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Using a functional genomic screen, researchers have defined elements that impact the responsiveness of cancer cells to drugs usually used as anticancer therapeutics. The research, reported in the recent issue of the journal Cancer Cell, published by Cell Press, identifies individual genes that are linked to resistance to chemotherapeutic drugs and sets the stage for future studies that may significantly enhance the ability to predict whether or not a particular tumor will respond to therapy.

Resistance to chemotherapeutic drugs is the primary cause of therapy failure in patients with metastatic cancer. Dr. Julian Downward from the Cancer Research UK London Research Institute and his colleagues used RNA interference to directly examine the contribution of over 800 candidate proteins to the sensitivity or resistance of cancer cells to several drugs that are usually used to treat cancer.

Using this technique, the scientists observed that resistance to the chemotherapeutic agent paclitaxel, a member of the taxane family, as expected, involves genes that impair drug-induced mitotic arrest following knockdown. Silencing of these genes in a number of cases also induces polyploidy and multinucleation in the absence of drug therapy. The scientists conclude that specific disruption of the mitotic checkpoint promotes paclitaxel resistance and that chromosomal numerical heterogeneity may be a useful predictor of paclitaxel resistance in some cancers.

Ceramide metabolism was identified as a critical regulator of sensitivity to a wide range of chemotherapeutic drugs. Eventhough ceramide has been linked to apoptosis for some time, the mechanisms have not been well understood. In this study, decreased expression of a ceramide transport protein, COL4A3BP, sensitized cancer cells to multiple cytotoxic agents. Further, expression of COL4A3BP was increased in drug-resistant tumor cells and in a small cohort of ovary cancers following paclitaxel therapy.

The scientists suggest that paclitaxel-induced prolonged mitotic arrest may result in ceramide accumulation and initiation of apoptosis, while inhibition of this arrest, characterized by polyploidy, may suppress ceramide generation and promote cell survival. These data suggest that the taxane class of drugs may lack efficacy in tumors with high levels of chromosomal instability characterized by chromosomal numerical heterogeneity and provide a rational basis for identification of patients likely to benefit from these drugs, explains Dr. Downward.


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