Small-Molecule Multidrug Resistance-Associated Protein 1 Inhibitor Reversan Increases the Therapeutic Index of Chemotherapy in Mouse Models of Neuroblastoma.

Small-Molecule Multidrug Resistance-Associated Protein 1 Inhibitor Reversan Increases the Therapeutic Index of Chemotherapy in Mouse Models of Neuroblastoma.

Cancer Res. 2009 Aug 4;

Authors: Burkhart CA, Watt F, Murray J, Pajic M, Prokvolit A, Xue C, Flemming C, Smith J, Purmal A, Isachenko N, Komarov PG, Gurova KV, Sartorelli AC, Marshall GM, Norris MD, Gudkov AV, Haber M

The multidrug resistance-associated protein 1 (MRP1) has been closely linked to poor treatment response in several cancers, most notably neuroblastoma. Homozygous deletion of the MRP1 gene in primary murine neuroblastoma tumors resulted in increased sensitivity to MRP1 substrate drugs (vincristine, etoposide, and doxorubicin) compared with tumors containing both copies of wild-type MRP1, indicating that MRP1 plays a significant role in the drug resistance in this tumor type and defining this multidrug transporter as a target for pharmacologic suppression. A cell-based readout system was created to functionally determine intracellular accumulation of MRP1 substrates using a p53-responsive reporter as an indicator of drug-induced DNA damage. Screening of small-molecule libraries in this readout system revealed pyrazolopyrimidines as a prominent structural class of potent MRP1 inhibitors. Reversan, the lead compound of this class, increased the efficacy of both vincristine and etoposide in murine models of neuroblastoma (syngeneic and human xenografts). As opposed to the majority of inhibitors of multidrug transporters, Reversan was not toxic by itself nor did it increase the toxicity of chemotherapeutic drug exposure in mice. Therefore, Reversan represents a new class of nontoxic MRP1 inhibitor, which may be clinically useful for the treatment of neuroblastoma and other MRP1-overexpressing drug-refractory tumors by increasing their sensitivity to conventional chemotherapy. [Cancer Res 2009;69(16):6573-80].

PMID: 19654298 [PubMed - as supplied by publisher]

Read the complete post at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?tmpl=NoSidebarfile&db=PubMed&cmd=Retrieve&list_uids=19654298&dopt=Abstract

Posted 6 Aug 2009 8:54 AM by pubmed: neuroblastoma
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There is nothing quite as devastating as hearing that word - neuroblastoma. In seconds your world is turned upside down and your normal life is but a distant memory. You are thrust into a confusing world full of fear. Your child has cancer.

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Welcome to our website. It is a place for you to find answers and ask questions. One of the primary goals of the Neuroblastoma Foundation is to ensure that parents, patients and health care professionals find the information they need to make the best treatment decisions possible for children and adults affected by neuroblastoma. There is a vast amount of information throughout the internet, much of which is encapsulated in medical jargon that is so complex that even many medical professionals have difficulty in interpreting its meaning. We are here to help to decipher this information and to make sure you (and your oncologist) understand exactly what it means to you. From treatment decisions to side effects we have parents and experts that have experienced it all and are willing to distill it for you.