Current cancer chemotherapies act somewhat like shotguns or assaultweapons. While aiming at target tumor cells, these toxic drugs tend tospray stray bullets at innocent bystander tissues. They thus causehair-loss, nausea and other, far more serious, side effects.

That's the trouble with trying to wipe out malignancies withexogenous weapons. So oncologists now strive to perfect therapiesbased on the body's own anti-cancer potential _ sharp-shootingtumors with suppressive rifle fire instead of scatter-shot destructionby chemicals.

One such class of smart-shooting weapons are the tumor-suppressorproteins, such as p53. Now another anti-cancer molecule, p16 byname, has just received its proof-of-principle suppressor certificate.

It takes the form of a paper in this week's journal Cell, dated April 5,1996, titled "Role of the INK4a locus in tumor suppression and cellmortality." The article reports confirmation of p16's association, in apositive sense, with cancer in mammals.

INK4a (inhibitor of kinase 4) denotes a gene locus on the short armof human chromosome 9 that encodes p16, along with othermolecules involved in fine-tuning the clock-like process by whichcells divide. (See BioWorld Today, Sept. 15, 1995, p. 1.)

David Beach, a senior staff scientist at the Cold Spring HarborLaboratory's Howard Hughes Medical Institute, showed in 1993, thatp16 plays a critical part in cell division, and that aberrant cellulargrowth is a key feature of malignancy. Beach is co-principal authorof the paper in Cell.

Later in 1993, scientists at Myriad Genetics Inc., in Salt Lake City,mapped the p16 gene. It has since turned up missing or mutated in 20to 60 percent of several cancers, including breast, bladder,esophageal and melanoma.

The experiment that Cell reports involved constructing transgenicmice lacking both the paternal and maternal INK4a loci (INK4a-/-) intheir genomes, hence, devoid of the p16 suppressor. (The papermentioned that "two cases of an INK4anull/INK4anull genotype havebeen reported in humans without attendant developmental effects.")At birth, these rodents were as healthy and fertile as their wild-typelittermates, but by 26 weeks of age, nine of 13 mice had developedspontaneous malignant tumors.

Next, the investigators treated cohorts of INK4a-/- animals with astrongly carcinogenic chemical, ultraviolet radiation, or both. Thedouble treatment produced tumors in 12 of 20 mice; the other sixdied of undetermined causes. In contrast, all 23 of their INK4a+/+littermates so treated remained healthy and tumor-free.

In vitro as well as in vivo, p16 proved its tumor-suppressingproperties. The well-known ras oncogene accelerated tumor growthin p16-minus cells, but not in cells with functioning p16.

"Together," the Cell paper concluded, "these findings demonstratethat the absence of INK4a results in increased susceptibility to thedevelopment of cancers."

Beach co-founded Mitotix Inc., of Cambridge, Mass. in 1992. Thecompany holds an exclusive worldwide license to p16 from ColdSpring Harbor.

"Detailed insight into the mechanisms of cell cycle control holdsenormous potential for the development of anti-cancer therapies,"said Mitotix's vice president of drug discovery, Muzammil Mansuri."Use of this information may lead to the development of drugs thattarget cancer cells with pinpoint accuracy, unlike traditional cancertreatments, many of which are unspecific toxins that kill many typesof cells."

The company now is developing small-molecule anticancer drugs thatinhibit inappropriate cell division through mimicking the p16 gene'seffects. "This new transgenic mouse model," Mansuri observed, "willprovide a highly specific tool with which to test and develop thesenew compounds." n

-- David N. Leff Science Editor

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