The experimental anticancer drug topotecan(Drug information on topotecan) shows continued promise as a potent anticancer drug, according to new research.
Scientists at Ohio State University's Comprehensive Cancer Center compared topotecan to four related experimental anticancer drugs. They found that topotecan, usually considered the least potent of the five drugs in certain laboratory studies, was most potent under conditions that closely resemble those found in the bloodstream.
The study tested the drugs on cancer cells in the presence and absence of albumin.
Topotecan's Potency Linked to Presence of Albumin
"Previous studies have compared the effectiveness of these drugs in the absence of albumin," said Thomas Burke, assistant professor of pharmacy, "and topotecan always ended up at the bottom of the list. But in the presence of albumin, that trend changes, and topotecan becomes the most potent."
The results, which were published in the October 24, 1995, issue of Biochemistry, are important because the amount of albumin in the blood can vary with a person's state of health, said Burke.
"The albumin levels in cancer patients can drop to half their normal level. It's quite possible that reduced albumin levels in a very sick patient could affect the activity of drugs that interact strongly with albumin."
"A physician might expect these albumin-interactive drugs to be more active in patients with low albumin levels, and might want to consider this when determining dosage."
Differences in serum albumin levels might also be responsible for producing variations in the outcome of treatment among patients receiving albumin-interactive drugs.
"Now that we are aware of these drug-albumin interactions, the next step is to make correlations about how patients fare when given these medications during clinical trials," said Burke.
It's also important to learn what happens to the drugs that interact strongly with albumin. These drugs attach tightly to the protein and may be carried to another area of the body where a different pH level could cause them to be released.
This could leave a high concentration of the drug in some healthy organ of the body and possibly cause damage there.
Important questions like these have to be answered using information gathered from clinical trials; animal experiments can't answer them because these drugs interact differently with the albumins found in animals.
Potency of Drugs Tested Varies Greatly in Presence of Albumin
Among the drugs tested, camptothecin was least potent in the presence of human serum albumin. The presence of albumin reduced the drug's effectiveness 2,600 times compared to its ability to kill cancer cells in the absence of albumin. The presence of albumin also reduced the potency of 9-aminocamptothecin (9-AC) by 220-fold, SN-38 by 27-fold, and CPT-11 by 2.5-fold.
Because topotecan interacts little with human serum albumin, its potency remained unchanged in the presence of albumin.
The drugs 9-AC, CPT-11, SN-38, and topotecan are all semisynthetic variations of camptothecin. The camptothecins are the only drugs known to block topoisomerase I, an enzyme that helps DNA unwind so it can replicate. The camptothecins block the enzyme, which halts cell division and causes cell death and destruction of the tumor.
Topoisomerase I is also an important target because the enzyme sometimes exits at slightly higher levels in cancer cells than in healthy cells. This presents the hope that drugs that block the enzyme might selectively kill cancer cells while leaving healthy cells relatively unharmed.
"We will soon be able to use the new information we're gaining about these drugs to refine and potentially improve their effectiveness and reduce their side effects," said Burke.