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Retroviral Transfer of Deoxycytidine Kinase into Tumor Cell Lines Enhances Nucleoside Toxicity¹

Departments of Pharmacology [D. M. H., A. P. A. S., B. S. M.] and Medicine [B. S. M.], University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599

Deoxycytidine kinase (dCK) phosphoryiates a number of nucleoside analogues that are useful in the treatment of various maligancies. Although the level of dCK activity in malignant cells is thought to correlate with chemotherapeutic response, no direct data are available to support this assumption. We have tested this hypothesis by infecting three tumor cell lines, MCF-7, HT-29, and H1437, with the retroviral vector LNPO containing either dCK or LacZ cDNA and measuring the corresponding sensitivity to nucleoside analogues. DCK activity was increased by 1.7-, 2.3-, and 16-fold in MCF-7, HT-29, and H1437 cells, respectively. Northern and Western blots demonstrated a similar increase in mRNA and protein levels. As a result of dCK expression, MCF-7 cells demonstrated a 2.5-fold increase in drug sensitivity to 1-ß-D-arabinofuranosylcytosine (AraC) and 2-chloro-2'-deoxyadenosine (CdA). HT-29 cells had a 7-fold increase in sensitivity to AraC, CdA, and 2-fluoro-9-ß-D-arabinofuranosyladenine, whereas H1437 cells demonstrated a 20- to 106-fold increase. For all three drugs, there was a linear relationship between dCK activity in clonally derived cell lines and IC₅₀s. These data demonstrate a direct effect of dCK activity on drug sensitivity in cell lines. Because many tumors have relatively low levels of dCK, it is possible that dCK gene transfer will be a useful adjunct to the treatment of these malignancies.

¹ This work was supported by NIH Grant RO-1-CA34085.

² To whom requests for reprints should be addressed, at CB #7365, 906 FLOB, Department of Pharmacology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.

Received 12/ 7/95. Accepted 1/30/96.

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