BETHESDA, Md. -- No one knows why many types of cancercells produce copious quantities of insulin-like growth factor(IGF-1) compared with normal cells, Joseph Ilan told BioWorld.But he is betting that suppressing IGF-1 synthesis andperforming some additional manipulations could destroy braintumors.
On Tuesday, the Recombinant DNA Advisory Committee (RAC)of the National Institutes of Health approved the Case WesternReserve University School of Medicine biologist's protocol totreat patients with gliomas that overexpress IGF-1 by a 19-0vote, with no abstentions. "This was a fascinating protocol," saidLeonard Post, vice president of experimental therapy for theParke-Davis Pharmaceutical Division.
The RAC members were impressed with Ilan's animal data; histechnique had cleared glioblastomas from all 30 of the ratstested.
Following the introduction of antisense IGF-1 cDNA into the ratgliomal cells, IGF-1 mRNA and protein levels plummeted. Next,the researchers irradiated the transfected tumor cells to killthem, and injected the cells subcutaneously into the rats. Forreasons not yet understood, the injected tumor cells induced CDT lymphocytes to destroy the tumor cells, which previously hadbeen invisible to the host's immune system, Ilan told BioWorld.
In mouse studies, tumors regressed in three to four weeksfollowing injection of antisensec DNA-treated, irradiated tumorcells. "We concluded that the IGF-1 antisense strategy mayreverse a phenotype which allows C6 glioma cells to evadeimmune surveillance," wrote Gary Nabel, professor of internalmedicine and biological chemistry at the University of MichiganMedical Center and associate investigator at Howard HughesMedical Institute, in his protocol.
Preventing the Spread of HIV.
One of Monday's highlights was the first approval of a directanti-viral therapy, by a vote of 14-0 with four abstentions. Thetherapy is designed to prevent the spread of HIV in infectedpeople.
The scientific mechanism is straightforward. The retroviralprotein, Rev, is necessary for viral replication, as it regulatestransport of viral RNA from the nucleus into the cytoplasm. Itbinds to an RNA sequence in the virus called the Revresponsive element.
Principal investigator Nabel proposed to block the Rev protein'saccess to the element. A mutant form of the Rev gene, RevM10, binds to the Rev responsive element without recruitingthe cellular factors that mediate export of viral RNA. "It's kindof like trying to unlock your car door when someone hasbroken a key off in the lock," said Nabel.
"We have taken T cells from patients and put the gene in,"Nabel told BioWorld. "The purpose of the study is to give thosecells back to the patient." If the T cells with the mutant form ofRev survive in the patients in greater numbers than in thosewithout it, "that will tell us they are going to be protective."And if so, the ultimate goal would be to install the mutant Revgene in stem cells, Nabel said. The technique would bebeneficial if it slowed viral replication enough to preserve afunctional immune system.
The vector is a murine virus, which has raised concerns aboutthe possibility that promiscuity among HIV-positive peoplemight broaden the virus' infectivity. But RAC members thoughtsuch risks were small. Nonetheless, Nabel is collaborating withVical Inc. of San Diego, Calif., on a cationicliposome that mightsubstitute for the murine virus, eliminating this risk.060993IGF-1
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.