Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination.

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Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia

cells in vitro, as single agent and in drug combination.

A Aleskog, M Norberg, P Nygren, L Rickardson, M Kanduri, G Tobin, M Aberg, MG

Gustafsson, R Rosenquist, and E Lindhagen

Leuk Lymphoma, December 1, 2008; 49(12): 2333-43.

Department of Medical Sciences (Hematology).

The mammalian target of rapamycin inhibitor rapamycin and its analogues show

promising anticancer activity in various experimental tumor models and are

presently evaluated in clinical trials. We, here, evaluated the in vitro

activity of rapamycin with regard to tumor-type specificity and possible

mechanisms of drug resistance in 97 tumor cell samples from patients and in a

resistance-based cell line panel, using the fluorometric microculture

cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor

cells and in cell lines. In primary cells, rapamycin was more active in

hematological than in solid tumor samples, with chronic lymphocytic leukemia

(CLL) and acute lymphocytic leukemia being the most sensitive tumor types.

Considerable inter-individual differences in sensitivity were apparent among CLL

samples, but no difference was observed between IGHV mutated and unmutated CLL

samples, whereas a tendency to lower rapamycin sensitivity was indicated for

samples displaying poor-prognostic genomic markers. Combination experiments in

CLL cells indicated that rapamycin acted synergistically with vincristine,

cisplatin, chlorambucil and taxotere. These results and the

clinically-experienced good tolerance to rapamycin analogues encourage clinical

studies of rapamycin in CLL treatment as single agent but also in combination

with, e.g., vincristine and chlorambucil.

PMID: 19052982