"Don't get mad _ get even," advised a once-prominent politician."Get MAD _ and get well," predicts a pediatric oncologist namedPerry Nisen.
MAD by definition (but not yet by proof positive) blocks the MYConcogene's tumor-propagating activity. Nisen, who directs themolecular oncology laboratory at the University of TexasSouthwestern Medical Center in Dallas, is senior author of a paper inthe July issue of Nature Medicine. Its title: "Effects of the MYConcogene antagonist, MAD, on proliferation, cell cycling and themalignant phenotype of human brain tumor cells."
MYC owes its acronym to a virus first found in chickens _ avianmyelocytomatosis virus. Wearing the white hat of a benign proto-oncogene, MYC supposedly helps control cellular proliferation anddifferentiation. Turnedtumorigenic, the black-hat MYC oncogene leaves its guiltyfingerprints in many human cancers, and pushes some cells intocommitting suicide (apoptosis).
To pull off its bad-cop cancer-causing crimes, MYC needs the helpof a co-conspirator gene, by the name of MAX. Nisen's experimentsshow that MAD can indeed drop its MYC/MAX antagonist in itstracks by a form of gene therapy. On the other hand, the MAD gene,located on the short arm of human chromosome 2, turns up missingor mutilated in certain human tumors.
This suggested to Nisen and his co-authors that "MAD may functionas a growth/tumor suppressor, the overexpression of which mayinhibit proliferation and/or tumorigenesis, and the inactivation ofwhich may contribute to oncogenesis."
To prove the MYC-antagonist's point, Nisen inserted his MADcDNA into recombinant adenovirus vectors (AdVV) and infectedhuman brain-tumor cells _ astrocytomas _ with this AdMADpackage. As a non-malignant control, he slipped the gene for b-galactosidase (b-gal) rather than MAD into another set of malignantcells.
The Dallas team then inoculated each version into left and rightflanks respectively of 11 female nude mice. By 25 days later, largetumors had grown out in all 11 animals on the side that got thecontrol (b-gal) gene dose. But all but one of the 11 flanks seeded withthe putatively protective MAD sequence were totally tumor-free. Theone exception turned out to have sprouted a malignancy unrelated tothe susceptible brain tumors being tested.
To measure the shelf-life of this anti-cancer effect, they plantedAdMAD vectors in four more mice; 45 days later, none had tumors."This suggests," Nisen wrote, "that these cells do not regain theability to form tumors over time."
He told BioWorld Today, "We've done many more animal studies,using that human xenograft mouse model. They further confirmedthat this MYC-antagonizing MAD gene is truly anti-tumorigenic."
In addition, he and his team have "looked at probably a dozendifferent human cancer types in vitro. It seems it's going to beeffective against all of the tumor types we've tested so far."
Two exceptions tended to prove the rule: Burkitt's lymphoma andovarian-cancer cells rebuffed the AdMAD gene therapy. "ThatBurkitt," Nisen explained "we subsequently discovered, does nothave a receptor for AdVV, so it didn't get in. It's purely an artifact,"he added, "that this virus infects most human cell lines, but notlymphocytes _ the cell type from which Burklitt tumors arise."
As for the refractory ovarian cells, "it didn't get into them either. Wedon't know why. Not that it got in and didn't work."
Now his goal is "to head toward clinical trials as soon as possible."
How soon is soon? "I would like to think," Nisen said, "within thenext year to two years. In consultation with FDA and theRecombinant Advisory Committee, we'll proceed with necessarypreclinical studies for approval.
"The reason we focused on brain tumors," Nisen explained, "isbecause I'm a pediatric oncologist, and among the most frustratingpatients are children with highly malignant brain tumors. They'refatal, and we have no therapy."
Nisen's second reason is that in healthy brains, most cells are notdividing. "Our basic research," he said, "led us to realize that byantagonizing MYC, we would affect cell division primarily, but withno substantial effect on non-dividing ones, we decided to pursuebrain cancer first."
Molecular geneticist Robert Eisenman of the Fred Hutchinson CancerCenter in Seattle first isolated MAD and MAX. He told BioWorldToday, "We've done something similar to Nisen et al. In a paper justsubmitted to Science, we show that ectopic expression of MAD intissue culture will arrest cell-cycle progression."
"It's a good concept," molecular neuro-oncologist Mark Israel of theUniversity of California, San Francisco, told BioWorld Today,"People who die of brain tumors right now die because their tumorscome back at the original site, after they've had current therapy. Ifyou've got a strategy to treat brain tumors at the current site," Israeladded, "it could improve the outlook for these patients some day."
As for other solid tumors on which Nisen is testing MAD, Israelallowed, "The concept is solid." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.