Cetuximab in combination therapy: from bench to clinic

Gerber, David E.; Choy, Hak

doi:10.1007/s10555-010-9215-6

Cited by 30 publications

(22 citation statements)

References 69 publications

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“…However, drug toxicity remains to be clarified in the clinic (2). Efforts have focused on incorporating cytotoxic and molecularly targeted agents into chemotherapy regimens to decrease toxicity and increase efficacy (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

et al. 2011

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Abstract. The present study aimed to examine the combined effects of oxaliplatin (L-OHP) and rapamycin (RAPA) in the HCT116 colon cancer cell line. The growth inhibitory effect was evaluated by MTT assay as a monotherapy or combination therapy. IC 50 values were determined using CalcuSyn 2.0 software. To determine the interaction of the drugs, the combination index (CI) was calculated using the Chou-Talalay method. Apoptosis was investigated using flow cytometry and Western blotting. Acridine orange staining was employed to observe morphological changes. The results showed the IC 50 values of L-OHP and RAPA to be 8.35±0.78 µM (r=0.99) and 223.44±38.10 nM (r=0.94), respectively. CI was ≤1 when L-OHP was used at doses ranging from 1 to 5 µM plus RAPA at a dose of 10 nM, suggesting synergistic or additive effects. CI was ≥1 when 100 nM RAPA was used in combination with low-dose L-OHP, showing additive to antagonistic effects. The combination of L-OHP (1 µM) and RAPA (10 nM) induced 19.76% Annexin V-positive cells, which was found to be higher than L-OHP (11.45%, p<0.01) or RAPA (6.89%, p<0.01) alone. The cleaved PARP protein expression levels were highest after 48 h of combination treatment. Acridine orange staining showed typical bright red Acidic vesicular organelles in the RAPA group, whereas the green condensed chromatin in the apoptotic bodies was found in both the L-OHP and combination groups. In conclusion, at a cytostatic concentration, RAPA was found to potentiate the anti-tumor effects of low-dose L-OHP in the HCT116 colon cancer cell by inducing enhanced apoptosis. IntroductionColorectal cancer (CRC) is the second most prevalent cancer and the third leading cause of cancer deaths worldwide (1). Oxaliplatin (L-OHP)-based chemotherapeutic regimens have proven to be effective in the prevention and treatment of tumor recurrence and metastasis in CRC. However, drug toxicity remains to be clarified in the clinic (2). Efforts have focused on incorporating cytotoxic and molecularly targeted agents into chemotherapy regimens to decrease toxicity and increase efficacy (3-5).The mammalian target of rapamycin (mTOR), an intracellular protein with a central role in the synthesis of key cellular proteins, has emerged as a significant target for anticancer therapy in various types of tumor. Phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway has been reported to be constitutively overexpressed in malignant tumors including CRC (6-7). Rapamycin (RAPA) is the special inhibitor of mTOR, which has demonstrated anti-tumor effects in a variety of malignancies in preclinical and clinical studies. In addition to being used as a monotherapy, RAPA and its analogs have been shown to enhance the efficacy of a number of cytotoxic chemotherapeutic agents in various types of cancer (8-11). Studies have shown that the anti-tumor mechanism of RAPA includes both apoptosis and autophagy, and its role in the fate of cancer cells remains controversial (12). The interaction between RAPA and L-OHP has yet to be clarified as the role of apo...

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Section: Introductionmentioning

confidence: 99%

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

et al. 2011

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“…To determine whether the information of Twist1-Jagged1-KLF4 axis can provide a guide to specific treatment strategy for patients with Twist1-overexpressing cancers, Twist1-overexpressing OECM1 cells were used to test drug response. Two commonly used drugs for HNC treatment, cetuximab and cisplatin 30,31 , were individually tested with or without a g-secretase inhibitor N-[N- …”

Section: Oecm1-twist1mentioning

confidence: 99%

“…Antigen retrieval processes were then performed twice by pressure cooker at 1.2 atm for 15 min with target retrieval solution (#S1700, Dako, Denmark) and then blocked with 0.3% hydrogen peroxide for 30 min. Biotinylated probes (20 ml) for general screening (HPV 6,11,16,18,30,31,33,45, 51, 52; #Y1404, DAKO) were applied on separate specimen and were covered with coverslips. Denaturation of DNA was performed at 92°C for 5 min in an oven.…”

Section: Oecm1-mentioning

confidence: 99%

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

et al. 2014

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The mechanisms controlling tumour-induced angiogenesis are presently not clear. In principle, angiogenesis can be achieved through the activation of endothelial cells in existing vessels or by transdifferentiation of tumour cells into endothelial cells. However, whether tumour cells can go through a prior epithelial-mesenchymal transition and further differentiate into endothelial cells remains unknown. Here we show that overexpression of Twist1, a transcriptional regulator that induces and promotes cancer metastasis, leads to endothelial differentiation in head and neck cancer (HNC) cells. Induction of Jagged1 expression by Twist1 is essential for Twist1-induced endothelial differentiation. The Jagged1/ Notch signalling subsequently activates KLF4, inducing stem-like properties in HNC cells and conferring them with drug resistance. Our results indicate that the Twist1-Jagged1/KLF4 axis is essential both for transdifferentiation of tumour cells into endothelial cells and for chemoresistance acquisition.

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“…At the extracellular level, it promotes immune system cytotoxic cells attack against EGFR-expressing tumor cells, due to the recognition of the IgG1 Fc region by natural killer cells. In combination with radiotherapy (RT), CTX inhibits DNA repair and tumor angiogenesis, while facilitating apoptosis, radio-sensitizing cells at G1 phase, and reducing radio-resistance of cells at S phase [1][2][3] . Head and neck squamous cell carcinoma (HNSCC) treatment of choice has been surgery followed by radiotherapy; however, at locoregionally advanced or inoperable stages, the association of chemotherapy (CT) with RT (CTRT) emerged in the 1990s as an alternative that offered better control than RT alone.…”

Section: Introductionmentioning

confidence: 99%

Multidisciplinary, Multi-Institutional Consensus on Cetuximab Usefulness in the Treatment of Patients with Head and Neck Squamous Cell Carcinoma

Barrera-Franco¹,

Bautista-Aragón²,

Gallegos-Hernández³

et al. 2022

GAMO

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Epidermal growth factor receptor is preferably expressed in head and neck squamous cell carcinomas and is a promising therapeutic target. Cetuximab is the only epidermal growth factor receptor-targeted agent that has been approved for the treatment of squamous cell carcinoma. The 2006 FDA-approved indication refers to the use of cetuximab in combination with radiotherapy for the treatment of locoregional, advanced, unresectable head and neck squamous cell carcinoma, except for nasopharyngeal carcinoma. In 2011, the use of cetuximab in combination with platinum and 5-fluorouracil was approved as first-line treatment for recurrent and/or metastatic head and neck squamous cell carcinoma. In order to homogenize and arrive at a multidisciplinary, multi-institutional consensus based on scientific evidence, a meeting was held where the existing literature was reviewed and the role of cetuximab in the treatment of patients with head and neck squamous cell carcinoma was discussed. This work reviews current evidence-based indications for the use of cetuximab in the treatment of patients with head and neck squamous cell carcinoma. (creativecommons.org/ licenses/by-nc-nd/4.0/).

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Cetuximab in combination therapy: from bench to clinic

Cited by 30 publications

References 69 publications

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

Multidisciplinary, Multi-Institutional Consensus on Cetuximab Usefulness in the Treatment of Patients with Head and Neck Squamous Cell Carcinoma

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