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Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug Z HER2:V2 -pemetrexed in lung adenocarcinoma Xenografts.
- Source :
-
Investigational new drugs [Invest New Drugs] 2020 Aug; Vol. 38 (4), pp. 1031-1043. Date of Electronic Publication: 2019 Nov 23. - Publication Year :
- 2020
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Abstract
- Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate Z <subscript>HER2:V2</subscript> -pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using Z <subscript>HER2:V2</subscript> -pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the <superscript>99m</superscript> Tc-labeled Z <subscript>HER2:V2</subscript> -pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with <superscript>99m</superscript> Tc-Z <subscript>HER2:V2</subscript> -pemetrexed demonstrated that in HER2+ A549 models, Z <subscript>HER2:V2</subscript> -pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that Z <subscript>HER2:V2</subscript> -pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the Z <subscript>HER2:V2</subscript> -pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the Z <subscript>HER2:V2</subscript> -pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the Z <subscript>HER2:V2</subscript> -pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.
- Subjects :
- A549 Cells
Adenocarcinoma of Lung diagnostic imaging
Adenocarcinoma of Lung pathology
Animals
Apoptosis drug effects
Cell Cycle Checkpoints drug effects
Female
Humans
Lung Neoplasms diagnostic imaging
Lung Neoplasms pathology
Mice, Inbred BALB C
Mice, Nude
Tomography, Emission-Computed, Single-Photon
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Adenocarcinoma of Lung drug therapy
Antineoplastic Agents therapeutic use
Lung Neoplasms drug therapy
Pemetrexed therapeutic use
Receptor, ErbB-2 genetics
Recombinant Fusion Proteins therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 38
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 31758360
- Full Text :
- https://doi.org/10.1007/s10637-019-00876-3