To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts.In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m(2)) and cytarabine (1 or 2 g/m(2) twice a day if ≥65 or <65 years old, respectively) were given. The study used a standard 3+3 dose escalation design.Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment.Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings.
The proline-rich homeodomain protein, PRH/HEX, participates in the early development of the brain, thyroid, and liver and in the later regenerative processes of damaged liver, vascular endothelial, and hematopoietic cells. A virulent strain of lymphocytic choriomeningitis virus (LCMV-WE) that destroys hematopoietic, vascular, and liver functions also alters the transcription and subcellular localization of PRH. A related virus (LCMV-ARM) that does not cause disease in primates can infect cells without affecting PRH. Biochemical experiments demonstrated the occurrence of binding between the viral RING protein (Z) and PRH, and genetic experiments mapped the PRH-suppressing phenotype to the large (L) segment of the viral genome, which encodes the Z and polymerase genes. The Z protein is clearly involved with PRH, but other viral determinants are needed to relocate PRH and to promote disease. By down-regulating PRH, the arenavirus is able to eliminate the antiproliferative effects of PRH and to promote liver cell division. The interaction of an arenavirus with a homeodomain protein suggests a mechanism for viral teratogenic effects and for the tissue-specific manifestations of arenavirus disease.
Human herpesvirus 8 (HHV-8) is a recently discovered, virus that is highly associated with Kaposi's sarcoma (KS) and AIDS-associated body cavity lymphomas, although it is also found in some normal individuals. HHV-8 is related by nucleotide sequence homology to herpesvirus saimiri (HVS), which causes T cell lymphomas in some New World monkeys, and to Epstein-Barr virus (EBV), a human herpesvirus linked etiologically with Burkitt's lymphoma and nasopharyngeal carcinoma. We report that, like HVS but unlike EBV, HHV-8 contains a gene (ORF74) with significant sequence homology to the high-affinity IL-8 receptor, a member of the alpha (CXC) chemokine receptor family of transmembrane G protein-coupled receptors. We also show by reverse transcription PCR that the chemokine receptor-related HHV-8 gene is detectable in some RNA samples from KS tissue, and that its expression varies independently from that of ORF26, a minor capsid protein. The presence of a potential chemokine receptor in HHV-8 and its expression in KS tissue suggests that it may be important in the regulation of viral gene expression and may play a role in the etiology of KS and AIDS-related body cavity lymphomas.
Abstract Background: DCA increases pyruvate dehydrogenase activity via inhibition of pyruvate dehydrogenase kinase, which shunts pyruvate away from lactate production into the mitochondrial respiration, resulting in enhanced mitochondrial activity. As2O3 is approved for treatment of relapsed/refractory acute promyelocytic leukemia (APL). As2O3 as a single agent or in combination with cytarabine is ineffective for treatment of non-APL acute myeloid leukemia (AML) by most studies. As2O3 affects several different molecular targets and cellular functions such as decreasing mitochondrial membrane potential by opening permeability transition pore complex in membranes, reactive oxygen species production, and caspase pathways activation. We hypothesized that combination of DCA, as a mitochondrial respiration enhancer, and As2O3, which impairs mitochondrial activity, would have anti-leukemic synergistic effects and potentially overcome drug resistance particularly in relapsed/refractory AML. Methods: IC50s for As2O3 and DCA were generated for two AML cell lines, MOLM-14 and MV4-11, the latter carries FLT3-ITD mutation. Cells were treated with DCA at IC30 and As2O3 either concurrently for 72 h or sequentially with 48 h exposure to DCA followed by the addition of As2O3 (100 nM - 5μM) for 48 h. Each experiment was terminated with WST-1 (Roche). Viability of cells was assessed by trypan blue exclusion. Experiments were performed in triplicate. Results: IC50s for As2O3 and DCA were 0.88 ± 0.02 μM and 15.87 ± 1.22 mM for MOLM-14, 0.54 ± 0.03 μM and 19.08 ± 2.25 mM for MV4-11, respectively. When treated concurrently, the potentiation factors were 1.8 and 1.3 for MOLM-14 and MV4-11, respectively. When the cells were pretreated or "primed" with DCA for 48 h and then exposed to As2O3 for 48 h, the potentiation factors were 2 and 1.8 for MOLM-14 and MV4-11, respectively. Viability tests showed a 33-50% increase in cell kill when DCA and As2O3 were used in combination compared to As2O3 or DCA alone. The number of viable cells remaining after combination treatment was significantly lower than the number of viable cells after either treatment alone when treated sequentially or concurrently (p<0.05). Further mechanistic studies and preclinical models are ongoing to best predict the future clinical dose and schedule. Conclusion: Combination of DCA (IC30, 11 mM) and As2O3 whether used sequentially or concurrently in AML cells caused significantly more cellular damage as compared to either drug alone. To the best of our knowledge, this is the first report of the combination of DCA+As2O3 against AML cells. These data suggest that targeting cellular metabolism in leukemia may provide a therapeutic option for AML patients with unfavorable risk, such as relapsed/refractory, FLT3-ITD or who are not candidates for cytotoxic agents and warrant further clinical investigation. Citation Format: Ashkan Emadi, Mariola Sadowska, Brandon A. Carter-Cooper, Rena G. Lapidus, Edward A. Sausville. Targeting leukemia metabolism: augmentation of anti-leukemic activity of arsenic trioxide (As2O3) against non-APL AML cell lines in presence of dichloroacetate (DCA). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3268. doi:10.1158/1538-7445.AM2013-3268
