scholarly journals Experimental Evaluation of Anticancer Efficiency and Acute Toxicity of Anthrafuran for Oral Administration

2020 ◽  
Vol 13 (5) ◽  
pp. 81 ◽  
Author(s):  
Andrey E. Shchekotikhin ◽  
Helen M. Treshalina ◽  
Michael I. Treshchalin ◽  
Eleonora R. Pereverzeva ◽  
Helen B. Isakova ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Antitumor Agent ◽  
Antitumor Efficacy ◽  
Mammary Adenocarcinoma ◽  
Treatment Schedule ◽  
Tumor Models ◽  
Cellular Targets ◽  
P388 Leukemia ◽  
Simultaneous Inhibition ◽  
Ld50 Value

The new antitumor agent anthrafuran has demonstrated a consistent effect in murine tumor models when administered parenterally due to the simultaneous inhibition of multiple cellular targets such as topoisomerases I/II and protein kinases. In this study, we assessed the anticancer efficiency and acute toxicity of anthrafuran administered orally. The action of anthrafuran was studied on transplanted tumor models which included P388 leukemia, Ca755 mammary adenocarcinoma, LLC lung carcinoma, and T47D human breast cancer xenografts on Balb/c nude mice. A significant antitumor efficacy of oral anthrafuran was revealed for all tested tumor models as follows: T/Cmax = 219% for P388, TGImax = 91% for Ca755, TGImax = 84% with CRmax = 54% for LLC, and T/C = 38% for T47D. The optimal treatment schedule of orally administered anthrafuran was 70–100 mg/kg given daily for five days. The LD50 value of orally administered anthrafuran (306.7 mg/kg) in mice was six times higher than that for i.p. administration (52.5 mg/kg). The rates of antitumor efficacy and acute toxicity indicate the high potential for further research on anthrafuran as a new original oral anticancer multitarget agent with an expected satisfactory tolerability and bioavailability.

scholarly journals Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models

2018 ◽  
Vol 13 (6) ◽  
pp. 810-820 ◽  
Author(s):  
Carminia Maria Della Corte ◽  
Vincenza Ciaramella ◽  
Claudia Cardone ◽  
Silvia La Monica ◽  
Roberta Alfieri ◽  
...  
Keyword(s):  
Antitumor Efficacy ◽  
Egfr Signaling ◽  
Tumor Models ◽  
Dual Blockade

scholarly journals Proximate and Acute Toxicity Profile of Vitex doniana (Black Plum) Fruit

2021 ◽  
Vol 46 (2) ◽  
Author(s):  
C. Imoisi ◽  
J.U. Iyasele ◽  
S.E. Okhale
Keyword(s):  
Acute Toxicity ◽  
Potable Water ◽  
Oral Treatment ◽  
Control Group ◽  
Toxicity Profile ◽  
North East ◽  
Capability Analysis ◽  
Edo State ◽  
Ld50 Value ◽  
Vitex Doniana

The fresh fruits of Vitex doniana sweet were collected from several randomly selected trees in a farm site in Uromi metropolis, Esan North-East Local Government Area of Edo state and then processed into an extract in form of syrup. The proximate composition and acute toxicity profile of Vitex doniana sweet fruit were investigated to ascertain its safety and nutritional capability. Analysis of the fruit showed it to be a highly nutritious food containing moisture of about, 9.90%, ash content: 21.5%, fat: 0.75%, fiber: Not detected (ND), protein: 0.006% and carbohydrate: 67.84%. Twenty mice were randomized based on body weight into five groups of four mice each. Three mice in each group were given syrup volumes of 100, 200, 300, 400 and 500 mg/ml respectively, corresponding to 1000, 2000, 3000, 4000 and 5000 mg/kg doses. In contrast, mice in the control group received potable water (10 mL/kg). The mice in all the groups were observed closely for mortality, toxicity signs and abnormalities in gross behaviour at 15 min, 30 min, 1, 2, 4 and 8 h, and then daily for 14 days. Based on the model used, the fruit was acutely safe in mice, since no death was observed within 24 hours after oral treatment and on extrapolation gave a high predictive value in humans. The LD50 value of black plum fruit was also found to be greater than 5000 mg/kg. Therefore, Vitex doniana fruit should be considered a source of edible syrup bearing in mind the safety, quantity and variety of nutrients it contains.

scholarly journals Concomitant or delayed anti-TNF differentially impact on immune-related adverse events and antitumor efficacy after anti-CD40 therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001687
Author(s):  
Celia Jacoberger-Foissac ◽  
Stephen J Blake ◽  
Jing Liu ◽  
Elizabeth McDonald ◽  
Hannah Triscott ◽  
...  
Keyword(s):  
Adverse Events ◽  
Mouse Model ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Clinical Score ◽  
Antitumor Efficacy ◽  
Tumor Models ◽  
Colon Tissue ◽  
Treg Depletion ◽  
The Impact

BackgroundConcomitant tumor necrosis factor (TNF) neutralization in combination with immune checkpoint inhibitors (ICIs) reduces clinical immune-related adverse events (irAEs) and appears to improve antitumor efficacy in preclinical tumor models. Agonistic antibodies targeting costimulatory receptors such as CD40 represent an additional strategy to boost antitumor immune response and potentiate the activity of ICIs. However, the dose-limiting toxicities observed in anti-CD40-treated cancer patients have hindered its clinical development.MethodsWe previously described a mouse model to assess both antitumor activity and irAEs induced by various effective combination immunotherapies. Using the BALB/c and C57BL/6 strains of FoxP3-GFP-DTR (FoxP3DTR) mice, transient depletion of T regulatory cells (Tregs) prior to immunotherapy with additional immunomodulatory antibodies, lowered immune self-tolerance, resulting in the development of a spectrum of physical and biochemical irAEs similar to that reported clinically. In MC38 and 4T1.2 tumor models, following transient Treg depletion, we evaluated the impact of anti-CD40 on antitumor efficacy and the development of irAEs and the impact of concomitant or delayed TNF blockade on both these parameters. Physical irAEs were scored and biochemical irAEs were measured in the serum (ALT and cytokine levels). Histopathological liver and colon tissue analysis were performed to assess immune cell infiltration and tissue damage.ResultsSimilar to early clinical trials of CD40 agonists, in our tumor models we observed liver toxicities and rapid release of proinflammatory cytokines (TNF, interleukin 6, interferon-γ). In the BALB/c strain, anti-CD40 induced severe physical and biochemical irAEs. Concomitant anti-TNF treatment abrogated weight loss, liver damage and colitis, which consequently resulted in an improved clinical score. However, concomitant anti-TNF impaired antitumor response in a proportion of anti-CD40-treated C57BL/6 FoxP3DTR mice. Delaying TNF blockade in these mice reduced biochemical but not physical irAEs while preserving antitumor efficacy.ConclusionsOur results suggest concomitant rather than delayed anti-TNF is most effective in reducing biochemical and physical irAEs induced by anti-CD40, although it had the potential to negatively impact antitumor efficacy. Furthermore, our findings highlight the utility of our mouse model to assess the severity of irAEs induced by novel immunotherapeutic agents and evaluate whether their toxicity and antitumor efficacy can be uncoupled.

Abstract 839: N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models

2014 ◽  
Author(s):  
Leslie L. Muldoon ◽  
Y. Jeffrey Wu ◽  
Michael A. Pagel ◽  
Kathleen A. Beeson ◽  
Edward A. Neuwelt
Keyword(s):  
Antitumor Efficacy ◽  
Tumor Models ◽  
Pediatric Tumor

scholarly journals Tin thiocarbonohydrazone complexes: synthesis, crystal structures and biological evaluation

2019 ◽  
Vol 8 (6) ◽  
pp. 862-867 ◽  
Author(s):  
Jin Wang ◽  
Yu-Ting Wang ◽  
Yan Fang ◽  
Yan-Li Lu ◽  
Ming-Xue Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Acute Toxicity ◽  
Hepg2 Cells ◽  
Biological Evaluation ◽  
Cytotoxic Potential ◽  
Dependent Effect ◽  
Ic50 Value ◽  
Ld50 Value ◽  
Dose Dependent ◽  
Dose Dependent Effect

Abstract In this article, three organotin complexes formulated as [(Me)2Sn(H2L1)] (1), [(Ph)2Sn(H2L1)]·MeOH (2) and [(Me)2Sn(HL2)(OAc)]4(Me)2O (3) (H4L1 = bis(2-hydroxybenzaldehyde) thiocarbohydrazone and H2L2 = bis(2-acetylpyrazine) thiocarbonohydrazone) have been synthesized and structurally characterized. Growth inhibition assays indicated that both the proligands and the three complexes are capable of showing anticancer activity against the human hepatocellular carcinoma HepG2 cells with H2L2 and complex 3 showing much higher cytotoxic potential. Subsequent toxicity studies on normal QSG7701cells showed that complex 3 has the highest tumor cell selectivity, and its IC50 value on QSG7701 cells is 8.48 fold higher than that in HepG2 cells. In acute toxicity experiments, complex 3 produces a dose-dependent effect in NIH mice with a LD50 value of 17.2 mg kg−1.

PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 1-1 ◽  
Author(s):  
Nicholas John Van As ◽  
Douglas Brand ◽  
Alison Tree ◽  
Peter James Ostler ◽  
William Chu ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Treatment Time ◽  
External Beam Radiotherapy ◽  
Radiation Therapy Oncology Group ◽  
Phase Iii ◽  
Treatment Schedule ◽  
External Beam ◽  
Clinical Failure ◽  
Gu Toxicity ◽  
Conventionally Fractionated

1 Background: External beam radiotherapy (EBRT) is a curative treatment for LPCa. Large randomised controlled trials (RCTs) have shown moderately hypofractionated regimens (2.5–3 Gy/fraction(f)) as non-inferior to conventionally fractionated regimens (2 Gy/f). PACE-B aims to demonstrate non-inferiority of SBRT compared to CFMHRT for biochemical or clinical failure. Compared to CFMHRT, SBRT reduces patient (pt) attendances but compressed overall treatment time may influence acute toxicity severity. Methods: PACE is a phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, ≤ Gleason 3 + 4, PSA ≤ 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible for the PACE-B cohort. Between 08/12-01/18, 874 pts (38 centres) were randomised (1:1) to SBRT or CFMHRT. SBRT dose was 36.25 Gy/5f in 1-2 weeks (wks), CFMHRT as 78 Gy/39f over 7.5 wks, or 62 Gy/20f in 4 wks. Androgen deprivation therapy was not permitted. Clinician reported acute toxicity was assessed at baseline, 2-weekly during CFMHRT and at 2, 4, 8 & 12 wks post-treatment. Key toxicity outcomes were worst grade 2+ Radiation Therapy Oncology Group (RTOG) genitourinary (GU) and gastrointestinal (GI) acute toxicities, compared by Chi-square test with alpha 0.05 divided between the two measures. Results: By per protocol analysis n=430 received CFMHRT, n=414 received SBRT. Key characteristics seen in the CFMHRT and SBRT groups respectively were: mean age: 69.5 vs 69.3 years; T-stage ≥T2b: 51.8% vs 56.6%; Gleason Score 3+4: 80.2% vs 85.0%; PSA 10-20 ng/mL: 30.9% vs 31.6%. RTOG G2+ toxicity was not significantly different for GI events (CMFHRT 52/430 (12.1%) vs SBRT 42/414 (10.1%), p=0.368), nor GU events (CFMHRT 117/430 (27.2%) vs SBRT 96/414 (23.2%), p=0.179). Conclusions: Despite an accelerated treatment schedule, RTOG assessments show similar rates of acute GI and GU toxicity for SBRT and CFHFRT. Pt follow-up in PACE-B continues and results of late toxicity and biochemical/clinical failure are awaited. Clinical trial information: NCT01584258.

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