Though it most often is associated with antibiotics, multidrug resistance is a major problem in cancer, too.
The problem comes in two forms.
"Some cancers, like colon cancers, have what is called intrinsic resistance'" to treatment, said Khew-Voon Chin, associate professor at Rutgers University's Ernest Mario School of Pharmacy in Piscataway, N.J. At 10 percent to 20 percent, the response rate of those cancers is low even at the onset of treatment.
Other cancers, such as breast cancer, initially show a higher response rate, on the order of 30 percent to 40 percent, but then show a high relapse rate after six months to two years of treatment, thought to be due to endogenous changes in gene expression that allow cells to survive chemotherapy.
"I couldn't give you an across-the-board number for all cancers," Chin said. "But it's a very, very common problem. Virtually every drug used in the clinic has encountered resistance."
In a Priority Report published in the March 1, 2005, issue of Cancer Research, Chin and his colleagues from Rutgers and King's College London, described a compound that is able to arrest cell growth and, ultimately, induce apoptosis in cells with a variety of acquired resistance mechanisms, as well as with intrinsic resistance. The paper is titled "Circumventing Multidrug Resistance in Cancer by ß-Galactoside Binding Protein, an Antiproliferative Cytokine."
Such broad-spectrum activity would be a very useful feature of a therapeutic agent, since "mechanisms of resistance vary immensely and, unfortunately, multiple mechanisms of resistance probably exist at any one time," Chin said. He added that it's a well-known feature of cancer and the reason why more than one drug usually is given during treatment. "It's less likely that cancer will develop simultaneous resistance mechanisms to three or four agents," he said.
Cells can become resistant to chemotherapy through a variety of mechanisms. One possibility is increased DNA repair through the overexpression, altered expression or mutation of topoisomerase I and II enzymes, which allows cancer cells to deal with the damage done by the therapeutics. Another is overexpression of metallothionein, which interferes with the effectiveness of platinum-based therapies.
There also is the possibility of mutations in the target (most famously the bane of Gleevec patients, but certainly not limited to them), and overexpression of P-glycoprotein, a member of the ATP-binding cassette, or ABC, transporter family.
"ABC transporters act pretty much like sump pumps" for chemotherapy, Chin said. "When Taxol gets into the cell, it gets pumped right back out and there is no accumulation" and, thus, insufficient intracellular concentration of the drug to kill the cancer cell.
Because of its broad-spectrum activity, Chin and his colleagues surmised ß-galactosidase binding protein might normally have a role in anticancer surveillance. In previous experiments, the scientists had shown that normal and cancer cells responded differently to the agent. While normal cells will interrupt their cell cycle and pause in S-phase for a relatively brief time following exposure to ß-galactosidase binding protein, the protein will induce apoptosis in cancer cells.
The scientists tested human recombinant ß-galactosidase binding protein against cells bearing each of those resistance-conferring mutations, as well as against parental cancer cells that had not been exposed to chemotherapy and thus not evolved the resistance mechanisms. In each case, ß-galactosidase binding protein was effective first in arresting the growth and then inducing the cell death of both the mutant and the parental cell line.
"This was very exciting," Chin said, "because there are currently no drugs on the market that are effective against all of these mechanisms of resistance."
So far, the results have all been obtained in cell culture, where (as Chin freely admits) cancer cures are fairly plentiful and easy to come by, at least compared to the frustrations of the clinic. His group plans to do preclinical toxicology and tumor response studies in animals next. Because ß-galactosidase binding protein occurs naturally in cells, there are relatively few concerns about toxicity.
The ultimate plan is to enter clinical trials, hopefully with an industrial partner.
"We have spoken with some industrial people, but that was about a year ago, when the research was still very preliminary. Now that the results have been published, we hope to find industry partners; we are certainly interested," he said.