In retrospect, the concept of antisense seems startlingly simple.
Find a protein that's essential to cancer cells, create a single-stranded sequence of nucleotides complementary to a part of the RNA from which the protein arises, and then send in a complementary sequence to "tie up" the RNA thus preventing protein production and stopping tumors cold.
Antisense research is not limited to cancer. In fact, the U.S. Food and Drug Administration recently approved the first antisense drug, fomavirsen (Vitravene®), for retinitis induced by cytomegalovirus. The drug, a product of ISIS Pharmaceuticals Inc., Carlsbad, Calif., is one of half a dozen antisense compounds that the company has in development.
Biotechnology companies are the easiest place to find antisense research pushing ahead full-throttle; this is because they have the capital, said Eric Wickstrom, Ph.D., professor of microbiology and immunology at Thomas Jefferson University, Philadelphia.
|
ISIS's lead antisense drug, ISIS2302, targets one of a family of intercellular adhesion molecules ( ICAM-1) involved in the inflammatory response. The drug is in a pivotal trial for Crohn's disease and Phase II trials for renal transplant rejection, and is being explored as a treatment for ulcerative colitis, psoriasis, and asthma.
ISIS3521 is an inhibitor of protein kinase C alpha, an enzyme important to tumor growth. Said Stanley Crooke, president and CEO of ISIS, "In animal models it didn't seem to work for quite a few things, but it did work for cancer. In Phase I trials we were able to go to very high doses and treat for very long periods of time without significant toxicities. We've never really achieved a dose-limiting dosage."
According to Crooke, ISIS3521 shows activity in ovarian, breast, lung and colon cancers, as well as in non-Hodgkins lymphoma. Phase II trials should be completed by the end of the year. Other ISIS anti-cancer antisense drugs include ISIS5132, a ras kinase inhibitor, and ISIS2503, an h-ras inhibitor. The National Cancer Institute is sponsoring three Phase II trials of ISIS compounds for metastatic breast cancer, recurrent or metastatic colorectal cancer, and recurrent ovarian epithelial cancer. The trials involve ISIS5132 and ISIS3521.
Antisense therapy against the bcl-2 protein a potent suppressor of apoptosis found at high levels in many types of tumors has shown promise since 1990, when antisense-mediated reductions in bcl-2 protein levels promoted cell death and reduced cell growth in a human leukemia cell line. Since then, similar results have been seen in acute myelogenous leukemia, non-Hodgkin's lymphoma, and prostate cancer cell lines. A 1994 study found that antisense bcl-2 therapy in a SCID mouse model was effective against human B-cell lymphoma cells.
Genta Inc., Lexington, Mass., is evaluating its antisense compound against bcl-2 in early-stage clinical trials of lymphoma, melanoma, and breast and prostate cancers. Called G3139, the compound will be in trials at the NCI as well, according to Robert Klem, chief technical officer at Genta.
"Our goal is to evaluate this compound in as many cancers as we can," said Klem. "I think the field is very promising; we're very excited about the progress we've made."
Milford, Mass.-based Hybridon, Inc.'s GEM231, a protein kinase A Type I inhibitor, is also in clinical trials. Thus far, the drug has shown effectiveness against renal cell cancer. In addition, in a colon cancer model, a combination of GEM231 and paclitaxel slowed tumor growth, compared with either therapy alone.
On the academic side, Gary Clawson, M.D., Ph.D., and colleagues at Penn State College of Medicine, Hershey, Pa., have taken antisense a step further; their oligonucleotides include a "catalytic core" that cleaves the target RNA, rendering it useless. Clawson is the acting director of the Jake Gittlen Cancer Institute, also in Hershey. "One of the big problems is choosing a target site" for antisense therapy, Clawson said. "There are modeling programs available for modeling RNA structure, but that's not always effective."
|
Getting antisense oligonucleotides that will bind to the target is an essential step, missing in most studies, Clawson said.
Other refinements, however, are possible, according to Clawson. "There are two ways to use antisense technology: to deliver the antisense molecules, or to deliver a DNA construct which then gets made into the antisense sequence that you want," he said. "The advantage to the latter is you can continue to have the antisense sequences made in the cell. But there you're dealing with the whole ballpark of gene therapy, and the safety and efficacy issues that presents."
Wickstrom sees antisense as an adjuvant therapy, rather than a standalone therapy. "At the moment antisense looks to have the best success as an adjuvant therapy after debulking the tumor," he said. "We hope that what we've seen in mice can be translated into humans at the earliest possible date."
The antisense therapy field, said Wickstrom, is "just slow moving. It's like penicillin was before World War II came along. . . . [After all,] people used to say the human body couldn't stand speeds of 100 miles an hour. These are easy things to say if you don't know."
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |