Chemotherapy Combinations May Benefit, If Ratios Are Controlled

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A study of a new drug for leukemia and lymphoma, designed to determine how well it works in combination with existing drugs, underscores the theory that dosing for chemotherapy drugs should be aimed at achieving the greatest effect with the lowest toxicity, instead of simply giving each drug in its "maximum tolerated dose," a method that is routinely used in clinical practice.

"When patients are dosed to maximum toleration, they often suffer side effects such as a loss of the ability to fight off infections, which can lead to death in the worst case scenarios," said David Adams, Ph.D., a Duke Comprehensive Cancer Center researcher and lead investigator on the study. "What we want to do is find the combination that is most synergistic, that is, where the activity of drugs in combination is greater than that of either agent used alone. Such synergistic combinations might not require giving any of the individual drugs in their maximum tolerated dose."

The researchers published their findings in the April issue of the journal Leukemia & Lymphoma, which was published online on April 7, 2008.

"Almost all chemotherapy drugs are used in combination with other drugs, so when a new drug is developed the question becomes: which drug would our drug work best with," Adams said. "That's what we were investigating with this study, but we also looked at the sequencing -- whether one drug should be used first -- and the ratio -- how much of each drug should be used to achieve maximum tumor-killing effect with minimum toxicity?"

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The drug the researchers studied was a DNA antimetabolite known as CP-4055. It works by blocking the replication and repair of DNA in tumor cells. This drug was combined with standard chemotherapeutic agents, such as idarubicin, an anti-tumor antibiotic that combats tumor growth by damaging DNA, and gemcitabine, another DNA antimetabolite which stimulates cancer cell death.

"The combination of CP-4055 and gemcitabine is perhaps the best example of the idea that optimal synergy and maximum tolerated dose are not necessarily synonymous," Adams said. "In this case, optimal synergy between the two drugs occurred when they were given in a ratio of 400 parts CP-4055 to just one part gemcitabine."

A move toward determining the optimal synergy between drugs in combination rather than relying on giving the drugs in their maximum tolerated doses is important, Adams said, because there are some drug combinations that might not be effective when given at their maximum tolerated doses. However, in the right ratio, these drugs could work very effectively in combating cancer, he said.

"When we combined our drug with topotecan, a chemotherapy agent that attacks cancer growth by creating DNA damage in cancer cells, for example, we found that there was a fine line between drug ratios that produced synergistic anti-tumor activity and those that produced drug antagonism" Adams said. "Because current clinical practice dictates that drugs are used in their respective maximum tolerated doses, this combination would likely not be used in patients, even though our data show that in the right drug ratio, the combination could be beneficial."

Further research in drug delivery and a shift in the culture of clinical practice will be needed for patients to benefit from combinations that have yet to be used, Adams said.

"There is definitely a move toward targeted therapeutics in the world of anti-cancer drug development, but there is still room for us to optimize the use of these more traditional chemotherapeutic drugs to achieve benefits for patients," he said.

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