An experimental drug designed to help standard chemotherapy drugs maintain their disease-fighting power has cleared its first round of clinical testing, according to investigators at Stanford University. The drug, identified as PSC-833, is the most promising compound tested so far to overcome the resistance many cancer cells develop against chemotherapy agents, said Stanford oncologist Dr. Branimir Sikic, who led the first phase of clinical trials for the drug.
In these Phase I trials, designed to establish safe dosages, researchers found that administering PSC-833 along with either of two anticancer drugs, paclitaxel(Drug information on paclitaxel) (Taxol) or etoposide(Drug information on etoposide) (VePesid), increased the anticancer drug's staying power. In fact, to protect the body's healthy tissues from damage due to the enhanced potency, clinicians must lower the anticancer drugs' dosages, the researchers found during the trials.
"A major consequence of using PSC-833 with these anticancer drugs is that the anticancer drugs' period of activity was prolonged by two to three times," said Sikic, an associate professor of medicine (oncology and clinical pharmacology).
"The implication is that you have to be careful when using the new drug in combination with anticancer drugs. The new drug increases the patient's exposure to the anticancer drugs, so you have to compensate by reducing the dosages of the anticancer drugs," Sikic said.
"However, the retention of anticancer drugs is greatly enhanced by PSC-833 in tumor cells which manifest multidrug resistance. The overall result is a selective enhancement of the beneficial effects 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 experimental treatments, several patients experienced a significant reduction in the size or rate of spread of their cancers, he said.
Researchers from Sikic's lab reported the findings from these trials at the annual meeting of the American Society of Clinical Oncology in Los Angeles.
Results of PSC-833 Plus Paclitaxel or Etoposide
In the trial investigating paclitaxel used in combination with PSC-833, the researchers looked at the responses of 41 adults (32 women and 9 men) with a variety of incurable cancers, including breast, colon, lung and ovarian cancers, and sarcoma. Another trial involved 26 patients (19 women and 7 men) who received etoposide in combination with PSC-833. In both studies, the investigators found that the new drug's dose-limiting side effect is a loss of coordination, especially in patients' legs. When dosages stayed below 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 and cyclosporine seem to reverse drug resistance by targeting its root cause: They block the action of P-glycoprotein, which pumps anticancer drugs out of tumor cells.
Based in part on the Stanford results, researchers nationwide have begun phase II clinical trials to test the effectiveness of PSC-833 in lymphoma, multiple myeloma, and ovarian cancer in adults and leukemia in adults and children.
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