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New Cyclin Dependent Kinase Inhibitors May Help Overcome Chemotherapy Resistance

New Cyclin Dependent Kinase Inhibitors May Help Overcome Chemotherapy Resistance

NEW YORK—Agents classified as cyclin dependent kinase (CDK)
inhibitors show promise in overcoming chemotherapy resistance, Gary K.
Schwartz, MD, said at a media briefing on new pathways to targeted treatments
sponsored by the American Society of Clinical Oncology (ASCO).

CDK inhibitors do not generally by themselves induce apoptosis in cancer
cells, said Dr. Schwartz, of Memorial Sloan-Kettering Cancer Center and Weill
Medical College-Cornell University. When combined with such standard cancer
drugs as fluorouracil, irinotecan (Camptosar), or paclitaxel (Taxol), however,
they enhance tumor response and pave the way to apoptosis.

Cells require CDKs to move from one phase of the cell cycle to the next in
order to proliferate, Dr. Schwartz said. Some of the CDK inhibitors now being
developed and tested are small molecules that bind directly to the kinase.
Others stimulate inhibitors intrinsic to cells.

Flavopiridol, an agent derived from Dysoxylum binectariferum, a plant
indigenous to India, inhibits CDK 1, 2, 4, and 6 in nanomolar concentrations,
Dr. Schwartz reported. Early laboratory studies focused on using the small
molecule to induce apoptosis, but only about 5% of cells succumbed. "These
cells are arrested at a particular phase of the cell cycle, but they’re not
gone," he said.

If flavopiridol in the same concentration is combined with mitomycin (Mutamycin),
however, profound apoptosis occurs (see Figure). "That is,"
Dr. Schwartz explained, "you can convert cells that were resistant to
apoptosis by exposing them to chemotherapy and a CDK inhibitor, in this case
flavopiridol."

When Dr. Schwartz and his associates combined flavopiridol and irinotecan in
a study in colon cancer xenograft models, the response rate was 80%, double
that seen with irinotecan alone. "And, for the first time, you can cure
about one third of these animals," he said. This combination is being
tested in a phase I trial.

The Sloan-Kettering researchers are also studying flavopiridol combined with
paclitaxel in patients with advanced metastatic esophageal cancer. Earlier
studies in gastroesophageal cancer cell lines, Dr. Schwartz reported, raised
the apoptosis rate from 10% with paclitaxel alone to 60% with the combination.

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