A method to predict response of cell populations to cocktails of chemotherapeutics and radiopharmaceuticals: Validation with daunomycin, doxorubicin, and the alpha particle emitter 210Po

Akudugu, John; Howell, Roger W.

doi:10.1016/j.nucmedbio.2012.01.011

Cited by 12 publications

(18 citation statements)

References 33 publications

(54 reference statements)

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“…Targeting of single signaling components often does not result in optimal cytotoxicity. This is partly due to non-uniform distributions of target antigen expression in cell populations, which may limit the ability to target all cells with toxic levels of therapeutic agents [14][15][16]. Therefore, developing therapeutic approaches that concomitantly target multiple signaling components of the EGFR and PI3K pathways might significantly sensitise prostate cancer cells to radiotherapy and improve treatment outcome.…”

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confidence: 99%

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

Maleka

Serafin

Hamunyela

et al. 2015

GJCT

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Targeted therapy for prostate cancer may offer potential improvement over current conventional therapiesÃ‚Â because of its specificity. Although conventional treatments are effective, they are not always curative, andhave several limitations. In prostate cancer, activation of the epidermal growth factor receptor (EGFR) and theÃ‚Â phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicatedin tumorigenesis, and resistance to both conventional and targeted anticancer therapies. Single-target therapiesÃ‚Â may fail due to cellular heterogeneity. Concomitant targeting of EGFR and PI3K/mTOR cell signaling componentsÃ‚Â may enhance the efficacy of radiotherapy. In this study, the effect of an EGFR inhibitor (AG-1478) and a dualÃ‚Â inhibitor of PI3K and mTOR (NVP-BEZ235) on the radiation response of a human prostate carcinoma cell lineÃ‚Â (DU145) and a normal prostate cell line (1542N) was investigated, using the colony forming assay. Treatment ofDU145 cells with AG-1478 and NVP-BEZ235, either singly or in combination, resulted in a slight radiosensitisationÃ‚Â of DU145 cells. Neither AG-1478 nor a cocktail of both inhibitors had an effect on the radiation response of theÃ‚Â 1542N cell line. Interestingly, NVP-BEZ235 significantly protected 1542N cells from radiation-induced cell death.Ã‚Â These data suggest that a specific inhibitor of PI3K and mTOR (NVP-BEZ235) could potentially be effective as aÃ‚Â radio-protector.

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mentioning

confidence: 99%

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

Maleka

Serafin

Hamunyela

et al. 2015

GJCT

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“…It has been suggested that shape parameter values for different histologic types of tumors and different radiopharmaceuticals could be cataloged based on quantitative autoradiography of tumor specimens surgically harvested after tracer administrations to a limited number of patients. 46 This information, along with supportive quantitative imaging, could be used to prescribe a cocktail of radiopharmaceuticals 41,47,48 for a patient's specific histologic tumor type (i.e., shape parameter value). 46 There is also for potential to use a combination of histology, multiparameter flow cytometry, and multicellular dose-response modeling to identify the optimal cocktail of therapeutic agents for a given patient.…”

Section: Discussionmentioning

confidence: 99%

Survival of tumor and normal cells upon targeting with electron‐emitting radionuclides

2012

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Purpose: Previous studies have shown that the mean absorbed dose to a tissue element may not be a suitable quantity for correlating with the biological response of cells in that tissue element. Cell survival can depend strongly on the distribution of radioactivity at the cellular and multicellular levels. Furthermore, when cellular absorbed doses are examined, the cross-dose from neighbor cells can be less radiotoxic than the self-dose component. To better understand how the nonuniformity of activity among cells can affect the dose response, a computer model of a 3D tissue culture was previously constructed and showed that activity distribution among cells is significantly more relevant than the mean absorbed dose for low-energy-electron emitters. The present work greatly expands upon those findings. Methods: In the present study, we used this same computer model but restricted the number of labeled cells to a fraction of the whole cell population (50%, 10%, and 1%, respectively). The labeled cells were randomly distributed among the whole cell population. Results: While the activity distribution is an important factor in determining the tissue response for low-energy-electron emitters, the fraction of labeled cells has an even more pronounced effect on survival response. For all electron energies studied, reducing the percentage of cells labeled significantly increases the surviving fraction of the whole population. Conclusions: This study provides abundant information on killing tumor and normal cells under some conditions relevant to targeted radionuclide therapy of isolated tumor cells and micrometastases. The percentage of cells labeled, activity distribution among the labeled cells, and electron energy play key roles in determining their response. Most importantly, and not previously demonstrated, lognormal activity distributions can have a profound impact on the response of the tumor cells even when the radionuclide emits high-energy electrons.

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“…The cell culture protocol followed that of Akudugu et al (6,15,16). Briefly, MDA-MB-231-luc-D3H1 (MDA-MB-231) human breast cancer cells (Caliper Life Sciences) were grown in minimum essential medium (Cellgro catalog number 10-010-CV).…”

Section: Cell Culturementioning

confidence: 99%

“…The Monte Carlo simulation developed by Akudugu et al (6,15), modified to account for specific activity and absorbed dose, was used to predict the SF of the cells for each antibody treatment assuming a mean lethal dose D 37 of 1 Gy. This approach calculates the probability that a given cell survives based on the absorbed dose contributions from each radiolabeled antibody on that particular cell and then uses a Monte Carlo approach to determine whether the cell lives or dies (15).…”

Section: Monte Carlo Modeling Of Surviving Fraction (Sf) Of Breast Camentioning

confidence: 99%

“…This approach calculates the probability that a given cell survives based on the absorbed dose contributions from each radiolabeled antibody on that particular cell and then uses a Monte Carlo approach to determine whether the cell lives or dies (15). Simulations were also conducted for all possible combinations of antibody treatments to determine the SF of cells in each case.…”

Section: Monte Carlo Modeling Of Surviving Fraction (Sf) Of Breast Camentioning

confidence: 99%

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The Advantage of Antibody Cocktails for Targeted Alpha Therapy Depends on Specific Activity

et al. 2014

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Nonuniform dose distributions among disseminated tumor cells can be a significant limiting factor in targeted α therapy. This study examines how cocktails of radiolabeled antibodies can be formulated to overcome this limitation. Methods: Cultured MDA-MB-231 human breast cancer cells were treated with different concentrations of a cocktail of 4 fluorochrome-conjugated monoclonal antibodies. The amount of each antibody bound to each cell was quantified using flow cytometry. A spreadsheet was developed to "arm" the antibodies with any desired radionuclide and specific activity, calculate the absorbed dose to each cell, and perform a Monte Carlo simulation of the surviving fraction of cells after exposure to cocktails of different antibody combinations. Simulations were performed for the α-particle emitters 211 At, 213 Bi, and 225 Ac. Results: Activity delivered to the least labeled cell can be increased by 200%-400% with antibody cocktails, relative to the best-performing single antibody. Specific activity determined whether a cocktail or a single antibody achieved greater cell killing. With certain specific activities, cocktails outperformed single antibodies by a factor of up to 244. There was a profound difference (#16 logs) in the surviving fraction when a uniform antibody distribution was assumed and compared with the experimentally observed nonuniform distribution. Conclusion: These findings suggest that targeted α therapy can be improved with customized radiolabeled antibody cocktails. Depending on the antibody combination and specific activity of the radiolabeled antibodies, cocktails can provide a substantial advantage in tumor cell killing. The methodology used in this analysis provides a foundation for pretreatment prediction of tumor cell survival in the context of personalized cancer therapy.

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A method to predict response of cell populations to cocktails of chemotherapeutics and radiopharmaceuticals: Validation with daunomycin, doxorubicin, and the alpha particle emitter 210Po

Cited by 12 publications

References 33 publications

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

NVP-BEZ235 Enhances Radiosensitivity of Human Prostate Cancer Cells but Acts as a Radioprotector to Normal Prostate Cells

Survival of tumor and normal cells upon targeting with electron‐emitting radionuclides

The Advantage of Antibody Cocktails for Targeted Alpha Therapy Depends on Specific Activity

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