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Lack of in Vitro Synergy between Etoposide and cis-Diammine-dichloroplatinum(II)¹

National Cancer Institute, Navy Medical Oncology Branch, Naval Hospital, Bethesda 20814-5101 [C-M. T., A. F. G., J. L. M., B. S. K.], Biostatistics and Data Management Section, National Cancer Institute, Bethesda 20892 [D. J. V., S. M. S.], Chemical Engineering Section, Division of Research Services, NIH, Bethesda 20892 [R. L. D.], and Uniformed Services University of the Health Sciences, Bethesda 20814 [B. S. K.], Maryland

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supraadditive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity.

The demonstration of true supraadditive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supraadditive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supraadditive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.

¹ The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense. This work was supported, in part, by a grant from the Harold G. Mathers Foundation.

² Present address: Chest Department; Veterans General Hospital; Taipei, Taiwan, Republic of China.

³ To whom requests for reprints should be addressed.

Received 10/ 5/88. Revised 1/31/89. Accepted 2/ 2/89.

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