Researchers at Wake Forest University Baptist Medical Center are reporting how a 15-year-old drug could have a promising new role in the treatment of rectal cancer.
The drug is oxaliplatin, and when administered in combination with fluorouracil (5-FU) plus leucovorin—standard therapy for patients with advanced/metastatic colorectal cancer—it makes the radiation therapy more effective. Oxaliplatin is one in a family of platinum-based drugs, which contain small molecules that interact with DNA and disrupt the replication process. Some cancers, however, have developed resistance to other platinum-based drugs.
“This the first drug to come along in a while that’s effective in treating human cancers that are resistant to other platinum-based therapies,” said Suzanne M. Hess, Ph.D., associate professor of Radiation Oncology at Wake Forest University School of Medicine, and one of the authors of an abstract presented at the American Association for Cancer Research meeting in Washington, D.C. “One of the other benefits is that it works with a combination of other drugs and doesn’t have the associated toxicities.”
Oxiliplatin was developed in 1987 and used to treat cancers of the colon and rectum that had already spread to other organs, but the drug had never been fully explored to determine if it would be safe or effective in patients with an earlier stage of the disease. Researchers at Wake Forest tackled that question in the lab, and in 2002 published the first abstract showing that oxaliplatin could safely and dramatically enhance the impact of standard radiation therapy.
After a speedy review in 2002, the Food and Drug Administration approved oxaliplatin (Eloxatin™, manufactured by Sanofi-Synthelabo) in combination with 5-FU and leucovorin for patients with metastatic cancer of the colon or rectum.
“The encouraging pre-clinical studies from Wake Forest, in part, resulted in several cooperative group clinical trials evaluating the combination of oxaliplatin and radiation for patients with rectal cancer,” said A. William Blackstock Jr., M.D., associate professor of radiation oncology and lead author on the abstract presented in Washington. “The clinical trials with oxaliplatin reported thus far make it clear that this drug will soon become an integral part of the treatment of all patients with colorectal cancer.”
Blackstock said Wake Forest researchers found that oxaliplatin works quite differently than cisplatin, a related platinum-based drug that has been widely used in cancer treatment for years. The mechanism remains under study, but oxaliplatin has a bulkier diaminocyclohexane (DACH) ligand not present in the structure of cisplatin. This line of research could demonstrate how oxaliplatin can be effective against tumors that are resistant to cisplatin.
In addition to basic research into the mechanism through which oxaliplatin prevents DNA replication in tumor cells, clinical research continues at Wake Forest and elsewhere on the effect and outcomes of using oxaliplatin with radiation in patients with an earlier stage of rectal cancer.
“It’s still early, but the studies are showing some activity,” Blackstock said. “We treated one patient here at Wake Forest with the combination, and she had a complete response,” Blackstock said. "Our laboratory data suggested that we might see significant anti-tumor effects."
According to the American Cancer Society, cancers of the colon and rectum (colorectal) are the third most common site of new cases and deaths among men and women in the United States. An estimated 148,300 new cases and 56,000 deaths are expected this year.
In addition to Hess, Blackstock’s co-authors on the abstract as are Joel Anderson, and Rachelle Johnson, research technicians at Wake Forest.
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