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 (Taxol) or 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,"
"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,
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.