To examine whether the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is altered in the endothelial cells in response to glucose and the significance of such alteration. We incubated human umbilical vein endothelial cells with media containing various glucose levels. We found an increase in MALAT1 expression peaking after 12 hrs of incubation in high glucose. This increase was associated with parallel increase in serum amyloid antigen 3 (SAA3), an inflammatory ligand and target of MALAT1 and was further accompanied by increase in mRNAs and proteins of inflammatory mediators, tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Renal tissue from the diabetic animals showed similar changes. Such cellular alterations were prevented following MALAT1 specific siRNA transfection. Results of this study indicate that LncRNA MALAT1 regulates glucose-induced up-regulation of inflammatory mediators IL-6 and TNF-α through activation of SAA3. Identification of such novel mechanism may lead to the development of RNA-based therapeutics targeting MALAT1 for diabetes-induced micro and macro vascular complications.

The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.

RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.

Lung cancer is the leading cause of cancer-related mortality in the United States. Only 15% of patients with this disease survive 5 years or longer. Early metastatic spread is the single most important reason for this poor outcome. The survival of patients with pathological stage I disease, that is, no evidence for metastatic spread, and molecular aberrations on chromosome 11p15.5 is equal to that of patients with stage II disease, that is, metastatic spread to hilar lymph nodes. RRM1 is a gene in this region, and it is haploinsufficient in at least 34% stage I patients. Here, we show that overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), suppressed migration, invasion, and metastasis formation, and increased survival in an animal model. Increased PTEN expression was required for the RRM1-induced suppression of cell motility and FAK phosphorylation. We conclude that RRM1 functions as a metastasis suppressor gene through induction of PTEN expression.

No abstract

The nucleotide metabolism enzyme ribonucleotide reductase is composed of a regulatory subunit (RRM1) and a catalytic subunit (RRM2). The RRM1 locus has frequent loss of heterozygosity in lung cancers, ectopic expression of RRM1 suppresses proliferation of ras-transformed mouse fibroblasts, and high levels of RRM1 expression are associated with a significant survival benefit in patients with lung cancer. In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G 2 cell cycle arrest, apoptosis, and efficient DNA damage repair. We generated strains of RRM1 transgenic mice and found that carcinogen-induced lung tumor formation was significantly suppressed. The tumor suppression was more pronounced in strains with high levels of RRM1 expression than in those with low levels of expression. DNA damage repair capacity in transgenic animals was determined, and RRM1 transgenic animals repaired chemically induced DNA damage with greater efficiency than control animals. We conclude that the regulatory subunit of ribonucleotide reductase has tumor suppressor activity that is mediated through efficient DNA damage repair. (Cancer Res 2006; 66(13): 6497-502)

There are several clinically useful endoperoxides, mainly artemisinin derivatives available in market for the treatment of malaria. These are highly potent drugs, with fastest parasite reduction ratio, broadest parasite stage specificity and effectiveness against all species of plasmodium in human. Endoperoxides are crystalline compounds having poor aqueous solubility. Several theories have been proposed for their mechanism of action, but the understanding is still incomplete. The major limitation of this class of compounds is the short half-life, requiring frequent administration, leading to noncompliance and recrudescence. Therefore, WHO recommends their use in combination with long acting antimalarial drugs (Artemisinin based combination therapy, ACT) to manage drug resistance, recrudescence, and non compliance. Endoperoxide compounds bind selectively to malaria-infected red blood cells and moderately to human plasma proteins. Artemisinin derivatives are converted primarily to the bioactive metabolite dihydroartemisinin after parenteral, oral or rectal administration. The rate of conversion is lowest for artelinic acid and highest for the water-soluble artesunate. Such conversion occurs largely in the liver by CYP enzymes. Oral bioavailability in animals ranges between 19 to 35%. Based on their liphophilicity, they tend to cross the blood-brain barrier, causing neurotoxicity in animal models. Efforts have been made to understand and develop pharmacokinetic-pharmacodynamic (PK-PD) correlation and identify PK-PD indices of endoperoxides. In the absence of the above, the selection of doses in ACTs has been empirical. There are several reports on clinical pharmacokinetic interactions of endoperoxides and their long acting partner drugs but as on date no clinically significant interaction has been reported. This review is an update on physicochemical, pharmacokinetic and pharmacodynamic properties of the endoperoxide antimalarials.

ClinicalTrials.gov identifier NCT00362050.