New Agent May Help Overcome Imatinib Resistance

SAN FRANCISCO—In vitro studies suggest that a new anticancer agent, SCH66336, can slow cell proliferation in drug-resistant forms of Philadelphia (Ph)-positive leukemia, according to a presentation by Japanese researchers at the 93rd Annual Meeting of the American Association for Cancer Research (abstract 4235). When used in combination with antileukemic agents, SCH66336 induced apoptosis in leukemia cells resistant to imatinib mesylate (Gleevec).

"SCH66336 is a promising candidate for treating patients with Gleevec-resistant Ph-positive leukemias," said Tetsuzo Tauchi, MD, PhD, associate professor of internal medicine, Tokyo Medical University. "Gleevec has shown promise in human clinical trials of Ph-positive leukemia, but the emergence of drug resistance in patients with acute forms of Ph-positive leukemia highlights the need for combination chemotherapy to eradicate the disease."

In the cell line study, SCH66336 and/or imatinib was added to BCR-ABL-positive acute myelogenous leukemia (AML) cells in culture. BCR-ABL is a chimeric oncoprotein generated by the Philadelphia chromosome in Ph-positive leukemia. Imatinib inhibits the tyrosine kinase activity of BCR-ABL in leukemia cells.

The scientists counted cell numbers every 24 hours for 5 days. When the cells were treated with SCH66336, cell growth was inhibited more than when they were treated with imatinib alone. In contrast to cells treated with imatinib, those treated with SCH66336 showed significant antiproliferative effects.

Despite the inhibition of cell proliferation, SCH66336-treated cells remained viable after 1 week in culture. Yet treatment with imatinib and SCH66336 together significantly increased apoptosis, compared with imatinib or SCH66336 alone.

The scientists also investigated whether SCH66336 could increase the effects of some antileukemic agents, including imatinib, in chronic myelogenous leukemia (CML) blast crisis cell lines. When SCH66336 was used with imatinib or cytosine arabinoside (ara-C), the antiproliferative activity of the drug combination increased. However, when the new compound was combined with daunorubicin (Cerubidine) or etoposide (VePesid), there was no increased antiproliferative effect.

The researchers then tested how leukemic bone marrow cells would react to the combination of SCH66336 and imatinib mesylate. The results showed that the combination produced a substantial decrease in colony formation, compared with that seen with each agent alone.

The researchers will now take SCH66336 into clinical trials. "We hope to implement clinical trials with this compound in Tokyo within the next 12 months," Dr. Tauchi said.

SCH66336 is a farnesyl transferase inhibitor that has been previously shown to possess potent antitumor activity in human cancer cell lines, Dr. Tauchi said. It stops Ras from moving to the plasma membrane and reaching its full activity. SCH66336 seems to inhibit H-Ras, and blocks the transformed properties of BCR-ABL-positive leukemia cells resistant to imatinib.

The use of SCH66336 with imatinib may be a promising therapy to circumvent drug resistance in Ph-positive leukemia, Dr. Tauchi concluded.