Anti-Cancer Drugs

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Modulation of oxidative stress/antioxidative defence in human serum treated by four different tyrosine kinase inhibitors

imageRecent findings implied the significance of reactive oxygen species (ROS) as a part of tyrosine kinase inhibitors (TKIs) pharmacological activity. Evidences also suggested that toxic effects of TKIs were related to ROS production. The results regarding benefits of vitamin E usage alongside with prescribed TKIs therapy are ambiguous. We aimed to examine oxidative stress and antioxidative defense in human serum treated with four different TKIs and their possible interactions with hydrosoluble vitamin E analog (Trolox). An in-vitro experiment with serum pool as a substitute model was performed. Different parameters of oxidative stress and antioxidative defense were measured in serum pool with and without addition of TKIs (axitinib, crizotinib, nilotinib, and imatinib), before and after addition of Trolox. Z score statistic was used for calculation of Prooxidative and Antioxidative scores. The highest oxidative potential was recorded for samples incubated with imatinib and nilotinib, while the lowest damaging scores were observed for crizotinib and axitinib (nilotinib vs. imatinib, P < 0.05; axitinib vs. imatinib, P < 0.01; crizotinib vs. imatinib, P < 0.001). The best capability for antioxidative protection was seen in samples with nilotinib, then with imatinib, while the lowest level was obtained in samples with crizotinib and axitinib (imatinib and axitinib vs. nilotinib, P < 0.05 for both; crizotinib vs. nilotinib, P < 0.01; axitinib vs. imatinib, P < 0.05, crizotinib vs. imatinib, P < 0.01). Our results demonstrated the opposite effects of Trolox in combination with imatinib and nilotinib. Usage of antioxidant in combination with TKIs should be carefully evaluated in each specific case.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Modulation_of_oxidative_stress_antioxidative.8.aspx

Granulocyte-macrophage colony-stimulating factor enhances effect of temozolomide on high-grade glioma cells

imageIn the present study, to delve into the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with temozolomide (TMZ) on high-grade glioma cells and related mechanism, six cases of high-grade glioma cells from patient’s tumor tissues were cultured. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay was performed to detect cell proliferation and toxicity. Flow cytometry was performed to ascertain cell cycle and apoptosis rate. To detect the expressions of O6-methylguanine-DNA methyltransferase (MGMT) methylation status and MGMT protein, respectively, specific PCR and immunofluorescence were performed. According to the results of MTT assay, compared with the results of control group, GM-CSF group exhibited enhanced cell viability in varying degrees. In three cases of cells (MGMT gene methylation), the combination group [(67.67 ± 1.16), (68.13 ± 1.06), (68.42 ± 1.73)] had noticeably lower cell viability than the corresponding TMZ group [(90.00 ± 1.73), (82.33 ± 1.53), (82.67 ± 2.11)] (P < 0.01). Nevertheless, the two groups showed no significant difference in another three cases (MGMT gene unmethylated) (P > 0.05). In combination group, the apoptosis rate of the MGMT methylation cells was higher than that in the corresponding TMZ group (P < 0.01), which is consistent with MTT assay results. In all six cases of primary glioma cells, the fraction of cells in G1 phase of GM-CSF-treated group was noticeably down-regulated and was up-regulated in S phase (P < 0.01). GM-CSF could induce high-grade glioma cells to rapidly enter the cell cycle, thereby enhancing the lethal effect of TMZ on glioma cells with MGMT gene promoter methylation. However, this effect is not ideal on glioma cells with MGMT unmethylation.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Granulocyte_macrophage_colony_stimulating_factor.9.aspx

Chemotherapy should be performed in epidermal growth factor receptor mutation-positive lung adenocarcinoma patients who had progressive disease to the first epidermal growth factor receptor-tyrosine kinase inhibitor

imageAfter the failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, some non-small cell lung cancer patients desire to receive switching with another EGFR-TKI (TKI-switching), although cytotoxic chemotherapy has been recommended as second-line therapy. It is unclear who should not receive TKI-switching in these patients. We retrospectively evaluated overall survival (OS) from the initiation of first EGFR-TKI (first-TKI) therapy in advanced lung adenocarcinoma patients with active EGFR mutations (deletion of exon 19 or L858R in exon 21) who received TKI-switching according to the best response of the first-TKI. There was no difference in the OS between patients receiving TKI-switching (n = 35) and patients receiving additional chemotherapy between the first-TKI and second-TKI therapy (n =10) (P = 0.614). Among patients receiving TKI-switching, the OS in cases with progressive disease to the first-TKI (n = 9) was shorter than that in cases with disease control to the first-TKI (n = 26) (12.7 months vs. 49.4 months, P < 0.001). Five of the nine progressive disease cases who received TKI-switching missed an opportunity to receive chemotherapy. Their OS tended to be shorter than that in patients who received chemotherapy during the whole period of anticancer therapy (12.2 months vs. 20.3 months, P = 0.060). The multivariate analysis showed that disease control to the first-TKI therapy (P = 0.005) or the presence of chemotherapy (P = 0.087) decreased the risk of mortality. Chemotherapy should be performed in patients with progressive disease to the first-TKI.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Chemotherapy_should_be_performed_in_epidermal.10.aspx

Platelet-to-lymphocyte ratio predicts therapy outcomes of transarterial chemoembolization plus apatinib in the treatment of advanced hepatocellular carcinoma

imageTo evaluate the predictive value of preoperative biochemical marker [platelet-to-lymphocyte ratio (PLR)] in patients with advanced hepatocellular cancer receiving transarterial chemoembolization (TACE) plus targeted molecular therapy (apatinib) treatment. Clinical records of 134 patients receiving the treatment of TACE + apatinib (TACE-A) and the treatment of TACE alone were compared in a single-center study. Time to progression (TTP) and overall survival (OS) were compared between TACE-A and TACE alone groups in patients with PLR > 150 and PLR ≤ 150, respectively. The area under the receiver operating characteristic (ROC) curve was used to determine the prediction power of PLR. The median TTP and OS in the TACE-A group were significantly longer than those in the TACE alone group (P < 0.001). The median TTP and OS in the TACE-A (PLR ≤ 150) group were longer than those in the TACE-A (PLR > 150) group (P < 0.05). There was no significant difference between TACE-A (PLR > 150) and TACE alone (P = 0.232) groups in OS, but the median TTP in the TACE-A (PLR > 150) group was longer than that in the TACE alone group (P = 0.001). ROC analysis showed that the area under the curve was 0.643 and 0.623 for 6- and 12-month survival, respectively. PLR might predict the results of patients with advanced hepatocellular carcinoma received TACE-A treatment.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Platelet_to_lymphocyte_ratio_predicts_therapy.11.aspx

Lower response to trastuzumab emtansine in metastatic breast cancer patients with human epidermal growth factor receptor 2 immunohistochemistry score of 2 and fluorescence in situ hybridization positive compared with immunohistochemistry score of 3: a retrospective study

imageTumor human epidermal growth factor receptor 2 (HER2) status is defined by either protein expression using immunohistochemistry (IHC) or gene amplification using fluorescence in situ hybridization (FISH). Approximately 20% of HER2-positive breast cancer is HER2 IHC 2+/FISH-positive. Unlike trastuzumab, it has not been studied whether the response to trastuzumab emtansine (T-DM1) differs according to HER2-positive status. We retrospectively identified and reviewed medical records of all patients with HER2-positive advanced breast cancer (ABC) who received T-DM1 in our hospital from October 2013 to December 2016. We compared the objective response rate (ORR) and progression-free survival (PFS) between patients in the HER2 IHC 3+ group and those in the HER2 IHC 2+/FISH-positive group. A total of 39 patients (IHC 3+: n = 32; IHC 2+/FISH-positive: n = 7) were analyzed. Nineteen (48.7%), 13 (33.3%), and 29 (74.4%) patients had received at least one prior chemotherapy, more than three lines of chemotherapy, and prior pertuzumab for ABC, respectively. ORR was significantly higher in the IHC 3+ group than in the IHC 2+/FISH-positive group (53.3% vs. 0%, P = 0.024). Median PFS was 7.9 months in the IHC 3+ group versus 3.9 months in the IHC 2+/FISH-positive group (hazard ratio 0.68; 95% confidence interval 0.28–1.69, P = 0.408). Among the HER2-positive ABC patients treated with T-DM1, ORR was significantly worse in HER2 IHC 2+/FISH-positive than in HER2 IHC 3+ patients. Median PFS tended to be shorter in patients with HER2 IHC 2+/FISH-positive.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Lower_response_to_trastuzumab_emtansine_in.12.aspx

Evaluation of RAS mutational status through BEAMing assay to monitor disease progression of metastatic colorectal cancer: a case report

imageSince the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutations: one in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Evaluation_of_RAS_mutational_status_through.13.aspx

Full-dose cisplatin chemotherapy combined with hemodialysis in a patient with impaired renal function and a mediastinal germ cell tumor

imageCisplatin is the first choice treatment in mediastinal germ cell tumors. However, concerns regarding increased toxicity of cisplatin hamper its administration in patients with impaired renal function. We describe a 42-year-old man with chronic kidney disease stage 4 who was diagnosed with a mediastinal germ cell tumor and metastases in lung and brain. Treatment with cisplatin-etoposide was considered essential for a chance of cure. In order to administer the full cisplatin dose, 4-hour hemodialysis sessions were performed after each cisplatin infusion. During treatment cycle 3, 4 and 5, total and unbound plasma platinum concentrations were measured. Trough concentrations and half-life were at the higher end of the range of those observed in patients with adequate renal function who received the same dose of cisplatin. Hemodialysis aided platinum clearance, although our patient was also able to clear some platinum by his own renal function. With this full dose treatment, our patient obtained a favorable tumor response, with a strong decrease of beta-human chorionic gonadotropin and tumor size. The side effects experienced by our patient were serious, although not worse than what could be expected with this type of treatment. His renal function remained stable during the treatment period.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Full_dose_cisplatin_chemotherapy_combined_with.14.aspx

Cloning of two splice variants of Spalax heparanase encoding for truncated proteins

imageHeparanase is an endoglycosidase that degrades heparan sulfate side chains of heparan sulfate-proteoglycans. It liberates heparan sulfate-bound growth factors and thereby promotes blood vessel sprouting and angiogenesis. The subterranean blind mole rat, Spalax, is a wild mammal that lives most of its life in underground tunnels where it experiences sharp fluctuations in oxygen and carbon dioxide levels. We described two splice variants of heparanase from Spalax, Splice 7 and splice 36, both devoid of heparanase enzymatic activity. Splice 7 increases tumor growth, while splice 36 functions as a dominant negative to wild-type heparanase and decreases tumor growth and metastasis. Here, we describe two novel splice variants of Spalax heparanase, splice 67 and splice 612. These splice variants result in production of a shorter heparanase proteins that are similar to the wild-type native heparanase in their N-terminal but have unique C-terminals. Both splice 67 and 612 lack heparan sulfate degradation activity.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Cloning_of_two_splice_variants_of_Spalax.1.aspx

A 3D screening approach identifies the compound epitajixanthone hydrate as a new inhibitor of cancer cell growth and invasion

imageWith unique advantages, the small-molecule anticancer drugs have recently gained growing attention. Particular strategies, exemplified by high-throughput screening, fragment-based drug discovery, virtual screening and knowledge-based design, have been developed to identify active compounds. However, such screens generally rely on sophisticated and expensive instrumentations. Herein, we developed a simple spheroids 3D culture system to enable direct screening of small molecules with reliable results. Using this system, we screened 27 fungal natural products and three fungal crude extracts for their inhibitory effects on cancer cell growth, and invasion. We identified that the compound M23 (epitajixanthone hydrate, a derivative of prenylxanthone) and the crude extracts (MPT-191) from the fungi Taxus chinensis showed potential anticancer activity. The effect of epitajixanthone hydrate on cancer cell growth and invasion were further confirmed by the assays of cells viability, trans-well migration and invasion, colony formation and cells reattachment. Overall, Epitajixanthone hydrate was identified as an effective inhibitor of cancer cell growth and invasion by our simple and fast screening platform.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/A_3D_screening_approach_identifies_the_compound.2.aspx

Transmembrane protein 45A regulates the proliferation, migration, and invasion of glioma cells through nuclear factor kappa-B

imageGliomas are the most common and aggressive type of primary brain cancer in adults. The expression of transmembrane protein 45A (TMEM45A) in glioma patients and glioma cell lines was analyzed by quantitative real-time PCR. The influence of TMEM45A on the survival of glioma patients was also explored in this study. To verify the interaction between TMEM45A and key genes, correlation analysis of expression levels and the siRNA knock down method were performed. TMEM45A was upregulated in glioma tissues, and its overexpression was strongly correlated with the poor survival of glioma patients. Experiments using the overexpression and knock down of TMEM45A were carried out to demonstrate its correlation with enhanced proliferation, migration, and invasion in glioma cells. Nuclear factor kappa-B (NFκB) expression was shown to be a downstream factor of TMEM45A in glioma cells. In conclusion, TMEM45A is an oncogenic gene in glioma. The proliferation, migration, and invasion of gliomas could be effectively impeded by inhibition of TMEM45A, and the cancer-promoting effect of TMEM45A on gliomas was involved with the NFκB pathway.

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https://journals.lww.com/anti-cancerdrugs/Fulltext/2020/10000/Transmembrane_protein_45A_regulates_the.3.aspx

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