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Fred West, 801 581-4954
([email protected])

RESEARCHERS DEVELOP ëTROJAN HORSE' TO DELIVER ANTICANCER DRUGS

Two University of Utah chemists have developed a potential new weapon in the fight against cancer.

Associate professors Charles B. Grissom and Frederick G. West have devised a targeted drug delivery method that is expected to greatly increase the effectiveness of chemotherapy treatments.

In developing their research, Grissom, West and their coworkers may have at least partially solved one of the major drawbacks to chemotherapy ó that of systemwide toxicity.

Most anticancer drugs are indiscriminate; they attack cancer cells and healthy cells alike. However, using this new research, doctors may one day be able to deliver more cancer-fighting drugs to targeted tumor cells and less to the normal cells of the body. Such an approach would increase the effectiveness of chemotherapy while greatly reducing its side effects.

"The name of the game with chemotherapy is, How do you select the cancer cells to attack, while sparing the cells you don't want to poison?" West says.

The answer, Grissom and West believe, is vitamin B-12.

Typically, anticancer drugs work by a process of passive diffusion. That is, the drug is introduced into the body and the cancer cells eventually absorb a certain amount of the molecules. The problem with that approach is that other cells in the body are also passively absorbing these molecules, usually at about the same rate.

Grissom's and West's plan involves using vitamin B-12 as a "Trojan Horse" to get more of the drug into the targeted cancer cells. The researchers take a vitamin B-12 molecule and join it with a molecule from an anticancer drug, such as taxol or doxorubicin, resulting in a "bioconjugate" molecule.

Replicating cells need more B-12, and cancer cells are often rapidly duplicating. As a result, "tumor cells will take up more than their share" of the B-12 vitamin, Grissom says, and, along with it in the case of the bioconjugate, more of the hitchhiking anticancer drug.

"The Trojan Horse is a good metaphor for what these molecules do," Grissom says. "The bioconjugates fool the cancer cells into bringing them in, but in doing so these cells assure their destruction."

However, the fact that cancer cells actively seek this bioconjugate rather than wait for passive diffusion is only half of the story. The drug molecule, because it is a part of a bioconjugate, remains inert in the body until it is activated by separation from the B-12 molecule. This is accomplished by processes within the cells that break the bond between the two molecules, thus freeing the anticancer drug to do its job.

Once a lethal dose of the anticancer drug is absorbed by the cancer cells, doctors then could flood a patient's system with vitamin B-12, flushing the remaining bioconjugate cancer drug from the body. This would further reduce the possibility of systemwide toxicity.

Preliminary tests have shown promise. In one experiment, Grissom and West ó along with John Munger of MantiCore Pharmaceuticals ó attached fluorescent "tags" to the modified B-12 molecules. Then, working with Dr. Joel Bentz of the U. Department of Pathology, they studied the absorption rates of these molecules for both healthy and cancerous bone marrow cells. The researchers found that while the healthy cells showed no detectable fluorescence, the leukemia cells lit up brightly, indicating the presence of large amounts of the bioconjugate and validating the B- 12 selective delivery hypothesis.

The two scientists are quick to point out that, while this research is encouraging, there's still much work to be done. Both say they won't be satisfied until it is actually helping cancer patients.

"I have always been excited about the potential of this approach, but what will truly be exciting is when we go beyond the potential to actually treating humans," West says.

All indications are that this eventually will happen. The National Institutes of Health recently approved a grant in excess of $875,000 to continue this basic research.

Grissom and West also hope to use their B-12 bioconjugates to deliver other substances to cells in the future. In theory, it could be used as a general method for getting therapeutic compounds into cells ó compounds that otherwise might not be able to cross the cell membrane.

The work was done in collaboration with Louis Barrows, an associate professor of Pharmacology and Toxicology at the U., and Raymond A. Daynes, co-chair of the U.'s Pathology Department.

Color art of Grissom and West can be seen at