Inpharma 1348 - 27 Jul 2002

Antisense Efp oligonucleotideshows antitumour activity

Tumour growth of breast cancer MCF7 cellsimplanted into intact female athymic mice is reduced bytreatment with antisense Efp oligonucleotide, reportresearchers from Japan.

In this study, athymic female mice were inoculatedwith MCF7 cells followed by ovariectomy or treatmentwith either sense/antisense Efp oligonucleotide orvehicle (controls).

Efp expression in tumours from ovariectomised orantisense Efp-treated mice were markedly reduced,compared with levels of Efp in controls, suggesting thatboth ovariectomy and antisense Efp oligonucleotideimpaired Efp expression. Tumour volume increased incontrols, but not in ovariectomised mice, and wasinhibited in a dose-dependent fashion in antisense Efp-treated mice, thereby implicating Efp as an oncogenicfactor in breast cancers.

In another series of experiments, the researchersconfirmed the role of Efp in tumour growth byinoculating intact athymic mice with transfected MCF7cells. Mice were ovariectomised at a tumour volume of180mm3. Tumours did not grow in vector-MCF7animals, whereas tumour volume increased in Efp-MCF7 animals.

The researchers then determined that loss of Efpfunction causes an accumulation of 14-3-3σ (a negativecell cycle regulator that arrests cells in G2 phase of thecell cycle before mitosis is initiated) and inhibits cellproliferation. They examined the effects of 14-3-3σantisense/sense oligonucleotides on mouse embryonicfibroblast (MEF) cell growth by collecting cells 24 or 48hours after initial incubation with oligonucleotides.Reduced growth in Efp-/- MEFs was rescued by antisense14-3-3σ oligonucleotide in a dose-dependent manner,‘suggesting that 14-3-3σ is the principal checkpoint inEfp-/- MEFs’, say the researchers.

The researchers conclude that their data ‘haveimportant clinical relevance because targeting the Efp-mediated breakdown of 14-3-3σ could provide a newtherapy to block breast tumour proliferation’.Urano T, et al. Efp targets 14-3-3-sigma for proteolysis and promotes breasttumour growth. Nature 417: 871-875, 20 Jun 2002 800901356

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Inpharma 27 Jul 2002 No. 13481173-8324/10/1348-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved