A checkerboard method to evaluate interactions between drugs

Martinez–Irujo, Juan J.; Villahermosa, Marı́a Luisa; Alberdi, Elena; Santiago, Esteban

doi:10.1016/s0006-2952(95)02230-9

Cited by 76 publications

(67 citation statements)

References 16 publications

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“…In all tumor models, both cytoxan and ABT-510 induced significant amount of apoptosis and reduced tumor microvascular density. However, cumulative action of the cytoxan/ABT combination far exceeded simple additive effect, as was determined using fractional product of Webb calculations (18). Low doses of ABT-510 and of cytoxan were moderately synergistic, whereas optimal, higher displayed strong synergy in PC-3 xenograft models (E OBS > 2 Â E EXP ; Table 1; P < 0.01).…”

Section: Resultsmentioning

confidence: 95%

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Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

Yap

Veliceasa²,

Emmenegger

et al. 2005

Clinical Cancer Research

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Blocking angiogenesis is a promising approach in cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose chemotherapy, given at short regular intervals with no prolonged breaks (metronomic chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors. ABT-510, a peptide derivative of thrombospondin, kills endothelial cell by increasing CD95L, a ligand for the CD95 death receptor. However, CD95 expression itself is unaffected by ABT-510 and limits its efficacy. We found that multiple chemotherapy agents, cyclophosphamide (cytoxan), cisplatin, and docetaxel, induced endothelial CD95 in vitro and in vivo at low doses that failed to kill endothelial cells (cytoxan > cisplatin > docetaxel). Thus, we concluded that some of these agents might complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining ABT-510 with cytoxan or cisplatin. Cyclophosphamide and cisplatin synergistically increased in vivo endothelial cell apoptosis and angiosuppression by ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model, ABT-510 and cytoxan, applied together at low doses, acted in synergy to delay tumor take, to stabilize the growth of established tumors, and to cause a long-term progression delay of PC-3 prostate carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95, CD95L, and apoptosis. Thus, our study shows a ''complementation'' design of an optimal cancer treatment with the antiangiogenic peptide and a metronomic chemotherapy.Thrombospondin-1 is a well-known antiangiogenic agent (1).Its mechanism of action and structure-function relationship have been analyzed in considerable depth, resulting in the discovery of a minimal active heptapeptide in which antiangiogenic activity is greatly enhanced by L-isoleucine to D-isoleucine replacement (2). ABT-526 and ABT-510 are modified versions of this minimal peptide with increased potencies (3) and improved clearance; ABT-510 is currently under evaluation in phase II clinical trials (4). Thrombospondin-1 has also been identified as a host-derived mediator of the antiangiogenic action of low-dose metronomic chemotherapy (5, 6). Thrombospondin-1 and ABT-510 act by inducing endothelial cell apoptosis in some cases via CD36 cell surface receptor (7,8). Proapoptotic signal elicited by thrombospondin-1 generates CD95L, a ligand for the CD95 death receptor (9). However, CD95 expression on vascular endothelial cell is independent of thrombospondin-1; thus, accessible CD95 limits the rate of apoptosis and antiangiogenesis due to thrombospondin-1 and consequently determines, at least in part, the efficacy of thrombospondin-1-based cancer treatments.Seeking agents to improve the efficacy of ABT-...

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Section: Resultsmentioning

confidence: 95%

“…Note the reversal of antiangiogenesis and apoptosis by CD36 antibody or by Fas decoy. (18), the interaction index was calculated as:…”

Section: Methodsmentioning

confidence: 99%

Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

Yap

Veliceasa²,

Emmenegger

et al. 2005

Clinical Cancer Research

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“…These noncytotoxic concentrations augmented in vitro EC sensitivity to apoptosis by DI-TSP via CD95 cascade. Modified isobologram analysis 27 yielded interaction coefficient of 450, clearly pointing to synergy. When DISC formation is followed by caspase activation, CD95/Fas is internalized to be recycled via clathrin-coated pits and caveolae (reviewed in Peter and Krammer 37 ), similar events are involved in the CD95 trafficking and surface upregulation by the endothelial cells in response to angiogenic stimuli.…”

Section: Discussionmentioning

confidence: 99%

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

et al. 2005

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Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/ 100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.

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“…Indeed, the scientific literature contains many publications describing methods for conducting interaction studies. Some examples that provide methodological background include: (Berenbaum 1978(Berenbaum , 1981(Berenbaum , 1984(Berenbaum , 1985(Berenbaum , 1989Carter et al 1979;Carter et al 1984;Carter and Wampler 1986;Caudle and Williams 1993;Chou and Talalay 1984;Gennings 1995Gennings , 1996Gennings et al 1990;Gessner 1995;Greco et al 1995;Greco et al 1990;Loewe and Muischnek 1926;Machado and Robinson 1994;Martinez-Irujo et al 1996;Poch 1980a,b;Poch et al1990a;Poch and Holzmann 1980;Londong 1985, 1993;Poch and Pancheva 1995;Poch et al 1995a. ;Poch et al 1990;Poch et al1990b;Scaramellini et al 1997;Suhnel 1990Suhnel , 1996 200350.pgs 4/13/01, 2:31 PM…”

Section: Introductionmentioning

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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A checkerboard method to evaluate interactions between drugs

Cited by 76 publications

References 16 publications

Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy

In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

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