The experimental anticancer drug topotecan shows continued promise as a potent anticancer drug, according to new research.
The experimental anticancer drug topotecan shows continued promiseas a potent anticancer drug, according to new research.
Scientists at Ohio State University's Comprehensive Cancer Centercompared topotecan to four related experimental anticancer drugs.They found that topotecan, usually considered the least potentof the five drugs in certain laboratory studies, was most potentunder conditions that closely resemble those found in the bloodstream.
The study tested the drugs on cancer cells in the presence andabsence of albumin.
Topotecan's Potency Linked to Presence of Albumin
"Previous studies have compared the effectiveness of thesedrugs in the absence of albumin," said Thomas Burke, assistantprofessor of pharmacy, "and topotecan always ended up atthe bottom of the list. But in the presence of albumin, that trendchanges, and topotecan becomes the most potent."
The results, which were published in the October 24, 1995, issueof Biochemistry, are important because the amount of albuminin the blood can vary with a person's state of health, said Burke.
"The albumin levels in cancer patients can drop to half theirnormal level. It's quite possible that reduced albumin levelsin a very sick patient could affect the activity of drugs thatinteract strongly with albumin."
"A physician might expect these albumin-interactive drugsto be more active in patients with low albumin levels, and mightwant to consider this when determining dosage."
Differences in serum albumin levels might also be responsiblefor producing variations in the outcome of treatment among patientsreceiving albumin-interactive drugs.
"Now that we are aware of these drug-albumin interactions,the next step is to make correlations about how patients farewhen given these medications during clinical trials," saidBurke.
It's also important to learn what happens to the drugs that interactstrongly with albumin. These drugs attach tightly to the proteinand may be carried to another area of the body where a differentpH level could cause them to be released.
This could leave a high concentration of the drug in some healthyorgan of the body and possibly cause damage there.
Important questions like these have to be answered using informationgathered from clinical trials; animal experiments can't answerthem because these drugs interact differently with the albuminsfound in animals.
Potency of Drugs Tested Varies Greatly in Presence of Albumin
Among the drugs tested, camptothecin was least potent in the presenceof human serum albumin. The presence of albumin reduced the drug'seffectiveness 2,600 times compared to its ability to kill cancercells in the absence of albumin. The presence of albumin alsoreduced 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, itspotency remained unchanged in the presence of albumin.
The drugs 9-AC, CPT-11, SN-38, and topotecan are all semisyntheticvariations of camptothecin. The camptothecins are the only drugsknown to block topoisomerase I, an enzyme that helps DNA unwindso it can replicate. The camptothecins block the enzyme, whichhalts cell division and causes cell death and destruction of thetumor.
Topoisomerase I is also an important target because the enzymesometimes exits at slightly higher levels in cancer cells thanin healthy cells. This presents the hope that drugs that blockthe enzyme might selectively kill cancer cells while leaving healthycells relatively unharmed.
"We will soon be able to use the new information we're gainingabout these drugs to refine and potentially improve their effectivenessand reduce their side effects," said Burke.