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Combination Chemotherapy in Sequence for the Treatment of L1210 Leukemia¹

Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

In the studies presented L1210 leukemia was used to show that various equipotent combinations of two drugs can be freely substituted for each other during the course of sequential treatment with other drugs and that the order of administration will influence the therapeutic response to sequential treatment with various drug combinations. Mice inoculated i.p. with L1210 ascites tumor cells were treated with 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-ß-D-glucopyranoside), 1-ß-D-arablnofuranosylcytosine plus methotrexate, or Adriamycin plus cyclophosphamide in various dosages and sequences. Three ratios of dosages for each two-drug combination were selected to produce equivalent prolongation of life span when administered on Days 1, 4, and 7. When these two-drug combinations were used for sequential treatment with 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-ß-D-glucopyranoside on Day 1, 1-ß-D-arabinofuranosylcytosine plus methotrexate on Day 4, and Adriamycin plus cyclophosphamide on Day 7, each of the three ratios of dosages for the two two-drug combinations was equivalent in prolonging the lives of mice inoculated with L1210 tumor cells. When the sequence of administration was varied, marked differences were observed in the effectiveness of treatment. These observations indicate that a variety of dosages of oncolytic drugs can be used to produce equivalent therapeutic response and that the order of administration may determine the overall effectiveness of sequential multiple-drug therapy.

¹ This investigation was supported by Research Project Grant CA12732, Childhood Cancer Center Grant CA08480, and Cancer Center Support (CORE) Grant CA21765 awarded by the National Cancer Institute, NIH, Department of Health, Education and Welfare, and by the American Lebanese Syrian Associated Charities.

Received 12/27/77. Accepted 5/ 5/78.