There have been a variety of studies completed which have suggested that the modified purine Queuine may be of importance in neoplastic disease. Furthermore, elucidation of its physiological role may offer useful novel diagnostic or therapeutic mechanisms for the treatment of human cancers. For these to be pursued, the level of expression of Queuine, and more specifically Queuine-tRNA, needs to be determined in human neoplastic and normal tissues. Previous studies in animals have suggested that Queuine-tRNA levels in cells may reflect the neoplastic state of the cells, and that Queuine may be an anti-tumor promoter. The studies outlined in this proposal will allow for determination of whether human malignancies are Queuine-deficient. White blood cells from leukemia patients will be examined both before and after chemotherapeutic treatment, and compared with normal white blood cells. Our preliminary results suggest that there is a significant difference between malignant compared to normal white blood cells. Our study will also be extended to examine malignant and benign human breast tumors compared with normal breast tissue. A monoclonal antibody specific for Queuine will be developed to optimize detection of Queuine-tRNA and to be used for analysis of Queuine pharmacology. Studies are also proposed to examine the functional properties of Queuine and Queuine- tRNA. Previous studies have established a structural and biochemical relationship between Queuine and the phorbol ester tumor promoters. Our studies will determine if Queuine is effective at blocking phorbol ester induction of epigenetic changes which have been shown to result in gene amplification and drug resistance. The gene for dihydrofolate reductase in MCF-7 breast carcinoma cells, which can be amplified by methotrexate and certain phorbol esters, will serve as our model system. The ability of Queuine to inhibit tumor-promoter enhancement of tumor metastatic activity will also be examined using the Lewis Lung murine carcinoma. A final project will be to determine the activity of Queuine-tRNA in preventing fusion protein production mediated at translational sites. In vitro translation experiments using retroviral mRNA will be used for this study. The results of the proposed studies should provide answers to the question of the potential value of Queuine-tRNA as a diagnostic or therapeutic target, and for an improved understanding of Queuine pharmacology and biochemical activity.
| Foster, B J; Wiegand, R A; LoRusso, P M et al. (1995) Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4, 5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials1. Clin Cancer Res 1:831-7 |
