ([3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride) and SH 3-28 (9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide). The former has a diphenyl-amine group in place of the carbazole moiety of rimcazole, giving the compound additional structural similarity to GBR 12909. The rimcazole analogues produced dose-related decreases in locomotor activity, and also decreased cocaine-stimulated activity in mice. In rats trained to discriminate 10 mg/kg cocaine (i.p.) from saline injections, cocaine and GBR 12909 each produced a dose-related increase in cocaine-appropriate responding. Cocaine also increased rates of responding. SH 3-28 decreased cocaine-appropriate responding at the cocaine training dose to about 58% (SH 3-28) with two of five subjects selecting the cocaine response key. Neither rimcazole nor SH 3-24 produced a significant attenuation of the discriminative effects of cocaine. Rimcazole and its analogs all attenuated the increases in rates of responding produced by cocaine. In contrast to effects obtained with rimcazole analogs, GBR 12909 potentiated the cocaine-induced increases in locomotor activity and operant behavior, as well as the discriminative-stimulus effects of cocaine. The present results indicate that analogues of rimcazole can attenuate the behavioral effects of cocaine, and though the mechanism for these effects is not presently clear, it is possible that this attenuation maybe mediated by actions of the rimcazole analogues at the dopamine transporter and/or sigma receptors.

[Studies on agonists and antagonists of smooth muscle contraction by the use of an actomyosin preparation].

The sites of action of many chemical agents that modify the contraction of smooth muscle are in the smooth muscle membrane. However, a few agents, such as calmodulin inhibitors and protein kinase inhibitors, interact directly with contractile elements of the actomyosin system so as to modify smooth muscle contraction. Here, we describe experimental procedures that are applicable for the screening of smooth muscle relaxants with this mode of action. Myosin B was extracted from chicken gizzard smooth muscle. Because myosin B was a crude preparation of smooth muscle actomyosin, it consisted of regulatory proteins of calmodulin, myosin light chain kinase and protein phosphatase in addition to the contractile proteins of actin and myosin. Interaction of chemical agents with these proteins could be detected by measuring the Mg-ATPase activity of the myosin B preparation. Then we examined whether the agents that altered the ATPase activity was associated with changes in phosphorylation of myosin light chain. If the levels are altered, the agents may interact with the regulatory protein(s). If not, the site of their action was in the contractile proteins. The analysis with these respective proteins will be also described.