-
1.
Antiproliferative and palliative activity of flavonoids in colorectal cancer.
Fernández, J, Silván, B, Entrialgo-Cadierno, R, Villar, CJ, Capasso, R, Uranga, JA, Lombó, F, Abalo, R
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:112241
Abstract
Flavonoids are plant bioactive compounds of great interest in nutrition and pharmacology, due to their remarkable properties as antioxidant, anti-inflammatory, antibacterial, antifungal and antitumor drugs. More than 5000 different flavonoids exist in nature, with a huge structural diversity and a plethora of interesting pharmacological properties. In this work, five flavonoids were tested for their potential use as antitumor drugs against three CRC cell lines (HCT116, HT-29 and T84). These cell lines represent three different stages of this tumor, one of which is metastatic. Xanthohumol showed the best antitumor activity on the three cancer cell lines, even better than that of the clinical drug 5-fluorouracil (5-FU), although no synergistic effect was observed in the combination therapy with this drug. On the other hand, apigenin and luteolin displayed slightly lower antitumor activities on these cancer cell lines but showed a synergistic effect in combination with 5-FU in the case of HTC116, which is of potential clinical interest. Furthermore, a literature review highlighted that these flavonoids show very interesting palliative effects on clinical symptoms such as diarrhea, mucositis, neuropathic pain and others often associated with the chemotherapy treatment of CRC. Flavonoids could provide a double effect for the combination treatment, potentiating the antitumor effect of 5-FU, and simultaneously, preventing important side effects of 5-FU chemotherapy.
-
2.
Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Zhou, T, Zhang, Z, Luo, F, Zhao, Y, Hou, X, Liu, T, Wang, K, Zhao, H, Huang, Y, Zhang, L
JAMA network open. 2020;(10):e2015748
-
-
Free full text
-
Abstract
IMPORTANCE Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is. OBJECTIVE To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019. STUDY SELECTION Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included. DATA EXTRACTION AND SYNTHESIS Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5. RESULTS A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97). CONCLUSIONS AND RELEVANCE The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
-
3.
Anticancer effect of nor-wogonin (5, 7, 8-trihydroxyflavone) on human triple-negative breast cancer cells via downregulation of TAK1, NF-κB, and STAT3.
Abd El-Hafeez, AA, Khalifa, HO, Mahdy, EAM, Sharma, V, Hosoi, T, Ghosh, P, Ozawa, K, Montano, MM, Fujimura, T, Ibrahim, ARN, et al
Pharmacological reports : PR. 2019;(2):289-298
-
-
Free full text
-
Abstract
BACKGROUND Nor-wogonin, a polyhydroxy flavone, has been shown to possess antitumor activity. However, the mechanisms responsible for its antitumor activity are poorly studied. Herein, we investigated the mechanisms of nor-wogonin actions in triple-negative breast cancer (TNBC) cells. METHODS Effects of nor-wogonin on cell proliferation and viability of four TNBC cell lines (MDA-MB-231, BT-549, HCC70, and HCC1806) and two non-tumorigenic breast cell lines (MCF-10A and AG11132) were assessed by BrdU incorporation assays and trypan blue dye exclusion tests. Cell cycle and apoptosis analyses were carried out by flow cytometry. Protein expression was analyzed by immunoblotting. RESULTS Nor-wogonin significantly inhibited the growth and decreased the viability of TNBC cells; however, it exhibited no or minimal effects in non-tumorigenic breast cells. Nor-wogonin (40 μM) was a more potent anti-proliferative and cytotoxic agent than wogonin (100 μM) and wogonoside (100 μM), which are structurally related to nor-wogonin. The antitumor effects of nor-wogonin can be attributed to cell cycle arrest via reduction of the expression of cyclin D1, cyclin B1, and CDK1. Furthermore, nor-wogonin induced mitochondrial apoptosis, (as evidenced by the increase in % of cells that are apoptotic), decreases in the mitochondrial membrane potential (ΔΨm), increases in Bax/Bcl-2 ratio, and caspase-3 cleavage. Moreover, nor-wogonin attenuated the expression of the nuclear factor kappa-B and activation of signal transducer and activator of transcription 3 pathways, which can be correlated with suppression of transforming growth factor-β-activated kinase 1 in TNBC cells. CONCLUSION These results showed that nor-wogonin might be a potential multi-target agent for TNBC treatment.
-
4.
Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study.
Jang, SI, Lee, KT, Choi, JS, Jeong, S, Lee, DH, Kim, YT, Lee, SH, Yu, JS, Lee, DK
Endoscopy. 2019;(9):843-851
Abstract
BACKGROUNDS The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.
-
5.
A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients.
Fujiwara, Y, Mukai, H, Saeki, T, Ro, J, Lin, YC, Nagai, SE, Lee, KS, Watanabe, J, Ohtani, S, Kim, SB, et al
British journal of cancer. 2019;(5):475-480
-
-
Free full text
-
Abstract
BACKGROUND NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer. METHODS Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215. RESULTS A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001). CONCLUSIONS The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov: NCT01644890.
-
6.
Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.
Kang, YK, Ryu, MH, Park, SH, Kim, JG, Kim, JW, Cho, SH, Park, YI, Park, SR, Rha, SY, Kang, MJ, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2018;(5):1220-1226
-
-
Free full text
-
Abstract
BACKGROUND Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. METHODS AND MATERIALS Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. RESULTS Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). CONCLUSIONS DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. CLINICALTRIALS.GOV: NCT01839773.
-
7.
Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract.
Otto, C, Hahlbrock, T, Eich, K, Karaaslan, F, Jürgens, C, Germer, CT, Wiegering, A, Kämmerer, U
BMC complementary and alternative medicine. 2016;:160
Abstract
BACKGROUND Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound. METHODS The IC50 values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 μmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD(+) ratio were measured. RESULTS The mean IC50 value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 μmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD(+) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy. CONCLUSIONS FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.
-
8.
Prospective Study of Transcatheter Arterial Chemoembolization (TACE) with Ginsenoside Rg3 versus TACE Alone for the Treatment of Patients with Advanced Hepatocellular Carcinoma.
Zhou, B, Yan, Z, Liu, R, Shi, P, Qian, S, Qu, X, Zhu, L, Zhang, W, Wang, J
Radiology. 2016;(2):630-9
Abstract
Purpose To conduct a single-center, open-label, randomized, controlled trial to compare the effectiveness and safety of (a) ginsenoside Rg3 combined with transcatheter arterial chemoembolization (TACE) and (b) TACE alone in patients with advanced hepatocellular carcinoma (HCC). Materials and Methods This trial was approved by the Fudan University Zhongshan Hospital ethics committee and was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-11001643). After informed consent was obtained, 228 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) were randomly assigned to receive an Rg3 capsule and undergo TACE (n = 152; mean age ± standard deviation, 52.4 years ± 11.8; 84.2% men) or undergo TACE alone (n = 76; mean age, 52.4 years ± 10.4; 82.9% men). TACE was performed by using iodized oil with epirubicin and gelatin sponge after oxaliplatin and 5-fluorouracil were infused. The primary end point was overall survival. Secondary end points included time to progression, time to untreatable progression, disease control rate, and safety. Data were compared with the log-rank test, and survival curves were generated with the Kaplan-Meier method. Results Median overall survival was 13.2 months (95% confidence interval [CI]: 11.15, 15.26) in the TACE with Rg3 group and 10.1 months (95% CI: 9.14, 11.06) in the control group (hazard ratio, 0.63 [95% CI: 0.46, 0.85]; P = .002). Median time to progression (4.3 vs 3.2 months, respectively; P = .151) and median time to untreatable progression (8.3 vs 7.3 months, respectively; P = .063) were similar in the two groups. Disease control rate was 69.7% in the TACE with Rg3 group versus 51.3% in the control group (P = .012). Constipation and epistaxis were more frequent in the Rg3 with TACE group (P < .05). Importantly, Rg3 alleviated some TACE-related adverse syndromes and blood anomalies. Conclusion In patients with advanced HCC and adequate liver function, the combination of TACE and ginsenoside Rg3 may prolong overall survival when compared with TACE alone. (©) RSNA, 2016.
-
9.
Paclitaxel-eluting versus bare metal stents in primary PCI: a pooled patient-level meta-analysis of randomized trials.
De Luca, G, Dirksen, MT, Kelbæk, H, Thuesen, L, Vink, MA, Kaiser, C, Chechi, T, Spaziani, G, Di Lorenzo, E, Suryapranata, H, et al
Journal of thrombosis and thrombolysis. 2015;(1):101-12
Abstract
Concerns have emerged regarding a higher risk of stent thrombosis after drug-eluting stent (DES) implantation, especially in the setting of ST-segment elevation myocardial infarction (STEMI). Therefore, we performed a meta-analysis based on individual patient data to evaluate long-term safety and effectiveness of paclitaxel-eluting stent (PES) as compared to bare metal stents (BMS) in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI. We examined all completed randomized trials on PES for STEMI. Individual patient data were obtained from six trials. We performed survival analyses with the use of Cox-regression analysis stratified according to trial. Kaplan-Meier survival curves are presented with event rates reported as estimated probabilities. A subsequent landmark analysis was performed for patients who were event-free at 1-year follow-up in order to define outcome in terms of early (≤1 year) and late (>1 year) events. A total of six trials were finally included in the meta-analysis with 4435 patients, 2875 (64.8 %) assigned to PES and 1560 (35.2 %) to BMS. No significant differences in baseline characteristics were observed between the two groups. However, a significantly higher percentage of patients in the DES group were on dual antiplatelet therapy during 3-year follow-up, as compared to BMS. At long-term follow-up (1,095 [1,090-1,155] days), no significant difference between PES and BMS was observed in mortality (9.2 vs 11.9 %, respectively, HR [95 % CI] = 0.84 [0.67, 1.06], p = 0.15, pheterogeneity = 0.59), reinfarction (8.8 vs 7 %, respectively; HR [95 % CI] = 1.10 [0.84, 1.44], p = 0.51, pheterogeneity = 0.32), stent thrombosis (6.7 vs 4.0 % respectively, HR [95 % CI] = 1.13 [0.82, 1.55], p = 0.45, pheterogeneity = 0.99) and TVR (11.9 vs 20.0 %; HR [95 % CI] = 0.64 [0.54, 0.77], p < 0.0001, pheterogeneity = 0.25). Landmark analysis showed that PES was associated with a significantly higher rate of very late reinfarction (>1 year) (5.6 vs 3.9 %, HR [95 % CI] = 1.61 [1.05-2.47], p = 0.03, pheterogeneity = 0.51], very late ST (2.9 vs 1.1 %, HR [95 % CI] = 1.88 [1.00-3.54], p = 0.05, pheterogeneity = 0.94]. The present pooled patient-level meta-analysis demonstrates that among STEMI patients undergoing primary PCI, PES compared to BMS is associated with a significant reduction in TVR at long-term follow-up. Although there were no differences in cumulative mortality, reinfarction or stent thrombosis, the incidence of very late reinfarction and stent thrombosis was increased with PES.
-
10.
Consistent efficacy and safety of gemcitabine-paclitaxel in patients with metastatic breast cancer: a retrospective comparison of East Asian and global studies.
Xu, B, Zhang, XQ, Chi, HD, Liu, Z, Quinlivan, M, Orlando, M
Asia-Pacific journal of clinical oncology. 2014;(4):330-9
Abstract
AIMS: The incidence of breast cancer in China is increasing at a rate greater than the global average. For treatment of metastatic breast cancer, a phase 3 trial of 529 patients (study JHQG) found that the combination of gemcitabine, a cytotoxic nucleoside analog, and paclitaxel, a taxane, significantly improved both overall and progression-free survival compared with paclitaxel monotherapy. As ethnic differences in the safety and efficacy of some anticancer therapies have been reported, this review provides oncologists treating East Asian patients with an evidence base to extrapolate results of the predominately Caucasian phase 3 JHQG study to their patients. METHODS Three phase 2 studies in Chinese or Japanese patients with metastatic breast cancer are reviewed with reference to the global study JHQG. The results of pharmacokinetic, efficacy and safety analyses are descriptively compared between the global and Asian studies. RESULTS Peak and total drug exposure values differed by less than 10% across the studies. Response rate, overall and progression-free survival values were similar, although values from the Asian studies for each of these parameters were slightly higher. Asian patients had higher rates of hematologic toxicities but lower rates of other adverse events. CONCLUSION Examination of the data from three studies of the gemcitabine-paclitaxel combination reveals no clinically significant ethnic differences in efficacy and safety between East Asian patients and their global counterparts. Given its demonstrated efficacy and safety profile, the gemcitabine-paclitaxel regimen should be one of the standard treatments for East Asian patients with metastatic breast cancer.