Mice, inoculated i.p. with 1 million L1210 ascites cells, were treated subsequently with 1,3-bis(2-chloroethyl)-1-nitrosourea plus 4′-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-β-d-glucopyranoside) in various combinations of dosages. The drugs were administered i.p. in rapid succession on one of four schedules. When treatment was administered on Day 1, 24 hr after inoculation, all mice treated with one of five combinations of dosages survived for 60 days, apparently free of leukemia, and another 16 combinations of the drugs cured 50%, or more, of the animals. Treatment with combinations of lower dosages of the drugs on Days 1, 4, and 7 was as effective as treatment with larger dosages on Day 1; all mice treated with 5 combinations of the drugs survived, and 17 other combinations cured 50%, or more, of the mice.
When mice were treated on similar schedules but the initiation of treatment was delayed until Day 4, the therapeutic efficacy of the individual drugs and of the combinations decreased. Some of the mice survived for 60 days after treatment with both drugs on Day 4, but the incidence was not greater than that achieved by treatment with the optimal dosage of 1,3-bis(2-chloroethyl)-1-nitrosourea on Day 4. The schedule of treatment on Days 4, 7, and 10 was the least effective, therapeutically, of the four schedules tested; only 12 of 235 mice survived for 60 days after treatment with the individual drugs or the drug combination. Because of a termination of the studies after 60 days, the data for all four studies were analyzed by the Cox multiple-regression technique. By this criterion, the incidence of mortality after treatment with the drugs on either Day 1 or Days 1, 4, and 7 was attributable in part to a therapeutic interaction between the drugs. This therapeutic interaction was not observed when mice were treated once on Day 4. Analysis of the incidence of mortality after three courses of treatment, i.e., treatment on Days 4, 7, and 10, indicated that, although each drug was oncolytic, an interaction between the drugs reduced the effectiveness of the combination. 4′-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-β-d-glucopyranoside) plus 1,3-bis(2-chloroethyl)-1-nitrosourea was remarkably effective for the treatment of L1210 leukemia, and on certain schedules the effectiveness resulted from a therapeutic interaction between the drugs.
This investigation was supported by Research Project Grants CA-12732 and CA-23337 and by Cancer Center Support (Core) Grant CA-21765 from the National Cancer Institute, NIH, Department of Health, Education and Welfare, and by the American Lebanese Syrian Associated Charities.