Interferon shot from guns, a ras oncogene impostor and heightenedbreast-cancer risk in some, but not all, cigarette smokers: These areonly three of 3,840 papers and posters scheduled for presentation atthe American Association for Cancer Research's 86th annualmeeting, now ongoing in Toronto.

Some 6,800 clinical and basic-science oncologists _ the largestregistrant roster in the association's 86-year history _ are attendingthe five-day conclave, which ends next Wednesday. Hardly a one ofthe 180 theme sessions and 30 symposia does not involve someaspect of biotechnology.

The following three papers suggest the flavor of the diverse databeing reported:

Gene Gun Shoots Cytokine Into First Cancerous Animal

A newly developed, hand-held, helium-driven, electrical dischargepulse gun drove millions of DNA-coated gold microspheres through50 cell layers, deep into subcutaneous tumors at Agracetus Inc., inMiddleton, Wisc.

Molecular oncologist Wenn Sun will report Tuesday to a session onExperimental and Clinical Gene Therapy that such non-viral, non-liposomal biolistic gene transfer "bypasses the need of in vitrotransfection and subsequent transplantation of gene-modified cells,and may have great clinical potential."

Using an earlier model instrument that fires through five cell layers,she and her co-workers co-transfected tumor-bearing mice with genesfor immunity-stimulating gamma interferon and interleukin-2.Twenty-five percent of the animals remained tumor-free for morethan 60 days after expressing these cytokine sequences in theirimplanted malignancies.

Molecular biologist Ning-Sun Yang, the principal author of Sun'spaper, is director of cancer gene therapy at Agracetus. He toldBioWorld Today that over the past 18 months, "my lab has carriedout 135 or so experiments, each involving 20 to 40 mice." Yang saidthat Agracetus has been developing the gene-projectile technologyover the past five to seven years, the last two in collaboration withgeriatric oncologist William Erschler at the University of Wisconsinin Madison.

Erschler is looking forward to eventual human trials with the heliumpulse gun. He said it "can potentially deliver any size gene to anytype of cell in any species."

Yang said, "We do not expect any human trials to happen until sometime next year at the earliest. We are still in the process offormulating our thoughts on this, what approach to take, what patientpopulation, and so on."

Meanwhile, the Agracetus-Wisconsin team, Yang added, "iscontinuing to optimize and evaluate the system." He pointed out that"among oncologists in the field, a mouse tumor model may be verydifferent from human clinical cancers."

Agracetus is a subsidiary of W.R. Grace & Co., of Boca Raton, Fla.

Neck-And-Neck Rival Tumor-Gene Inhibitors

Before the infamous ras oncogene can make cells malignant, it mustundergo an enzymatic processing step called farnesylation. Theenzyme that performs this oncogenic turn-on is farnesyltransferase.Molecular mimics of that peptide, aimed at beating the ras gene'sencoded product to the punch, have too many drawbacks to be usefulcancer therapy drugs.

Tomorrow, at a mini-symposium session on "Targeting ras," researchpharmacologist Said Sebti, of the University of Pittsburgh School ofMedicine, will introduce a non-peptide look-alike. This impostormolecule selectively inhibits farnesyltransferase, and thus preventsthe oncogene's pro-cancer processing.

Sebti will describe the compound's "several desirable features forfurther therapeutic development as anticancer drugs," notably itsresistance to enzymatic breakdown.

He is reporting that "in animal studies we and other groups haveselectively suppressed tumor growth without harmful effects."

"These really are the first drugs designed to block the action of asingle specific cancer gene," said Allen Oliff, executive director ofcancer research at Merck & Co., West Point, Pa. He added, "Theirspecificity will mean safer and more effective patient therapies."

Oliff has two reports on farnesyltransferase inhibitors in the same"Targeting-ras" mini-symposium. He said that Merck believes itsversion of the peptide mimetic is as potent as Pittsburgh's.

Smokers Have Higher Breast Cancer Risk

Why do some cigarette smokers get breast cancer and others don't?Is there a gene for this apparently random susceptibility?

Yes there is, reports Christine Ambrosone of the State University ofNew York at Buffalo, and it encodes an enzyme named N-acetyltransferase _ NAT for short.

Today, Ambrosone is presenting "NAT, cigarette smoking and breastcancer" in a poster session on the epidemiology of carcinogenmetabolism.

In the human body, NAT detoxifies certain cancer-causingcompounds, notably the aromatic amines present in cigarette smoke.Various polymorphisms on the NAT gene sort people into twoclasses: those whose NAT enzyme acetylates these oncogenesrapidly, and those who do so slowly.

In the U.S., an estimated 40 to 70 percent of the Caucasianpopulation are slow acetylators. In Japan, where only 10 percent ofwomen acetylate slowly, breast cancer is far less prevalent thanamong American women.

Ambrosone and her co-workers at Buffalo compared 159postmenopausal breast cancer patients with 203 healthy controlwomen. They found that the 56 percent of their affected populationwho were slow acetylators had an increased, dose-dependent, risk ofbreast cancer. In this group, heavy smokers ran an eight-fold greaterrisk of the disease than non-smokers.

At present, smoking is not regarded as a risk factor for mammarycancer. Ambrosone suggests that "Understanding genetic variabilityin carcinogen metabolism may explain previously inconsistentfindings for cigarettes and breast cancer."

Neil Caporaso of the National Cancer Institute, which collaborated inthe study, observed that polymorphisms such as the NAT variants"increase cancer risk only when a person is exposed to certainenvironmental agents, such as cigarette smoke." He added, "Thisgives hope that cancer may eventually be preventable, not throughexotic gene therapies, but through a person's own lifestyle changes.These genes are harmless when the environmental exposure iseliminated."

Caporaso went on to emphasize that "This by no means makes it safefor some women to smoke cigarettes. Even if smoking is proven notto be a breast cancer risk factor, cigarettes still dramatically increasethe risks of heart attacks, lung cancer, emphysema, and a host ofother deadly diseases."n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.