Chemotherapy Enhancer Passes First Test

An experimental drug designed to help standard chemotherapy drugsmaintain their disease-fighting power has cleared its first roundof clinical testing, according to investigators at Stanford University.The drug, identified as PSC-833, is the most promising compoundtested so far to overcome the resistance many cancer cells developagainst chemotherapy agents, said Stanford oncologist Dr. BranimirSikic, who led the first phase of clinical trials for the drug.

In these Phase I trials, designed to establish safe dosages, researchersfound that administering PSC-833 along with either of two anticancerdrugs, paclitaxel (Taxol) or etoposide (VePesid), increased theanticancer drug's staying power. In fact, to protect the body'shealthy tissues from damage due to the enhanced potency, cliniciansmust lower the anticancer drugs' dosages, the researchers foundduring the trials.

"A major consequence of using PSC-833 with these anticancerdrugs is that the anticancer drugs' period of activity was prolongedby two to three times," said Sikic, an associate professorof medicine (oncology and clinical pharmacology).

"The implication is that you have to be careful when usingthe new drug in combination with anticancer drugs. The new drugincreases the patient's exposure to the anticancer drugs, so youhave to compensate by reducing the dosages of the anticancer drugs,"Sikic said.

"However, the retention of anticancer drugs is greatly enhancedby PSC-833 in tumor cells which manifest multidrug resistance.The overall result is a selective enhancement of the beneficialeffects of anticancer drugs," he added.

Clinical observations during the trials were promising, said Sikic,who directs the General Clinical Research Center at Stanford,where the patients were studied. While undergoing the experimentaltreatments, several patients experienced a significant reductionin the size or rate of spread of their cancers, he said.

Researchers from Sikic's lab reported the findings from thesetrials at the annual meeting of the American Society of ClinicalOncology in Los Angeles.

Results of PSC-833 Plus Paclitaxel or Etoposide

In the trial investigating paclitaxel used in combination withPSC-833, the researchers looked at the responses of 41 adults(32 women and 9 men) with a variety of incurable cancers, includingbreast, colon, lung and ovarian cancers, and sarcoma. Anothertrial involved 26 patients (19 women and 7 men) who received etoposidein combination with PSC-833. In both studies, the investigatorsfound that the new drug's dose-limiting side effect is a lossof coordination, especially in patients' legs. When dosages stayedbelow the maximum tolerated dose, there were no serious side effects,Sikic said.

PSC-833, originally developed by Sandoz Pharmaceutical Corp.,is closely related to cyclosporine (Sandimmune).Both PSC-833 andcyclosporine seem to reverse drug resistance by targeting itsroot cause: They block the action of P-glycoprotein, which pumpsanticancer drugs out of tumor cells.

Based in part on the Stanford results, researchers nationwidehave begun phase II clinical trials to test the effectivenessof PSC-833 in lymphoma, multiple myeloma, and ovarian cancer inadults and leukemia in adults and children.