Preclincal Study Digest | Parkinsons, Nanoparticles & Ovarian Cancer
Parkinson’s disease
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| Source: Carestream |
Proc Natl Acad Sci U S A. 2010 Sep 28; 107(39):16970-5.
Findings from human patients, yeast and a mouse model imply that defects in polyamine pathway play a role in Parkinson’s disease pathogenesis, suggesting that existing drugs may be able to slow progression of the disease. Using high-resolution functional MRI, researchers identified a region in the brainstem of patients with Parkinson’s that was consistently less active than in healthy control subjects. Next, using brain tissue from deceased patients with Parkinson’s, the researchers looked for proteins that could potentially explain the brainstem imaging differences and identified a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). To validate the finding, three separate studies—in yeast, mice and people—were performed by the researchers.
The yeast studies found that yeast cells, engineered to produce the toxic Parkinson’s protein, die more quickly in the presence of increasing polyamine levels.
In the mice studies, a link was established among SAT1, polyamines, and Parkinson’s toxins in a mammalian brain. These experiments also revealed that drugs that target SAT1 may be able to slow down the progression of Parkinson’s disease. Using drugs that increase SAT1 activity and therefore lower polyamine levels, researchers found a decrease in Parkinson’s toxins and the damage which they cause within brain regions affected by the disease.
Genetic studies in patients with Parkinson’s provided further evidence that polyamines may help drive Parkinson’s disease in people. After examining the SAT1 gene in 92 patients with Parkinson’s and additional genotyping in a further 797 subjects (389 PD patients and 408 controls), the researchers uncovered a novel genetic variant that was found exclusively in the study’s patients with Parkinson’s but not in controls. The group is now testing current polyamine-lowering drugs to see if the compounds pass through the blood-brain barrier, or if they can be altered to do so.
Nanoparticles in multimodal imaging
In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imagingJ Am Chem Soc. 2010 Sep 29; 132(38):13270-8.
Iron-platinum alloy (FePt) nanoparticles can potentially be used as dual modal CT/MRI molecular imaging contrast agents in clinical settings. The water-solvable FePt nanoparticles of 3nm, 6 nm and 12 nm in diameter were synthesized and applied as a dual modality contrast agent for CT/MRI molecular imaging by researchers. The biodistribution analysis revealed the highest serum concentration and circulation half-life for 12 nm-FePt, followed by 6 nm-FePt and then 3 nm-FePt. The researchers demonstrated molecular expression dependent CT/MRI dual imaging contrast effect in MBT2 cell line and in tumor-bearing mice. The 12 nm-FePt outperformed 3nm-FePt in both imaging modalities. These results indicate the potential of FePt nanoparticles to serve as novel multimodal molecular imaging contrast agents in clinical settings.
Ovarian cancer
18F-FLT PET as a surrogate marker of drug efficacy during mTOR inhibition by everolimus in a preclinical cisplatin-resistant ovarian tumor modelJ Nucl Med. 2010 Oct; 51(10):1559-64.
PET with 18F-FLT can monitor early response to treatment for cisplatin-resistant ovarian tumors by mammalian target of rapamycin (mTOR) inhibitors. BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle. During the treatment period, no significant change in tumor 18F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, 18F-FLT SUV mean decreased by 33 percent at day two and 66 percent at day seven, compared with baseline. The study showed that 18F-FLT PET was able to predict early response to mTOR inhibition in a cisplatin-resistant ovarian cancer in mice.