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Waldemar Priebe 

The University of Texas M D Anderson Cancer Center, Holcombe Boulevard 1515, Houston, TX 77030, United States


Malignant gliomas are devastating cancers, which due to infiltration and location are difficult to treat and also represent significant mortality in young populations. Development of effective chemotherapeutic strategies has been limited in part by the inaccessibility of the CNS to pharmacological intervention. As a possible target, topoisomerase II (topo II) overexpression has been documented in human gliomas and correlated to poor survival, but no effective topo II poison capable of reaching the target tissue after systemic administration has yet been developed. Immunohistochemical studies of primary and secondary glioblastomas and their astrocytic precursor tumors have demonstrated that like topo II, ATP-binding cassette (ABC) transporters like MRP1, LRP, and P-gp are overexpressed in glioblastomas. We hypothesized that the presence of ATP-binding cassette (ABC) transporters in the blood-brain barrier (BBB) might, in part, be responsible for limiting the CNS penetration of most anticancer drugs, while their presence in tumor tissue also confers resistance to wide range of drugs at a cellular level. To identify new agents effective in vivo against glioblastomas, we have developed an innovative approach combining our modular design of DNA-binding agents allowing for the creation of unique libraries of DNA binders and potential topo II poisons. By systematically screening such libraries, we have identified highly apoptotic compounds that can circumvent Pgp and MRP1-mediated resistance mechanisms, suggesting that such compounds will be potent cytotoxins against gliomas, while possessing the ability to cross the BBB. We prepared and screened a selected library of over 400 DNA binding agents against a panel of cells overexpressing P-gp and MRP1, identifying < 10 compounds possessing the necessary characteristics from which the compounds WP744 and WP769 were selected for more detailed evaluation. Both compounds are structurally related to the well-known anticancer drug doxorubicin (DOX), but they possess in vitro and in vivo properties that are very different from those of DOX. WP744 and WP769 are significantly more apoptotic than DOX against both wild-type tumor cells and multidrug-resistant tumor cell lines with the MDR1 and MRP1 phenotypes. WP769 is also a significantly more potent topo II poison than either DOX or WP744. Both WP744 and WP769 cross the BBB, reaching CNS and tumor concentrations that exceed that of plasma. In vitro, both are effective at nanomolar concentrations in inhibiting growth of the glioma cell lines U87MG, D54MG, and U251MG. Because of their unique biological characteristics (potent topo II poisons, ability to cross BB barrier, activity against multidrug resistant tumors) these agents are uniquely placed to become effective therapeutic agents for the treatment of GBM. We will discuss the design, synthesis, screening, selection, and unique properties of compounds WP744 and WP769. Currently, WP744 is entering Phase I clinical studies in humans.


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Related papers

Presentation: Invited Oral at V Multidyscyplinarna Konferencja Nauki o Leku, by Waldemar Priebe
See On-line Journal of V Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2006-02-23 11:05
Revised:   2009-06-07 00:44