Z01 BC 010382 (Z01) | |||
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Title | Chemotherapy Adjuvants | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Moschel, Robert | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $273,819 | Project Dates | 10/01/2000 - N/A |
Fiscal Year | 2007 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Chemotherapy (50.0%) Neurosciences Research (50.0%) |
Brain (50.0%) Nervous System (50.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Resources and Infrastructure Related to Treatment and the prevention of recurrence |
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Abstract | |||
The human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT)is primarily responsible for the resistance exhibited by tumor cells to a number of chemotherapeutic drugs. This project focuses on design, synthesis and development of drugs that can inactivate this protein. The drugs are used as adjuvants to enhance the effectiveness of chemotherapeutic agents that modify the O6-position of DNA guanine residues. The prototype AGT inactivator, O6-benzylguanine (b6G) is very insoluble in water and, as a result, is difficult to handle. A compound we developed this year, O6-[3-(aminomethyl)benzyl]guanine (3AM-b6G), is approximately 1000 times more soluble in neutral water than benzylguanine and is 20 times more active as an AGT inactivator in vitro. Cell killing experiments in combination with BCNU show the new compound to be about as active as the parent b6G. The very high solubility of O6-[3-(aminomethyl)benzyl]guanine compared to b6G should greatly simplify formulation as a chemotherapy adjuvant. In addition, the ability to make concentrated solutions of this compound will allow it to be delivered directly to a brain tumor using an osmotic pump and capillary system. Site-specific drug delivery is expected to alleviate the side effects of systemic drug delivery (principally myelotoxicity). Henry Friedman (Duke University, Robert Preston Tisch Brain Tumor Center) has shown that rats could tolerate receiving a 2 ml dose of 10 mM 3AM-b6G over 7 days directly into the brain. This is probably vastly more than is required to eliminate AGT activity in the brain. Dr. Friedman is currently conducting animal studies aimed at determining an effective dose of drug administered by this route. He will then begin xenograft experiments with a brain tumor model using site-specific 3AM-b6G delivery in combination with systemic alkylating agent delivery. The alpha folic acid receptor has been used to deliver a variety of agents selectively into tumor cells. This laboratory developed O4-Benzylfolic acid (b4FA), which is a very potent and highly water soluble AGT inactivator that binds the alpha folic acid receptor. In vivo studies are currently underway with this compound in collaboration with Frank Balis (Pediatric Oncology Branch, CCR) and Melinda Hollingshead (NCI-Developmental Therapeutics Program-DCTD). Related to this work, we have synthesized several conjugates of folic acid with previously developed AGT inactivators such as b6G or O6-benzyl-2'-deoxygganosine (b6dG). The selective uptake of these compounds by tumor cells, mediated by the folic acid receptor, will allow tumor-specific AGT inactivation while allowing the protective acion of AGT to remain active in non-tumor cells. |