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Combination Therapy of Mouse Leukemia L1210 by 1-ß-D-Arabinofuranosylcytosine and 6-[(4-Nitrobenzyl)thio]-9-ß-D-ribofuranosylpurine¹

Cancer Research Unit (McEachern Laboratory) [C. E. C., H. M., A. R. R. P] and Department of Biochemistry [C. E. C., A. R. P. P.] University of Alberta, Edmonton, Alberta, Canada T6G 2E1

Nitrobenzylthioinosine (NBMPR), an inhibitor of nucleoside transport, was tested in combination with 1-ß-D-arabinofuranosylcytosine (ara-C) for therapeutic activity against mouse leukemia L1210. NBMPR alone had no activity, whereas therapy with NBMPR and ara-C in combination was significantly better than with ara-C alone. The therapeutic potentiation resulting from the combination of NBMPR and ara-C appeared to be host mediated since NBMPR alone was not toxic to cultured L1210 cells. NBMPR treatment of normal mice increased the plasma half-time of ara-C and decreased rates of urinary excretion of ara-C and 2'-deoxycytidine; however, these effects were not large enough to explain the therapeutic potentiation. Because the drug combination appeared to be no more effective than ara-C alone in therapy of mouse leukemia L1210/TG (a thiopurine-resistant L1210 subline lacking hypoxanthine-guanine phosphoribosyltransferase), the host-mediated therapeutic potentiation was attributed in in vivo breakdown of NBMPR to 6-mercaptopurine.

¹ This work was supported by the Medical Research Council of Canada and the National Cancer Institute of Canada. Portions of this work were described in a preliminary report (12).

Received 8/26/74. Accepted 1/21/75.