NOVEL NUCLEOSIDES FOR IMAGING DURING CANCER THERAPY

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DESCRIPTION: Cancer treatment by gene therapy, in which an exogenous gene is introduced into tumor cells, is receiving increasing attention. Metabolism of a specific substrate by the enzyme encoded by the transduced gene produces a substance toxic to the tumor. In the most common approach, the gene for the Herpes Virus Thymidine Kinase has been introduced by retroviral transduction. Although promising, development of treatment protocols is limited by the difficulty of determining the efficiency of transduction and the extent of HSV1-TK expression. Knowledge of the level of expression, the optimal time for application substrate, and the time over which treatment is feasible would be of considerable value in guiding the clinician. A noninvasive, clinical method for imaging cells and tissues would greatly enhance the likelihood of successful therapy. In applicants earlier work a radioiodinated fluorouracil analogue, FIAU, was shown in an animal tumor model to be a promising imaging substrate with acceptable selectivity and specificity. Although these data were encouraging, more active substrates which display greater selectivity and specificity would be of considerable value. Based on the preliminary data applicants propose to synthesize a series of xylo- nucleoside analogues (Figure 1) that show enhanced activity as substrates for HSV1-TK. These compounds will be radioiodinated and tested for enhanced selectivity and specificity in a cell line based assay. Promising candidates will be tested for activity as imaging substrates in an animal tumor model. In Phase II applicants will develop additional compounds based on the leads developed in Phase I. The applicants will expand the preclinical testing of promising candidates so as to define pharmacologic issues of clearance, retention, organ distribution, etc. They will also develop a program to produce variants of the HSV-TK. These will be challenged with the new compounds to find the most active combination of variant enzyme and novel substrate.