Combination Effect of Mycophenolate Mofetil with Mizoribine on Cell Proliferation Assays and in a Mouse Heart Transplantation Model

Shimmura, Hiroaki; Tanabe, Kazunari; Habiro, Katsuyoshi; Abe, Ryo; Toma, Hiroshi

doi:10.1097/01.tp.0000226227.79142.31

Cited by 14 publications

(12 citation statements)

References 33 publications

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“…Analysis of growth factor activity, drug screening and serum batch testing are just a few of the applications that rely on cell proliferation assays [36][37][38][39]. Commonly, cells are plated on poly-lysine-coated tissue culture plates, and cell proliferation is assessed for a predetermined period of time.…”

Section: Discussionmentioning

confidence: 99%

Effects of extracellular matrix analogues on primary human fibroblast behavior

2008

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In vitro cell culture is a vital research tool for cell biology, pharmacology, toxicology, protein production, systems biology and drug discovery. Traditional culturing methods on plastic surfaces do not accurately represent the in vivo environment, and a paradigm shift from two-dimensional to three-dimensional (3-D) experimental techniques is underway. To enable this change, a variety of natural, synthetic and semi-synthetic extracellular matrix (ECM) equivalents have been developed to provide an appropriate cellular microenvironment. We describe herein an investigation of the properties of four commercially available ECM equivalents on the growth and proliferation of primary human tracheal scar fibroblast behavior, both in 3-D and pseudo-3-D conditions. We also compare subcutaneous tissue growth of 3-D encapsulated fibroblasts in vivo in two of these materials, Matrigel ™ and Extracel ™ . The latter shows increased cell proliferation and remodeling of the ECM equivalent. The results provide researchers with a rational basis for selection of a given ECM equivalent based on its biological performance in vitro and in vivo, as well as the practicality of the experimental protocols. Biomaterials that use a customizable glycosaminoglycan-based hydrogel appear to offer the most convenient and flexible system for conducting in vitro research that accurately translates to in vivo physiology needed for tissue engineering.

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Section: Discussionmentioning

confidence: 99%

Effects of extracellular matrix analogues on primary human fibroblast behavior

2008

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“…Two drugs of potential utility in such a strategy are methotrexate (MTX) and mycophenolate mofetil (MMF), which competitively inhibit dihydrofolate reductase (DHFR), involved in synthesis of thymidylate nucleotides [16], and inosine-5′- monophosphate dehydrogenase II (IMPDH2), a rate-limiting enzyme in the de novo synthesis of guanosine nucleotides [17], [18] respectively. Proliferation of T and B cells is dependent on the activity of both DHFR and IMPDH2 [19], and thus MTX and MMF are known to inhibit the proliferation and survival of T lymphocytes [20].…”

Section: Introductionmentioning

confidence: 99%

Engineering Human T Cells for Resistance to Methotrexate and Mycophenolate Mofetil as an In Vivo Cell Selection Strategy

et al. 2013

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Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFRFS; L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2IY; T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt+DHFRFS+IMPDH2IY+ T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFRFS/MTX and IMPDH2IY/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

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“…The estimatorˆ d, is substituted into equation (8) to obtain the Loewe index as a function of . Although the estimator is not in closed form, the implicit function theorem can be used to obtain derivatives for computing confidence intervals using equations similar to (14) and (15).…”

Section: Modified Mixlow Modelmentioning

confidence: 99%

“…For simulations A-D, the standard deviations of log(L ) for the MixLow method were 1.4to 3.2-fold lower than those for the Median-Effect method. Also listed in Table IV are means of the standard errors for log(L ), as calculated using equation (14). The last two columns of Table IV list ratios of the mean standard errors of log(L ) to empirical standard deviations.…”

Section: Loewe Index Estimatesmentioning

confidence: 99%

“…While response surface methods do provide more information than can be obtained from analysis of single-ray experiments, they require that more data be collected. For this reason, single-ray experiments remain common and the Median-Effect method is widely used in practice [13][14][15]. Therefore, investigating coverage of confidence intervals for the interaction index from single-ray experiments is pertinent.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying synergism/antagonism using nonlinear mixed‐effects modeling: A simulation study

Boik

Newman

Boik

2007

Statistics in Medicine

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Cancer drugs are commonly administered in the clinic in the form of mixtures, also called cocktails or combinations. Assessment of synergistic and antagonistic interactions between drugs is therefore an important aspect of cancer research. Numerous methods have been proposed to assess drug interactions, each one based on a null (or additive) model. In this paper, the Loewe additivity index is used as a basis. Parameters of concentration-response curves, used as input to the Loewe equation, are estimated with a nonlinear mixed-effects model. The use of a nonlinear mixed-effects model, in combination with the Loewe index and a procedure to calculate confidence intervals of the index, is referred to as the 'MixLow' method. Simulations of a sham mixture of a drug with itself show that the MixLow method provides parameter estimators that are more precise than those produced by the Median-Effect method, a popular approach that uses log linearization of the concentration-response curves. Coverage of confidence intervals for the interaction index is acceptable for the MixLow method but poor for the Median-Effect method. This is the first comparison report of coverage of confidence intervals for the Loewe interaction index. A mixture of vincristine and topotecan is also analyzed by the MixLow method and the results are compared with those previously published. The MixLow method can be used to quantify drug interactions in any fixed-ratio drug combination study that includes within-group and between-group replicates, and where responses follow a sigmoidal pattern.

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Combination Effect of Mycophenolate Mofetil with Mizoribine on Cell Proliferation Assays and in a Mouse Heart Transplantation Model

Cited by 14 publications

References 33 publications

Effects of extracellular matrix analogues on primary human fibroblast behavior

Effects of extracellular matrix analogues on primary human fibroblast behavior

Engineering Human T Cells for Resistance to Methotrexate and Mycophenolate Mofetil as an In Vivo Cell Selection Strategy

Quantifying synergism/antagonism using nonlinear mixed‐effects modeling: A simulation study

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