Alkylator chemotherapy plays a significant role in the treatment of brain tumors and other malignancies. However, its effectiveness is all too often limited by drug resistance, which leads to lethal growth of tumors despite further rounds of alkylator chemotherapy. Drug resistance to alkylator chemotherapy is primarily due to the repair of induced O6-alkylguanine DNA lesions by the protein alkylguanine-DNA alkyltransferase (AGT). There is a well-established inverse correlation between tumor AGT content and therapeutic outcome;generally, survival rates are higher when the AGT content of tumor is below a threshold. We hypothesize that it should be possible to decide whether to administer alkylator chemotherapy in individual patients based on noninvasive imaging of tumor AGT levels prior to therapy. The goal of this work is to develop radiolabeled agents that will allow assessment of AGT levels using SPECT or PET imaging. We propose to synthesize radioiodinated derivatives of O6- benzylguanine (BG), a potent AGT inactivating agent, coupled to nuclear localizing peptide sequences (NLS) to enhance delivery of the labeled substrate to the cell nucleus where AGT is predominantly present. These labeled agents will be evaluated in vitro using pure AGT and AGT-expressing cell lines and in vivo using xenograft models.
The specific aims are: 1. To synthesize benzylguanine derivatives and their NLS conjugates. 2. To evaluate the radiolabeled benzylguanines and their NLS conjugates for binding to pure AGT and in tumor cells in vitro. 3. To evaluate AGT-specific radiolabeled agents developed in athymic mouse xenograft models. A successful agent for the molecular imaging of AGT could be an important tool that can be used to avoid unnecessary chemotherapy;in addition to the economic benefits, it can spare patients from the major side effects of alkylator chemotherapy, and allow them to be triaged earlier to alternative treatments.
The goal of this project is to develop radiolabeled tracers that can be utilized as molecular imaging agents for the noninvasive assessment of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) in brain cancers and other tumors. AGT is primarily responsible for the drug resistance that frequently compromises the effectiveness of alkylator-based chemotherapy of many cancers. Because drug resistance is a major road block in the cancer treatment process, the availability of a molecular imaging technique to quantify AGT will have a significant clinical impact. With such a technique, chemotherapy can be personalized because it should be possible to predict which patients will benefit from chemotherapy and which will not. This will help avoid treating patients for whom alkylator chemotherapy will be largely ineffective, sparing them of unwarranted side effects and expense, and providing an earlier rationale for seeking alternative treatments that might be more successful, given their AGT status.
| Vaidyanathan, G; White, B J; Affleck, D J et al. (2012) SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies. Bioorg Med Chem 20:6929-39 |
| Vaidyanathan, Ganesan; White, Benjamin; Affleck, Donna J et al. (2011) Radioiodinated O(6)-Benzylguanine derivatives containing an azido function. Nucl Med Biol 38:77-92 |
| Vaidyanathan, Ganesan; McDougald, Darryl; Grasfeder, Linda et al. (2011) An alternative and expedient synthesis of radioiodinated 4-iodophenylalanine. Appl Radiat Isot 69:1401-6 |
