Anticancer drugs: in vivo la difference!

Anticancer drugs: In vivo la difference!

When tumors develop resistance to anticancer drugs, chemotherapy becomes a toxic exercise in futility. For decades, scientists have assumed that lab-cultured tumor cells and tumors in the body develop drug resistance in much the same way -- a belief that has formed the basis for in vitro studies of tumor cells to pinpoint the genetic, metabolic and molecular changes accompanying drug resistance in vivo. "We've thought all along that in vivo and in vitro drug resistance were pretty much the same," says Beverly Teicher of the Dana-Farber Cancer Institute in Boston.

Now, Teicher and her colleagues have discovered striking differences between chemotherapy resistance in vivo and in vitro. To survive the toxic onslaught, resistant tumor cells in the body appear to rely in part on interactions with non-cancerous tissues -- an assist unavailable to cells growing in culture.

The group found that the drug resistance displayed by breast-cancer cells in mice vanished when those cells were removed and cultured -- only to reappear when the resulting cell lines were reinjected into other mice. Moreover, the body's distribution and processing of anticancer drugs differed between mice with resistant tumors and control mice with drug-sensitive tumors, the team reports in the March 23 SCIENCE.

The researchers began by injecting breast-cancer cells into four groups of healthy mice and allowing the tumors to grow. Each group of mice then received a different anticancer drug. Twenty-four hours later, the team excised the tumors and transplanted the cells into four new groups of mice, again allowing each cell line to proliferate and exposing it to the same drug as before. They repeated the process 10 times in all, using new host mice each time to ensure that the tumor -- and not the liver or kidney -- was the site of drug resistance, Teicher says.

Next, they removed some resistant tumor cells from each of the mouse groups and grew them in vitro. After exposing these cells to the corresponding anticancer drug for one hour on three different occasions, the team observed "virtually no resistance," Teicher says. They left the cells untreated for the next four to six weeks, then injected them into yet another set of host mice. Drug resistance returned almost immediately.

The researchers continued passing the tumor cells into fresh hosts and leaving them drug-free. Three to five months after the last drug exposure, tests showed that three of the cell lines had lost their in vivo drug resistance. Teicher says this suggests that drug resistance in the body is reversible, most likely via a modification in the transcription of DNA to RNA and the translation of RNA into proteins. One cell line, however, continued to resist chemotherapy. These cells may have used a separate mechanism of resistance, Teicher speculates.

The team also looked at the distribution of two of the anticancer drugs in the animals' bodies. Compared with drug-sensitive tumors, resistant tumors absorbed the drugs more slowly and at lower levels, with the overflow excreted more rapidly from the body.

Some tumors secrete hormones capable of influencing normal tissue in yet-undetermined ways, Teicher notes. It's possible, she told SCIENCE NEWS, that these secretions play an indirect role in in vivo drug resistance.

If researchers can duplicate the new results with other tumor cells, physicians might consider waiting longer between chemotherapy treatments to allow drug resistance to fade from surviving tumor cells, Teicher suggests.

The study may also have implications for in vitro research into the mechanisms of chemotherapy resistance. If the findings are confirmed, says Kurt Kohn of the National Cancer Institute in Bethesda, Md., scientists will have to interpret results from tissue culture studies more carefully.