The Search for Cytotoxic Synergy Between Anticancer Agents: a Case of Dorothy and the Ruby Slippers?

Greco, William R.; Faessel, Hélène M.; Levasseur, Laurence M.

doi:10.1093/jnci/88.11.699

Cited by 79 publications

(70 citation statements)

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“…As is often emphasized (19,49,65,142), quantitative synergy analyses are formal mathematical exercises, not wet physiology. There are two main reasons.…”

Section: Mathematical Nature Of Synergymentioning

confidence: 99%

Understanding synergy

Geary¹

2013

American Journal of Physiology-Endocrinology and Metabolism

138

181

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Analysis of the interactive effects of combinations of hormones or other manipulations with qualitatively similar individual effects is an important topic in basic and clinical endocrinology as well as other branches of basic and clinical research related to integrative physiology. Functional, as opposed to mechanistic, analyses of interactions rely on the concept of synergy, which can be defined qualitatively as a cooperative action or quantitatively as a supra-additive effect according to some metric for the addition of different dose-effect curves. Unfortunately, doseeffect curve addition is far from straightforward; rather, it requires the development of an axiomatic mathematical theory. I review the mathematical soundness, face validity, and utility of the most frequently used approaches to supra-additive synergy. These criteria highlight serious problems in the two most common synergy approaches, response additivity and Loewe additivity, which is the basis of the isobole and related response surface approaches. I conclude that there is no adequate, generally applicable, supra-additive synergy metric appropriate for endocrinology or any other field of basic and clinical integrative physiology. I recommend that these metrics be abandoned in favor of the simpler definition of synergy as a cooperative, i.e., nonantagonistic, effect. This simple definition avoids mathematical difficulties, is easily applicable, meets regulatory requirements for combination therapy development, and suffices to advance phenomenological basic research to mechanistic studies of interactions and clinical combination therapy research.

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“…As is often emphasized (19,49,65,142), quantitative synergy analyses are formal mathematical exercises, not wet physiology. There are two main reasons.…”

Section: Mathematical Nature Of Synergymentioning

confidence: 99%

Understanding synergy

Geary¹

2013

American Journal of Physiology-Endocrinology and Metabolism

138

181

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“…This approach allows visualization of percent inhibition at each combination of concentrations, as well as calculation of measures of synergy such as the Bliss independence model (35). Under Bliss independence, the fractional inhibition from a combination of 2 agents at specific concentrations is predicted as the sum of the inhibitions of each agent applied alone at the specific concentrations minus the product of those single-agent inhibitions (36). Deviations from additive effects in each well can be summed across the plate to give an overall Bliss score, with positive Bliss scores indicating greater than additive effects.…”

Section: Meki-1 Erkimentioning

confidence: 99%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

192

155

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The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/ extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogenactivated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.

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“…Synergistic cytotoxicity presents the potential for increased efficacy against disease without increasing toxicity to the patient (Greco et al 1996). The combination of paclitaxel and cisplatin shows good clinical efficacy against ovarian carcinoma.…”

Section: Levasseur Et Al (1997)mentioning

confidence: 99%

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

Borgert

Price

Wells

et al. 2001

Human and Ecological Risk Assessment: An International Journal

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We describe a set of criteria to evaluate the quality of data and interpretations in chemical interaction studies. These criteria reflect the consensus of the literature on interaction analysis developed over decades of research in pharmacology, toxicology, and biometry; address common pitfalls in published interaction studies; and can be easily applied to common methods of interaction analysis. The criteria apply broadly to interaction data for drugs, pesticides, industrial chemicals, food additives, and natural products and are intended to assist risk assessors who must evaluate interaction studies for use in component-based mixture risk assessments. The criteria may also assist researchers interested in conducting interaction studies to inform mixture risk assessment. The criteria are also intended to serve larger scientific goals, including increasing the repeatability of results obtained in chemical interaction studies, enhancing the reliability of conclusions drawn from interaction data, providing greater consistency of interpretations among various analysts, and decreasing uncertainty in using interaction data in risk assessments. We describe the basis for each criterion and demonstrate their utility by using them to evaluate interaction studies from the recent toxicological and pharmacological literature, which serve as examples of different types of data sets that the risk assessor may encounter.

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The Search for Cytotoxic Synergy Between Anticancer Agents: a Case of Dorothy and the Ruby Slippers?

Cited by 79 publications

References 0 publications

Understanding synergy

Understanding synergy

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

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