The experimental anticancer drug 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
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
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.