Visit our Expo - Redox and Inflammation signaling 2012

IV. Protein kinase inhibitors: insights into drug design from structure Poster IV, 5
Exploring the chemotherapeutic benefit of combining Gemcitabine (Gemzar) and
Rapamycin
Ofer Merimsky1,2, Yaara Gorzalczany2 and Ronit Sagi-Eisenberg2
1Department of Oncology, The Tel-Aviv Sourasky Medical Center, Sackler School of
Medicine, Tel Aviv University, Tel Aviv 69978 Israel and 2Dept. of Cell and
Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978
Israel
Two major obstacles encountered while treating cancer patients are achieving the right
balance between the effectiveness of the drug and its cytotoxic side effects as well as
overcoming mechanisms of existing or acquired resistance. The emerging solution appears to
constitute a combination of a “traditional” cytotoxic drug with a “signaling” drug.
Gemcitabine (Gemzar), is an antimetabolite drug that inhibits DNA synthesis and displays
some activity as a single agent in treating pancreatic and sarcoma cancer. However,
gemcitabine treatment is often associated with acquired resistance. Rapamycin is a selective
inhibitor of mTOR, a phosphatidylinositol-3-kinase (PI3K)-related kinase that controls cell
proliferation, cell survival and adhesion-independent survival and migration. Combining
Gemzar and rapamycin might thus provide a therapeutic advantage. Here we report a patient
who underwent resection of abdominal leiomyosarcoma at the time of renal transplantation.
While on rapamycin for rejection prevention, no sarcoma re-growth was evident. On
interruption of rapamycin, after spontaneous kidney rejection, the sarcoma relapsed, and
metastasized. Re-introduction of rapamycin and co-administration of gemcitabine yielded a
prolonged remission and symptoms alleviation. To define the molecular impact of this drug
combination, we have used SK-LMS cells, a human leiomyosarcoma cell line as a model.
Indeed, we show that both gemcitabine and rapamycin inhibit cell proliferation, only
rapamycin alone or when combined with gemcitabine reduce significantly the amount of
phosphorylated ERK as well as a the amount of bcl-2. In view of the fact that gemcitabineinduced
cell death is determined by bcl-2 content, our results provide a strong basis for a
novel regimen based on Gemzar/rapamycin combination in cancer treatment.
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