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Development of Resistance to 1-ß-D-Arabinofuranosylcytosine after High-Dose Treatment in Childhood Lymphoblastic Leukemia: Analysis of Resistance Mechanism in Established Cell Lines¹

Leukaemia Research Laboratory, Clinical Immunology Research Unit, Princess Margaret Hospital, G. P. O. Box D 184, Perth, Western Australia 6001 [U. R. K., J. F., V. M. D.], and Department of Biochemistry, University of Surrey, Guildford Surrey GU2 5XH, England [E. P., G. W. A.]

Cell lines PER-163 and PER-164 are derived from a patient with acute lymphoblastic leukemia who developed resistance to 1-ß-D-arabinofuranosylcytosine (ara-C) after high-dose (HD) therapy. Both lines are highly resistant to ara-C and have maintained stable resistance for more than 18 mo. The resistance in PER-164 cells is the result of a selection process in vivo only, while PER-163 cells have in addition been exposed to ara-C in culture. Comparison with cell line PER-145, which is sensitive to ara-C and was established from the same patient before HDara-C therapy, revealed no differences with respect to surface markers, morphology, cytochemical stains, or requirements for growth in vitro. The leukemic origin of the three cell lines is indicated by the close similarities of all three cell lines to the patient's fresh cells. The analysis of the two resistant cell lines shows that resistance to ara-C is not due to lower ara-C transport capacity nor to cytokinetic reasons, since the percentage of cells in S-phase is similar in all three cell lines. In addition, the resistant cell lines do not show any increased cytidine deaminase activity. PER-164 cells show a markedly reduced deoxycytidine kinase activity, 4.8 nmol/h/mg of protein, compared to PER-145 cells with an enzyme activity of 21.48 nmol/h/mg of protein. In PER-163 cells, no deoxycytidine kinase activity could be detected. Furthermore, the two resistant cell lines show significantly different dCTP levels. The sensitive PER-145 cells generated 97.9 pmol of 1-ß-D-arabinofuranosylcytosine triphosphate (ara-CTP)/10⁷ cells during a 45-min incubation period in the presence of 10^-6 M ara-C. This contrasts with 0.16 and 12 pmol of ara-CTP/10⁷ cells for PER-163 and PER-164 cells, respectively. These investigations suggest that cell phenotypes with distinct features can be generated after HDara-C treatment and that decreased deoxycytidine kinase activity appears to be one of the major mechanisms of resistance.

¹ This work was supported by the Children's Leukaemia Research Fund of the Princess Margaret Children's Medical Research Foundation and grants from the National Health and Medical Research Council of Australia, the Cancer Research Campaign of Great Britain, and from the Upjohn Company.

Received 7/25/88. Revised 12/28/88. Accepted 3/ 7/89.

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