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THE LANCET Oncology Vol 5 June 2004 http://oncology.thelancet.com336

Newsdesk

Scientists have developed a molecularcomputer, made of DNA, with thepotential to analyse and control geneexpression. Although years away fromclinical application, the device mighteventually be used to diagnose sometypes of cancer and to react by releasinga drug molecule against cancer cells.

The minuscule machine, so smallthat one trillion would fit into a dropof water, has been programmed toidentify and analyse mRNA of disease-related genes associated with a modelof small-cell lung cancer (SCLC) and

prostate cancer, and to produce asingle-stranded (ss) DNA moleculemodelled on a drug with knownanticancer activity.

The molecular computer has inputand output programmable modules aswell as software, which are encoded inthe four letters of the genetic code. Thehardware (the part of the device thatdoes not change) is an enzyme (Fok1)that cuts the strands of DNA in a

specific way. The automation has twostates: positive and negative. Thecomputation starts in the positive state

and if it ends in that state, then it iscalled a positive diagnosis; otherwise itis called a negative diagnosis.

The authors of the study (Nature,published online April 28, 2004; DOI:10.1038/nature02551) programmed thecomputer to detect the type of mRNAthat would be present if specificgenes associated with cancer wereupregulated or downregulated. In theSCLC model used in the experiments,

the computer was instructed toadminister the ssDNA moleculeoblimersenpurported to be anantisense drug for treatment of SCLCprovided that the genes ASCL1, GRIA2,INSM1 and PTTG1 were over-expressed. In the prostate cancermodel, PPAP2Band GSTP1 needed tobe underexpressed and PIM1 and HPNoverexpressed.

The ultimate idea is that thesedevices could diagnose cancer fromwithin cells and dispense drugs asnecessary, says lead author Ehud

Shapiro, Weizmann Institute ofScience, Rehovot, Israel. Our medicalcomputer might one day beadministered as a drug, and bedistributed throughout the body by thebloodstream to detect disease markersautonomously in every cell. He adds:In this way, a single cancer cell couldbe detected and destroyed before thetumour develops.Xavier Bosch

Nanocomputers to diagnose and treat cancer

By screening the activity of as few as six genes, clinicianshave predicted the very different outcomes of patients withdiffuse large B-cell lymphoma, the most common form ofnon-Hodgkin lymphoma. Their screen uses RT-PCRtechnology, making the test manageable for routine use.

Keen to find genetic signatures that would predict apatients survival or their response to treatment, scientistshave been toying with microarrays for the past 5 years. Theirefforts resulted in long lists of candidate genes; however, noroutine screen is available. It is also a concern that manyclinical laboratories do not have the technology to screen

large numbers of genes.Ronald Levy and colleagues at Stanford University

(Stanford, CA, USA) therefore wanted to identify a smallgroup of genes whose expression predicts survival inpatients with diffuse large B-cell lymphoma, and which canbe measured easily. They used RT-PCR to measure theactivity of 36 genes in tumour samples from 66 patients withdiffuse large B-cell lymphoma. These 36 genes hadpreviously been identified as predictors of positive andnegative prognosis.

The researchers found that expression of only sixgenesLM02, BCL6, FN1, CCND2, SCYA3, and BCL2could predict how long the patients survived (N Engl J Med

2004;350:

182837). The scientists validated the six-genemodel in 298 patients who had participated in two previous

microarray studies and concluded that the model couldidentify patients who do not respond well to standardtherapy and who might benefit from new treatments.

According to Levy, the group will now check how wellthe six genes discriminate between good and bad respondersin other groups of patients, especially those who arereceiving treatments that were not available when theoriginal patients were treated. If all goes well, the scientistswant to make the screen widely available.

Levy believes an RT-PCR-based test is more likely to beused in routine practice than a microarray assay because

medical labs already use RT-PCR for other disease tests.However, Louis Staudt at the National Cancer Institute(Bethesda, MD, USA) emphasises that a diagnostic methodthat could use more genes to measure the biological features[of tumours] would have greater predictive accuracy.Staudt and colleagues previously published a 17-gene modelthat was associated with a higher degree of accuracy than thesix-gene model (N Engl J Med 2002; 346: 193747).Screening more genes would require the use of microarraytechnology, but Staudt points out that a miniarray canaccommodate more than 2000 genes and could be as costeffective as using RT-PCR. I guess the future will tell whichof the particular diagnostic platforms will prove to be most

valuable for patients, concludes Staudt.Martina Habeck

Six-gene profile predicts survival of lymphoma patients

Small-scale detection aids cancer treatment.

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