Re-ex­am­in­ing Chemo­ther­apy Drugs

Pow­er­ful Help in Prostate Can­cer Treat­ment

Wellness Update - - Health Watch MD -

The power of tax­ane-based chemo­ther­apy drugs are mis­un­der­stood and po­ten­tially un­der­es­ti­mated, ac­cord­ing to re­searchers at Weill Cor­nell Med­i­cal Col­lege in the Septem­ber 15, 2012 is­sue of the jour­nal Can­cer Re­search. Most physi­cians and in­ves­ti­ga­tors be­lieve that tax­ane chemo­ther­apy (pa­cli­taxel, do­c­etaxel and cabaz­i­taxel) just does one thing — stop a can­cer cell from di­vid­ing — but the team of Weill Cor­nell sci­en­tists have re­vealed it acts much more pow­er­fully and broadly, es­pe­cially against prostate can­cer. "Tax­anes are one of the best class of chemo­ther­apy drugs that we can use to treat our can­cer pa­tients, but while they are ef­fec­tive against a wide range of tu­mors, they don't work in all of them, and of­ten pa­tients be­come re­sis­tant," says the study's se­nior in­ves­ti­ga­tor, Dr. Paraskevi Gian­nakakou, an as­so­ciate pro­fes­sor of phar­ma­col­ogy in medicine and phar­ma­col­ogy and di­rec­tor of lab­o­ra­tory re­search for the Di­vi­sion of He­ma­tol­ogy and Med­i­cal On­col­ogy at Weill Cor­nell. "How­ever, our new un­der­stand­ing of the pre­cise ac­tion of tax­anes in a can­cer cell may help us over­come drug in­sen­si­tiv­ity or ac­quired re­sis­tance to the drugs and de­sign ther­a­pies that can be used in com­bi­na­tion with them to im­prove can­cer con­trol." In their study, the re­searchers stress that in­ves­ti­ga­tors must shift their at­ten­tion away from tax­ane's func­tion dur­ing cell di­vi­sion to the drugs' ef­fects on halt­ing the ev­ery­day move­ment of pro­teins and pro­tein-to-pro­tein com­mu­ni­ca­tion within can­cer cells — and to un­der­stand­ing how and why a can­cer cell can still sur­vive. Re­searchers sug­gest that can­cers that are in­sen­si­tive to tax­anes — or those that have be­come re­sis­tant to them — may, for ex­am­ple, switch to al­ter­nate forms of "trans­porta­tion" to shut­tle pro­teins within cells in a way that does not de­pend on the cell's skele­tal struc­ture which is the tar­get of tax­ane ther­apy. Re­searchers showed in the study that the an­dro­gen re­cep­tor (AR), which is a driv­ing force in prostate can­cer growth and metas­ta­sis, "moves" along mi­cro­tubules to be trans­ported to the nu­cleus. When a tax­ane binds mi­cro­tubules, it stops AR from trav­el­ing, thus in­hibit­ing its ac­tiv­ity. Tax­ane chemo­ther­apy drugs such as pa­cli­taxel, do­c­etaxel and cabaz­i­taxel work by bind­ing tubu­lin, a pro­tein that makes up mi­cro­tubules.

Mi­cro­tubules are the rope-like chan­nels that pro­vide both a skele­tal struc­ture to cells as well as pro­vide "high­ways" along which molecules, such as pro­teins, RNA com­plexes and vesi­cles, can travel from one part of the cell to an­other and in­ter­act with each other. "Mi­cro­tubules are the highly dy­namic net­work of wires within cells, and when tax­anes are used, the net­work stops mov­ing," says Dr. Gian­nakakou. This is best ob­served when can­cer cells at­tempt to di­vide, she says. "It is easy to see in the lab­o­ra­tory, that prostate can­cer cells dou­ble ev­ery 30-48 hours, and tax­ane stops them from do­ing that, which pushes th­ese cells to die. This leads ev­ery­one to think that this is ex­clu­sively how tax­anes work – they stop cells from di­vid­ing." But Dr. Gian­nakakou and her re­search team point out in their new study that pa­tients have sig­nif­i­cantly lower rates of cell di­vi­sion in their tu­mors than do can­cer cells grow­ing in the lab. In fact, can­cer cells in prostate can­cer pa­tients only di­vide ev­ery 33-577 days, she says. "Thus, the ther­a­peu­tic ben­e­fit of tax­anes on mi­cro­tubules de­pends on more than just stop­ping cell di­vi­sion." The new in­sights pro­vided by this study about the ac­tion of tax­anes on AR traf­fick­ing helps ex­plain the clin­i­cal ac­tiv­ity of th­ese drugs in the treat­ment of prostate can­cer while at the same time can help re­searchers bet­ter un­der­stand why an in­di­vid­ual pa­tient might re­spond or not to tax­ane ther­apy. Such in­sights are crit­i­cal for fu­ture chemo­ther­apy cus­tomiza­tion, ac­cord­ing to re­searchers. The drug that was later named Taxol (pa­cil­i­taxel) was iso­lated from the bark of a Pa­cific yew tree by fed­eral re­searchers in 1967 and was later syn­the­sized. It 1993 it was ap­proved for use in ovar­ian can­cer, and has since been used for lung, breast, head and neck and other can­cers. Tax­otere (do­c­etaxel), syn­the­sized from chem­i­cals ex­tracted from the Euro­pean yew tree, was de­vel­oped as an al­ter­na­tive to Taxol, and is used for the treat­ment of many of the same can­cer types. Cabaz­i­taxel, the new­est tax­ane, is a semi-syn­thetic pa­cli­taxel ana­log and is used to treat pa­tients with prostate can­cer who have failed prior do­c­etaxel chemo­ther­apy. "In the 20 years since Taxol was ap­proved, hun­dreds of labs world­wide are try­ing to un­der­stand how tax­anes work to stop cell di­vi­sion in can­cer," Dr. Gian­nakakou says. "How­ever, we think they need to now take a fresh ap­proach and look at what th­ese drugs do dur­ing the nor­mal life cy­cle of a can­cer cell and tar­get the newly re­vealed un­der­ly­ing mech­a­nisms and modes of move­ment with novel ther­a­pies, in com­bi­na­tion with tax­ane ther­apy, to pro­vide life-sav­ing ther­apy for pa­tients who don't ben­e­fit from tax­anes." -This in­for­ma­tion pro­vided courtesy of Weill Cor­nell Med­i­cal Col­lege

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