Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer

Falcetta, Francesca; Bizzaro, Francesca; D'Agostini, Elisa; Bani, Maria Rosa; Giavazzi, Raffaella; Ubezio, Paolo

doi:10.1158/0008-5472.can-17-1099

Cited by 5 publications

(5 citation statements)

References 31 publications

(29 reference statements)

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“…Therefore, conventional chemotherapy can directly exert antitumor effect on tumor cells, whereas bevacizumab can indirectly inhibit cell proliferation and increase apoptosis by decreasing nutrition supply to the tumor ( 55 ). In addition, bevacizumab can be expected to have further antitumor effects if combined with conventional antitumor agents ( 56 ). Hence, the current combination therapy may be used as a new treatment for OSCC due to its enhanced antitumor effects.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

et al. 2021

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Vascular endothelial growth factor (VEGF) serves an important role in new blood vessel formation or angiogenesis, which is a critical event in tumor growth and metastasis. Bevacizumab is a humanized monoclonal antibody against VEGF-A, whereas S-1 is a fluoropyrimidine antineoplastic agent that induces apoptosis in various types of cancer cells. The present study evaluated the antitumor effects of bevacizumab in combination with 5-fluorouracil (5-FU) or S-1 against oral squamous cell carcinoma (OSCC) in vitro and in vivo . Two human OSCC cell lines were used, namely the high VEGF-A-expressing HSC-2 cells and the low VEGF-A-expressing SAS cells. MTT assay was used to evaluate the effect of bevacizumab and/or 5-FU against HSC-2 and SAS cell proliferation. Additionally, the antitumor effect of bevacizumab was evaluated alone and in combination with S-1 against HSC-2 tumors in nude mice. S-1 (6.9 mg/kg/day) was administered orally every day for 3 weeks, and bevacizumab (5 ml/kg/day) was injected intraperitoneally twice per week for 3 weeks. Apoptotic cells in mouse tumors were detected using the TUNEL method, and cell proliferation and microvessel density (MVD) were determined by immunohistochemical staining of Ki-67 and CD31, respectively. Bevacizumab alone did not inhibit OSCC cell proliferation in vitro , and did not exhibit any synergistic inhibitory effect in combination with 5-FU in vitro . However, combined bevacizumab and S-1 therapy exerted synergistic and significant antitumor effects in vivo on HSC-2 tumor xenografts, and induced apoptosis in tumor cells. Furthermore, this combination therapy led to decreased MVD and cell proliferative abilities, as well as increased apoptosis in residual tumors. The present findings suggested that the bevacizumab plus S-1 combination therapy may exert antitumor effects in high VEGF-A-expressing OSCC cells.

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Section: Discussionmentioning

confidence: 99%

Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

et al. 2021

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“…cytotoxic effects, exploiting in silico modeling. 27 In study, by simulation of the growth curves of the MNHOC18 model, we demonstrated that DDP and PTX were both cytotoxic and cytostatic, while BEV was only cytostatic, and that more cells were killed by PTX dose-dense than with PTX conventional. Moreover, we showed that the cytotoxicity of the DDP/PTX combined treatment was similar to the single PTX treatment and considerably less than expected from the cytotoxicity of individual drugs, but the addition of BEV increased cell kill in all schemes.…”

Section: Discussionmentioning

confidence: 86%

“…Experimental models enable to analyze the response to treatment in a way unachievable in clinical setting, disclosing its dynamics with frequent measures, using complementary techniques and gaining information to optimize the treatment. Recently, we have shown the feasibility of decoding growth curves of treated tumors in terms of underlying cytostatic and cytotoxic effects, exploiting in silico modeling . In that study, by simulation of the growth curves of the MNHOC18 model, we demonstrated that DDP and PTX were both cytotoxic and cytostatic, while BEV was only cytostatic, and that more cells were killed by PTX dose‐dense than with PTX conventional.…”

Section: Discussionmentioning

confidence: 98%

Tumor progression and metastatic dissemination in ovarian cancer after dose‐dense or conventional paclitaxel and cisplatin plus bevacizumab

Bizzaro

Falcetta

D'Agostini

et al. 2018

Intl Journal of Cancer

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The efficacy of therapeutic regimens incorporating weekly or every-3-weeks paclitaxel (PTX) for ovarian cancer is debated. We investigated the addition of bevacizumab in regimens of chemotherapy with different PTX doses and schedules in preclinical models. Treatments were cisplatin (DDP) with weekly PTX (conventional), or dose-dense-equi (every other day to the conventional cumulative dose), or dose-dense-high (total dose 1.5 times higher), with or without bevacizumab. Treatment efficacy was evaluated analyzing tumor growth in different time-windows in two patient-derived ovarian cancer xenografts with different sensitivity to cisplatin. Tumor progression, metastasis and survival were studied in ovarian cancer models growing orthotopically and disseminating in the mouse peritoneal cavity. Short-term effects on cell cycle, tumor cell proliferation/apoptosis and vasculature were evaluated by flow cytometry and immunohistochemistry. PTX dose-dense (with/without DDP) was superior to the conventional scheme in a dose-dependent manner; the high efficacy was confirmed by the lower ratio of tumor to normal cells. All schemes benefited from bevacizumab, which reduced tumor vessels. However, DDP/PTX dose-dense-high (only chemotherapy) was at least as active as DDP/PTX conventional plus bevacizumab. DDP/PTX dose-dense-high plus bevacizumab was the most effective in delaying tumor progression, though it did not prolong mouse survival and the continuous treatment with bevacizumab was associated with a malignant disease. These findings indicate that the effect of bevacizumab in combination with chemotherapy may depend on the schedule-dose of the treatment and help to explain the unclear benefits after bevacizumab.

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“…Because early diagnosis cannot be made without de nite symptoms, the vast majority of patients with OC are diagnosed in late stage [3]. Currently, OC is usually treated by surgery and chemotherapy combined with cisplatin and paclitaxel, as well as appropriate radiotherapy [17]. Although OC patients have short-term remission, recurrence and metastasis rates are still high.…”

Section: Discussionmentioning

confidence: 99%

LINC01638 regulates miR-128/PDK1 to promotes cell proliferation and drug resistance in ovarian cancer

Wang

2022

Preprint

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This study aims to explore the functional mechanism of LINC01638 in ovarian cancer (OC). The OC cell proliferation, viability and colony formation were respectively measured using CCK-8, MTT and colony formation assay. The cell cycle and apoptosis were both assessed using flow cytometry. Online bioinformatics tools were performed to predict the downstream gene of LINC01638. RNA pull down experiment and luciferase reporter assay were processed to verify the predictions. The expression of LINC01638, miR-128-3p and PDK1 in OC tissues and cells were detected using qRT-PCR and ISH analysis. The expressions of cisplatin-related proteins were determined by western blot. OC mice model was constructed to carry out in vivo experiment. LINC01638 was highly expressed in OC tissues and cells, and its high expression was related to poor OC prognosis. LINC01638 knockdown inhibited cell proliferation, colony formation and cisplatin resistance, promoted cell apoptosis and induced cell cycle arrest in OC cells. LINC01638 knockdown suppressed tumor growth, proliferation and cisplatin resistance and enhanced apoptosis in vivo. LINC01638 directly targeted miR-128-3p/PDK1 in OC cells. LINC01638 affected OC cell proliferation, survival and cisplatin resistance via combing miR-128-3p and promoting PDK1 expression.

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Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer

Cited by 5 publications

References 31 publications

Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

Antitumor effects of bevacizumab in combination with fluoropyrimidine drugs on human oral squamous cell carcinoma

Tumor progression and metastatic dissemination in ovarian cancer after dose‐dense or conventional paclitaxel and cisplatin plus bevacizumab

LINC01638 regulates miR-128/PDK1 to promotes cell proliferation and drug resistance in ovarian cancer

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