To Combine or Not Combine: Drug Interactions and Tools for Their Analysis. Reflections from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology

Abstract

Combination therapies are used in the clinic to achieve cure, better efficacy and to circumvent resistant disease in patients. Initial assessment of the effect of such combinations, usually of two agents, is frequently performed using in vitro assays. In this review, we give a short summary of the types of analyses that were presented during the Preclinical and Early-phase Clinical Pharmacology Course of the Pharmacology and Molecular Mechanisms Group, European Organization for Research and Treatment on Cancer, that can be used to determine the efficacy of drug combinations. The effect of a combination treatment can be calculated using mathematical equations based on either the Loewe additivity or Bliss independence model, or a combination of both, such as Chou and Talalay's mediandrug effect model. Interactions can be additive, synergistic (more than additive), or antagonistic (less than additive). Software packages CalcuSyn (also available as CompuSyn) and Combenefit are designed to calculate the extent of the combined effects. Interestingly, the application of machinelearning methods in the prediction of combination treatments, which can include pharmacogenomic, genetic, metabolomic and proteomic profiles, might contribute to further refinement of combination regimens. However, more research is needed to apply appropriate rules of machine learning methods to ensure correct predictive models.Even as early as the 1960s, the majority of clinical treatments consisted of combination regimens. Combinations such as mechlorethamine, vincristine, procarbazine and prednisone (MOPP), and cyclophosphamide, hydroxydaunorubicin and oncovin with prednisone (CHOP) represented a breakthrough in the cure of lymphoma, while other combinations led to a high curation rate in childhood leukaemia (1). Depending on the type of combination used, the treatment rationale is to i) increase the efficacy of each separate drug without increasing toxicity, ii) add a drug which offers protection against toxicity, iii) bypass resistance development, or iv) target different subpopulations in a heterogeneous tumour. The initial clinical rationale was to achieve a better therapeutic effect (e.g. a complete response) than accomplished by each drug separately (e.g. only a partial response) (2). Historically, the selection of drugs to apply in combination therapies was based on the observation that each of the drugs showed antitumor activity against a certain tumour type, preferably with different toxicities of the two drugs. Doses and schedules were determined by trial and error. Soon thereafter, a complementary scientific approach was used to select combinations based on the mechanisms of action of each drug (3). An excellent example is the gemcitabine-cisplatin combination, which was initially developed by our group (4) (with the aim of preventing repair of DNA-platinum adducts) and is now standard therapy for tumours such as non-small cell lung cancer and bladder cancer. Another combination is 3303

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using in-silico and in-vitro Methods in the Treatment of Drug-Resistant Glioma

“…Based on CI values obtained for these drug combinations, it is possible to determine the type of interaction. If CI value is <0.8, then combinatorial drugs show synergism (i.e., its effect is better than the expected theoretical effect); when CI value lies between 0.8 and 1.2, combinatorial drugs show additive behavior i.e., it means the effect of combination will be equal to sum or product of each separate effect; and when CI value is more than 1.2, combinatorial drugs show antagonism i.e., its effect is worse than expected theoretical effect (48,49).…”

Using Split Luciferase Assay and Anti-Herpes Simplex Virus Glycoprotein Monoclonal Antibodies To Predict a Functional Binding Site between gD and gH/gL

“…Plasmids. Split luciferase Rluc8 (1-7) and Rluc8 (8)(9)(10)(11) and the wild-type (wt) glycoprotein constructs pTC580 (gB 2 ), pTC510 (gH 2 ), and pTC579 (gL 2 ) have all been described previously (37,41,54,55).…”

“…A master mix containing 125 ng each of the gB, gH, gL, and Rluc8 (1-7) plasmids was split over three wells of effector cells. Target cells were transfected with 1 mg of Rluc8 (8)(9)(10)(11) plasmid per well. At 24 h posttransfection, effector cells were preincubated for 1 h at 37°C with EnduRen substrate (Promega) diluted 1:1,000 in fusion medium (DMEM without phenol red supplemented with 50 mM HEPES and 5% FBS).…”

“…The expectation was that in a preformed glycoprotein-antibody complex, Mabs that bound epitopic sites that were physically close on the two interacting proteins would inhibit fusion through a similar mechanism, while those that were spatially separated would have different mechanisms in blocking fusion or affect different parts of an overall mechanism. Because the gD and gH/gL Mabs used did no compete for binding to their respective proteins, the contribution of the two Mabs to the inhibition of fusion was evaluated using the Bliss independence model (10)(11)(12)(13). This model assumes that two inhibitors of function (here, antibodies) have independent binding sites and independent mechanisms of action and act in such a manner that neither of them interferes with each other but both contribute to the overall inhibitory event (10).…”

Research on the Constructing the Holistic Thinking Mode and Teaching Effect of Pharmacology

“…Pharmacology textbooks are designed according to the systematic classification of drug use. 5 Students are required to first construct a holistic view of medicine combined with basic courses such as physiology and pathophysiology, 6 and then apply pharmacological knowledge to the knowledge system that has been constructed to gradually master emerging nervous system pharmacology, central nervous system pharmacology, cardiovascular system pharmacology, visceral system pharmacology, endocrine and so on. Constantly enrich the medical knowledge system.…”