Synergistic cytotoxicity of interferonα-2b and interleukin-2 in combination with PBMC against ovarian cancer: Development of an experimental model for cellular therapy

Ingersoll, Susan B.; Patel, Sona; Caballero, Lizette; Ahmad, Sarfraz; Edwards, Dawn; Holloway, Robert W.; Edwards, John

doi:10.1016/j.ygyno.2008.09.028

Cited by 10 publications

(21 citation statements)

References 22 publications

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“…Although conceptually appealing, the study from Ma et al (20) suggests that 18 F-FDG may not be the optimal PET probe for evaluation of treatment with mTOR inhibitors in cancer patients. The present study demonstrates that 18 F-FLT imaging is useful in a widely applied ovarian cancer cell line (23,24) and may also be useful for early evaluation of molecularly targeted therapies developed for ovarian cancer.…”

Section: Discussionmentioning

confidence: 72%

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Aide¹,

Kinross²,

Cullinane³

et al. 2010

J Nucl Med

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Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin-resistant ovarian tumor. Methods: BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and 18 F-FLT PET was performed at baseline, day 2, and day 7 of treatment. 18 F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation. Results: During the treatment period, no significant change in tumor 18 F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, 18 F-FLT SUVmean decreased by 33% (P 5 0.003) at day 2 and 66% (P , 0.001) at day 7, compared with baseline. Notably, the reduction of 18 F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in 18 F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P 5 0.0008) and day 7 (P 5 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P 5 0.02) and 91% reduction at day 7 (P 5 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P 5 0.02) in drug versus vehicle groups. Conclusion: Reduction in 18 F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by 18 F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatinresistant ovarian tumors by mTOR inhibitors.

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Section: Discussionmentioning

confidence: 72%

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Aide¹,

Kinross²,

Cullinane³

et al. 2010

J Nucl Med

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“…Cell line culture SKOV3-AF2 cells were derived from SKOV-3 (ATCC, Manassas, VA) cells as recently described by Ingersoll et al [7,8]. Briefly, SKOV3-AF2 cells were derived by first stably transfecting SKOV-3 cells with red-fluorescent protein (SKOV3-RFP), so that the cells could be distinguished from the immune effector cells by fluorescence.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, SKOV3-AF2 cells were derived by first stably transfecting SKOV-3 cells with red-fluorescent protein (SKOV3-RFP), so that the cells could be distinguished from the immune effector cells by fluorescence. Next, the cells were passaged through nude mice to make the cells more tumorigenic in a xenograft mouse model as described previously [7,8]. Single-cell suspensions were made from solid tumor and ascitic fluid harvested from the parental SKOV3-RFP tumors and grown in culture.…”

Section: Methodsmentioning

confidence: 99%

“…The line derived from this tumor suspension was called SKOV3-AF2. We have previously shown that these SKOV3-AF2 cells are more tumorigenic in nude mice, show increased resistance to IFNa-2b in vitro, and are sensitive to immune-mediated cytotoxicity in vitro [7,8]. All the cells were grown in McCoy's media (Invitrogen, Carlsbad, CA) supplemented with 10 % fetal bovine serum (FBS; ATCC) and 1 % penicillin and streptomycin (Invitrogen) in 5 % CO 2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMC) in the presence of the cytokines [interleukin-2 (IL-2) and interferon a-2b (IFNa-2b)], elicit up to a 70 % cytotoxic response against ovarian cancer cells in vitro [7][8][9][10]. This cytotoxic response was not observed in the absence of IL-2 indicating that IL-2 is necessary for the PBMC to elicit the cytotoxic response [7,10].…”

Section: Introductionmentioning

confidence: 99%

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Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer

et al. 2015

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Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNα-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra-peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 × 10(6) PBMC) and cytokine combinations [IL-2 ± pegylated-IFNα-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model.

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Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

Godman

Fadare

Kibuule

et al. 2017

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Synergistic cytotoxicity of interferonα-2b and interleukin-2 in combination with PBMC against ovarian cancer: Development of an experimental model for cellular therapy

Cited by 10 publications

References 22 publications

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer

Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

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Synergistic cytotoxicity of interferonα-2b and interleukin-2 in combination with PBMC against ovarian cancer: Development of an experimental model for cellular therapy

Cited by 10 publications

References 22 publications

18F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

18F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer

Drug Resistance in Bacteria, Fungi, Malaria, and Cancer

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¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model

¹⁸F-FLT PET as a Surrogate Marker of Drug Efficacy During mTOR Inhibition by Everolimus in a Preclinical Cisplatin-Resistant Ovarian Tumor Model