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Combination Chemotherapy with Cytosine Arabinoside, L-Asparaginase, and 6-Azauridine for Transplantable Murine Leukemias¹

Laboratory of Pharmacology, St. Jude Children's Research Hospital, and Departments of Anatomy [T. L. A.] and Pharmacology [D. R.], University of Tennessee Medical Units, Memphis, Tennessee 38101

Survival times of C57BL/6J x DBA/2J F₁ mice, inoculated with L1210 or L5178Y ascites tumor cells, were monitored following treatment with cytosine arabinoside, L-asparaginase, and 6-azauridine, alone and in combination. Each tumor line was sensitive to cytosine arabinoside. L-Asparaginase produced cures (60-day survivors) in 20 to 30% of L5178Y hosts but was totally ineffective against L1210. 6-Azauridine was marginally effective against L1210 and ineffective against L5178Y.

Cytosine arabinoside plus 6-azauridine was not superior to cytosine arabinoside for treatment of L1210 or L5178Y. 6-Azauridine plus L-asparaginase was slightly more effective than 6-azauridine for L1210, and for L5178Y the incidence of cures with this combination did not significantly exceed that obtained with L-asparaginase alone. Synergistic responses to cytosine arabinoside plus L-asparaginase were manifested by both tumor lines. This drug combination cured 84% of L5178Y-inoculated mice, and the mean life-span of hosts succumbing to L1210 was extended 25% beyond that attained with cytosine arabinoside. Tumor response to this combination of drugs was largely independent of dosage over the range used.

Synergism between L-asparaginase and cytosine arabinoside was lost when 6-azauridine was added to the treatment regimen, and therapeutic responses by L1210 and L5178Y became a function of cytosine arabinoside dosage. Life-span increased with increasing cytosine arabinoside dosage, but at our maximum dosage therapeutic effectiveness was impaired by an increased incidence of fatal host toxicity.

These results indicate that: (a) combinations of L-asparaginase and cytosine arabinoside can act synergistically against tumor cell lines with varying sensitivities to the individual drugs; (b) drug dosages may be less important to response in some combinations than in single-drug therapy; (c) combination chemotherapy based upon response to single agents may result in either improvement or impairment of therapy.

¹ Supported by Research Grants CA-11148, CA-12732, and CA-08480 from the National Cancer Institute, NIH, and by ALSAC.

Received 10/23/72. Accepted 12/29/72.