John Wayne Cancer Institute

Other

Myles C Cabot

Barry J Maurer

C Patrick Reynolds

Methods of detecting novel therapeutically active compositions based on their ability to modulate the glycolipid metabolism and overcome multidrug resistance are described. These methods are particularly useful in screening for novel chemotherapeutic agents for the treatment of cancer, as well as chemosensitizers that are capable of enhancing the cytotoxicity of such chemotherapeutic agents. A combination of one or more of these compositions can be used in the treatment of a various cancers.

Methods for screening therapeutically effective agents

A method of treating a hyperproliferative disorder in a subject in need of such treatment, comprising administering to said subject, in combination, a treatment effective amount of: (a) a ceramide-generating retinoid such as fenretinide or a pharmaceutically acceptable salt thereof; and (b) at least one (and in certain embodiments at least two) ceramide degredation inhibitor, such as compounds selected from the group consisting of (i) glucosylceramide synthesis inhibitors, (ii) sphingosine-1-phosphate synthesis inhibitors, and (iii) protein kinase C inhibitors. A preferred glucosyl ceramide synthesis inhibitor is 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. A preferred sphingosine-1-phosphate synthesis inhibitor is D-erythro-N,N-dimethylsphingosine. A preferred protein kinase C inhibitor is L-threo-dihydrosphingosine.

Treatment of hyperproliferative disorders

The present invention involves the identification of sphingoglycolipid species that are indicative of multidrug resistance in certain types of cells, including cancer cells. The association of multidrug resistance with the expression of certain sphingoglycolipids provides a new method for identifying multidrug resistant cancers. In addition, it has been determined that reducing the levels of certain sphingoglycolipids results in enhanced chemosensitivity of drug resistant cancer cells. This offers the opportunity to develop new treatments for multidrug resistant cancers.

Sphingoglycolipids as markers for multidrug resistant cancers

The present invention provides for the screening of candidate substances to identify active compounds that inhibit multidrug resistance (MDR). The expression of glucosylceramides has been determined to be a marker of MDR. By measuring glucosylceramide expression in cells exhibiting MDR, and the reduction in glucosylceramide levels in the presence of a candidate substance, the present invention provides for the identification of MDR inhibitory compounds.

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Santa Monica, CA, United States of America

Myles C Cabot