Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Chou, Ting‐Chao

doi:10.1124/pr.58.3.10

Cited by 4,347 publications

(4,829 citation statements)

References 297 publications

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“…Based on the Combination Index to determine synergy, 25 most DNA-damaging agents we tested synergized with AZD7762 only in G 1 checkpoint-defective neuroblastoma cells. Interestingly, gemcitabine clearly synergized with AZD7762 in all tumor cells regardless of G 1 checkpoint status, although smaller CI values did suggest better synergy when G 1 checkpoint was defective (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…IC 50 (half maximal inhibitory concentration) and Combination Index (CI) values were calculated using CompuSyn software (ComboSyn, Paramus, NJ), a computer program for the quantitation of synergism and antagonism in drug combinations based on Ting-Chao Chou's median-effect principle. 25 CI values were calculated for each concentration tested and were averaged as an integrated value for each drug combination. CI < 1 indicates synergism, CI ¼ 1 additive effects, and CI > 1 antagonism.…”

Section: In Vitro Cytotoxicity Assaysmentioning

confidence: 99%

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Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Xu¹,

Cheung²,

Wei³

et al. 2011

Intl Journal of Cancer

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Checkpoint kinase inhibitors can enhance the cancer killing action of DNA-damaging chemotherapeutic agents by disrupting the S/G 2 cell cycle checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor AZD7762 when combined with these agents were examined using neuroblastoma cell lines with known p53/MDM2/p14 ARF genomic status. Four of four p53 mutant lines and three of five MDM2/p14 ARF abnormal lines were defective in G 1 checkpoint, correlating with failure to induce endogenous p21 after treatment with DNA-damaging agents. In cytotoxicity assays, these G 1 checkpoint-defective lines were more resistant to DNA-damaging agents when compared to G 1 checkpoint intact lines, yet becoming more sensitive when AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G 2 checkpoint arrest both in vitro and in vivo. In xenograft models, a significant delay in tumor growth accompanied by histological evidence of increased apoptosis was observed, when AZD7762 was added to the DNA-damaging drug gemcitabine. These results suggest a therapeutic potential of combination therapy using checkpoint kinase inhibitor and chemotherapy to reverse or prevent drug resistance in treating neuroblastomas with defective G 1 checkpoints.

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Cytotoxicity Assaysmentioning

confidence: 99%

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Xu¹,

Cheung²,

Wei³

et al. 2011

Intl Journal of Cancer

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“…Median-Effect or the concentrations of platinum compound required to inhibit 50% of colony formation (IC50) were plotted. CI as well as linear correlation coefficient (r) were calculated using CALCUSYN software from BIOSOFT (Ferguson, MO) developed by Chou [21]. Briefly, the CI were calculated using the equation:…”

Section: Clonogenic Assay and Synergistic Effect Determinationmentioning

confidence: 99%

“…To determine whether the concomitant treatment obtained with these platinum compounds led to a synergistic effect, the CI was calculated according to the method developed by Chou et al (2006). A CI value lower than 1 indicates that the drug tested acts as a radiosensitizer (synergic effect), whereas a CI value higher than 1 indicates that a radioprotective effect results from the addition of the drug.…”

Section: Concomitance Effect Of Platinum Compounds With Radiationmentioning

confidence: 99%

Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation

et al. 2009

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Despite significant advances, the radiotherapy and chemotherapy protocols marginally improve the overall survival of patients with glioblastoma. Lipoplatin ™ , and Lipoxal ™ , the liposomal formulations of cisplatin and oxaliplatin respectively, were tested on the F98 glioma cells for their ability to improve the cell uptake and increase the synergic effect when combined with ionizing radiation. The cytotoxicity and synergic effect of platinum compounds were assessed by colony formation assay, while the cellular uptake was measured by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). After 4 h exposure with platinum compounds, cells were irradiated (1.5 to 6.6 Gy) with a 60 Co source. The liposomal formulations were compared to their liposome-free analogs and to carboplatin. The concomitant treatment of F98 cells with carboplatin and radiation produced the highest radiosensitizing effect (30-fold increase). Among the platinum compounds tested, Lipoplatin ™ produced the most promising results. This liposomal formulation of cisplatin improved the cell uptake by 3-fold, and its radiosensitizing potential was enhanced by 14-fold. Although Lipoxal ™ can potentially reduce the adverse effect of oxaliplatin, a synergic effect with radiation was measured only when incubated at a concentration higher than its IC50. Conversely, concomitant treatment with cisplatin did not result in a synergic effect, as in fact a radioprotective effect was measured on the F98 cells. In conclusion, among the five platinum compounds tested, carboplatin and Lipoplatin ™ showed the best radiosensitizing effect. Lipoplatin ™ seems the most promising since it led to the best cellular incorporation and has already been reported to be less neurotoxic than other platinum compounds.

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“…Interactions between irradiated PpIX (given as light dose at constant ALA concentration = 1 mM) and TSC (as concentration) were measured according to Chou−Thalay method. 21 Increasing the doses in a constant manner we calculated the combination index (CI) as a ratio of the sum of the doses in TSC or ALA-PDT to the doses of each therapy alone, having the same cytotoxic effect 22 (see Supporting Information for the detailed combination of doses, Table S2). A value of CI below 1 indicates synergy, CI amounting to 1 indicates an additive effect, whereas the CI value greater than 1 implies antagonism.…”

mentioning

confidence: 99%

Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

Mrozek-Wilczkiewicz

Serda

Musioł

et al. 2014

ACS Med. Chem. Lett.

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In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe 2+ forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe 2+ affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX.

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Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Cited by 4,347 publications

References 297 publications

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation

Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

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Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Cited by 4,347 publications

References 297 publications

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G1 checkpoint‐defective neuroblastoma

Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation

Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

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Product

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Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma

Checkpoint kinase inhibitor synergizes with DNA‐damaging agents in G₁ checkpoint‐defective neuroblastoma