MICRO-PET IMAGING OF ALKYLGUANINE-DNA ALKYLTRANSFERASE (AGT)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytotoxic action of chemotherapeutic alkylating agents stems from the alkylation of DNA at the O6-position of DNA guanine residues. Subsequent to alkylation, a cascade of events takes place resulting in eventual DNA strand breaks. Drug resistance seen in alkylator chemotherapy of various cancers has been primarily attributed to the DNA repair protein Alkylguanine-DNA alkyltransferase (AGT). AGT transfers the guanine O6-alkyl group to a cysteine in its active site thereby repairing the DNA. This is a stoichiometric or suicidal process; once its cysteine-145 is alkylated, AGT undergoes degradation via ubiquitin pathway and new AGT can only be regenerated by de novo synthesis. A number of preclinical as well as retrospective and prospective clinical studies have demonstrated an inverse correlation between the tumor AGT content and the positive clinical outcome of alkylator chemotherapy. Also, tumor AGT content varies not only between different tumor types but also within a group of patients of same malignancy. Thus, a prior knowledge of the tumor AGT content can help oncologists to tailor chemotherapy on a patient-specific basis. Our goal is to develop radiolabeled agents with which it should be possible to quantify tumor AGT content in a noninvasive fashion by PET or SPECT imaging. O6-benzylguanine (BG) is a substrate for AGT and is undergoing clinical studies as an AGT modulator. We have developed a radioiodinated BG analogue namely, O6-3-[*I]iodobenzylguanine (IBG) which has shown to label AGT specifically. Recently this compound has been tagged with I-124. The goal of this work is to track this agent in a mouse xenograft model. We would like to determine whether tumors of a control group and of a group whose tumor AGT is depleted can be differentiated. The ultimate goal of our project is to develop radiolabeled agents with which it should be possible to quantify AGT by PET or SPECT imaging. Thus it is critical to demonstrate that it can be done in an animal model first. In addition, it is necessary to eatablish that it is possible to image animal models with DUMC microPET using I-124 tagged radiopharmaceuticals.