Synergy analysis of "classic" and newer drug combinations.

Introduction: Combination chemotherapy frequently, but not always, has produced greater degrees of clinical benefit than single agent therapy. There are two potential explanations for this.  Firstly, when two or more drugs are given, there is a greater probability that at least one of the drugs will be active.  Second, there is the potential for true synergy, where the whole is greater than the sum of the parts.

Methods: We tested fresh human solid tumors against a variety of drug combinations at two different dilutions.  We also tested the constituent single agents, again at two different dilutions.  All drugs were tested with two different cell death endpoints (DISC and MTT, technologies described elsewhere on this website). The number of fresh human tumor specimens tested ranged from 19 (gemcitabine + etoposide) to greater than 1, 400 (gemcitabine + cisplatin). In most cases, greater than 100 different tumors were tested. Based on the activity of the individual single agents, we calculated the expected results for each combination, based on the expectation that the combination would be only additive, and not synergistic.  The additive results are normalized on the two graphs in the Figure as "1.0"  Sub-additive results are less then 1.0  Synergistic results are greater than 1.0

Results: Most "classic" drug combinations are only additive or are, at most, minimally synergistic.  Examples of merely additive drug combinations are cisplatin/5FU, cisplatin/Taxol, and cisplatin/etoposide. However, some newer combinations show greater degrees of synergy, including cisplatin/topotecan, gemcitabine/platinum, and gemcitabine/alkylators. The profound synergy between gemcitabine/platinum in vitro has now been confirmed in the clinic in a number of settings. The similar degree of synergy between gemcitabine and alkylating agents suggest that these combinations should be explored in clinical settings in which alkylating agents are known to be important, particularly higher dose regimens with growth factor and/or stem cell support.