Radiolabeled F(ab')2-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. Methods: We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results: Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions: 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging

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Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

Radiotherapy modulates expression of EGFR, ERCC1 and p53 in cervical cancer.

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.

Interacción de la radioterapia con los nuevos agentes con dianas moleculares / Interaction of radiotherapy and new agents with molecular targets

La radioquimioterapia supuso uno de los mayoreslogros en el tratamiento del cáncer en las últimas décadas,aunque con una importante toxicidad para los enfermos.La investigación desarrollada recientemente enla biología molecular del cáncer ha permitido conocerlos cambios genéticos y moleculares que determinan latransformación maligna celular, lo que ha conducido aidentificar moléculas claves convirtiéndolas en dianasmoleculares además de revolucionar los conceptos radiobiológicosde respuesta celular a las radiaciones yde radiorresistencia.Los nuevos agentes contra dianas moleculares poseenmayor especificidad y menos efectos adversos, loque les hace más atractivos que la quimioterapia paraser combinados con radioterapia. Pueden actuar inhibiendolas señales de transducción intracelular, modulandoel ciclo celular, la apoptosis o inhibiendo la angiogénesis.El efecto de la radioterapia puede potenciarsea través de una inhibición de la repoblación celular, mejoríade la oxigenación tumoral, redistribución duranteel ciclo celular, inhibición de la invasión y metástasis, yaumento de la radiosensibilidad. Los datos disponiblesapoyan su eficacia y aplicabilidad en estudios preclínicosy clínicos en diversos modelos tumorales y abrenuna vía esperanzadora de cambio en el tratamiento del cáncer(AU)

Radiochemotherapy represents one of the greatestachievements in cancer treatment in recent decades,although it involves significant toxicity for patients.Research developed recently in the molecular biologyof cancer has enabled understanding of the geneticand molecular changes that determine malign cellulartransformation, which has led to the identification ofkey molecules, converting them into molecular targetsthat have led to a revolution in radiobiological conceptsof cellular response to radiations and radioresistance.The new agents against molecular targets possessgreater specificity and less adverse effects, makingthem more attractive than chemotherapy for combinationwith radiotherapy. They can act by inhibitingintracellular transduction signals, modulating the cellularcycle, apoptosis or inhibiting angiogenesis. Theeffect of radiotherapy can be strengthened throughinhibition of cellular repopulation, improvement of tumouroxygenation, redistribution of the cellular cycle,inhibition of invasion and metastasis, and increase ofradiosensitivity. The available data support its efficacyand applicability in preclinical and clinical studies in differenttumour models and open up a promising path in cancer treatment(AU)