Liposomal-polyene preliposomal powder and method for its preparation

A method is disclosed for preparing a stable preliposomal powder which, when reconstituted with water or saline solution, forms a suspension of liposomes containing a polyene drug, such as nystatin. The method involves the steps of combining at least one phospholipid with a first organic solvent to form a first solution, adding a clarifying amount of water to the first solution, combining a polyene with a second organic solvent to form a second solution, combining the first and second solutions to produce a substantially clear combined solution, and then removing the organic solvents, leaving a powder.Board of Regents, University of Texas Syste

Hydrophobic cis-platinum complexes efficiently incorporated into liposomes

The present invention involves the synthesis and use of new platinum compounds. These new platinum compounds are easy to encapsulate in liposomes at high efficiencies. They are further characterized as platinum (II) four coordinate complex having the formula: ##STR1## wherein R.sub.1 and R.sub.2 are carboxylato monoanions bearing a hydrophobic radical function or a single carboxylato dianion bearing a hydrophobic radical function and R.sub.3 is a vicinal diaminoalkane or vicinal diaminocycloalkane. The complex is substantially soluble in methanol or chloroform and substantially insoluble in water. Said complex may be incorporated into phospholipid liposomes. Such platinum complexes encapsulated in phospholipid liposomes are useful for chemotherapy of platinum complex-sensitive tumors.Board of Regents, University of Texas Syste

Method of identifying inhibitors of glutathione S-transferase (GST) gene expression

Complementary DNA and genomic clones for three variants of GST-.pi. are disclosed. It is demonstrated that certain of these variants are overexpressed in gliomas, thereby indicating an involvement with that form of cancer. This permits the detection and treatment of certain classes of tumors using new compositions such as GST-.pi. genes, oligonucleotides, peptides and antibodies.Board of Regents, University of Texas Syste

Targeting Interleukin-27 Receptor α in Murine HGSC Cells

https://openworks.mdanderson.org/sumexp23/1119/thumbnail.jp

Targeting AXL with a Highly Stable Modified Aptamer in Medulloblastoma Cell Lines

https://openworks.mdanderson.org/sumexp22/1081/thumbnail.jp

Anti-tumoral activity of Acetogenins derived from Soursop Fruit (Annona muricata L.) in High Grade Serous Ovarian Cancer

https://openworks.mdanderson.org/sumexp21/1253/thumbnail.jp

Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression

MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer, and resulting in increased tumor growth and metastasis. Here, we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using DOPC nanoliposomes resulted in increased tumor growth and metastasis and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line based overexpression of sense or anti-sense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer

MicroRNA 603 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting elongation factor 2 kinase

Triple negative breast cancer (TNBC) is an aggressive type of breast cancer characterized by the absence of defined molecular targets, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and is associated with high rates of relapse and distant metastasis despite surgery and adjuvant chemotherapy. The lack of effective targeted therapies for TNBC represents an unmet therapeutic challenge. Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical calcium/calmodulin-dependent serine/threonine kinase that promotes TNBC tumorigenesis, progression, and drug resistance, representing a potential novel molecular target. However, the mechanisms regulating eEF2K expression are unknown. Here, we report that eEF2K protein expression is highly up-regulated in TNBC cells and patient tumors and it is associated with poor patient survival and clinical outcome. We found that loss/reduced expression of miR-603 leads to eEF2K overexpression in TNBC cell lines. Its expression results in inhibition of eEF2K by directly targeting the 3-UTR and the inhibition of tumor cell growth, migration and invasion in TNBC. In vivo therapeutic gene delivery of miR-603 into TNBC xenograft mouse models by systemic administration of miR-603-nanoparticles led to a significant inhibition of eEF2K expression and tumor growth, which was associated with decreased activity of the downstream targets of eEF2K, including Src, Akt, cyclin D1 and c-myc. Our findings suggest that miR-603 functions as a tumor suppressor and loss of miR-603 expression leads to increase in eEF2K expression and contributes to the growth, invasion, and progression of TNBC. Taken together, our data suggest that miR-603-based gene therapy is a potential strategy against TNBC

Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia

: Recent studies suggest that the Bcl-2 and mitogen-activated protein kinase (MAPK) pathways together confer an aggressive, apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells. In this study, we analyzed the effects of simultaneous inhibition of these 2 pathways. In AML cell lines with constitutively activated MAPK, MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the synergistic nature of this interaction. Moreover, MEK blockade overcame Bcl-2 overexpression-mediated resistance to the proapoptotic effects of HA14-1. Most importantly, simultaneous exposure to PD184352 significantly (P =.01) potentiated HA14-1-mediated inhibition of clonogenic growth in all primary AML samples tested. These findings show that the Bcl-2 and MAPK pathways are relevant molecular targets in AML and that their concurrent inhibition could be developed into a new therapeutic strategy for this disease