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Synergistic Effect of 4-Hydroperoxycyclophosphamide and Etoposide on a Human Promyelocytic Leukemia Cell Line (HL-60) Demonstrated by Computer Analysis¹

Hematology Lymphoma Service Department of Medicine (T. T. C., S. C. G., R. V., L. G., S. M. E. I., J. Y., B. D. C.) and Pharmacology Laboratory [T-C. C.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and The Department of Pharmacology, Johns Hopkins University Oncology Center, Baltimore, Maryland 21205 [M. C.]

Autologous stem cell transplantation using cryopreserved bone marrow offers the opportunity to rescue patients from hematopoietic toxicity caused by intensive chemotherapy. This approach is potentially useful for high-risk leukemias as well as for other cancers. The development of suitable methods for purging malignant cells from the bone marrow will offer a better chance of success for autologous stem cell transplantation. In this paper, we describe our efforts at purging myeloid cells. HL-60, a promyelocytic leukemia cell line, was used as a model. 4-Hydroperoxycyclophosphamide (4-HC) and VP-16-213 (VP-16) (either alone or in combination) were used to treat HL-60 cells and normal bone marrow. The cytotoxic effect of 4-HC (29.2 µg/ml; 100 µM) upon the HL-60 cell line was 99.8 ± 0.12% (SE), and the colony-forming units-granulocyte, macrophage (CFU-cs) of normal bone marrow was inhibited by 82.5%. VP-16, at a concentration of 25 µg/ml (42.5 µM), can kill 99% of HL-60 cells and inhibit 72.7% of the CFU-cs. A drug mixture containing 4-HC (29.2 µg/ml) and VP-16 (10 µg/ml) (combination ratio, 1:0.342) reduces HL-60 cells to an undetectable number, and the CFU-cs were inhibited by 87.2%. The laboratory data were further analyzed for the synergistic effect of these two drugs by quantitative determination of the median effect plot and the multiple drug equation recently described by Chou and Talalay (Adv. Enz. Regul., 22: 27–55, 1984). Interactions of two drugs at different effect levels and at different combination ratios were then determined by computer simulation. At high effect levels, 4-HC and VP-16 in combination gave a synergistic cytocidal effect on HL-60 leukemic cells and gave an antagonistic inhibitory effect on normal bone marrow CFU-cs. This combination greatly increases the safety margin. Computer simulation of a dose effect relationship has also shown that the 4-HC:VP-16 combination ratio of 1:0.342 yields a better selective effect than a ratio of 1:0.856. This quantitative analysis suggests that the combination of these two drugs at the selected dose level offers a good method for purging nonlymphoblastic leukemia cells.

¹ This work was supported in part by NIH CA-19117 and Elsa U. Pardee Foundation.

² Visiting fellow in the Memorial Sloan-Kettering Cancer Center; supported by Chung-Ho Memorial Hospital, Kaohsiung Medical College, Kaohsiung, Taiwan, Republic of China.

³ To whom requests for reprints should be addressed at MSKCC, 1275 York Avenue, New York, NY 10021.

⁴ Fellow of Associazione Italiana perla Ricerca sul Cancro.

Received 9/26/84. Revised 2/18/85. Accepted 2/20/85.

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