Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma
Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 25, 2019 Category: Drugs & Pharmacology Source Type: research

Naked antisense double-stranded DNA oligonucleotide efficiently suppresses BCR-ABL positive leukemic cells
In conclusion, ADO technology is an attractive method for therapeutic application. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2019 Category: Drugs & Pharmacology Source Type: research

Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach
SummaryEpithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 orBRCA2) mutation carriers. Apart from inducing synthetic ...
Source: Investigational New Drugs - October 24, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical efficacy and safety of apatinib combined with S-1 in advanced esophageal squamous cell carcinoma
Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2019 Category: Drugs & Pharmacology Source Type: research

Prolonged response to 177 Lu-DOTATATE therapy of a bone marrow infiltration in a refractory thymic neuro endocrine tumor
This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2)
Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1 –5). (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 21, 2019 Category: Drugs & Pharmacology Source Type: research

Phase II study of apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, as second-line treatment for recurrent or advanced cervical cancer patients
This study was designed to evaluate the efficacy and safety of apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, as second-line treatment in recurrent or advanced cervical cancer patients. Twenty patients who failed cisplatin/paclitaxel ± bevacizumab treatment received a 4-week cycle of apatinib, with a daily dosage of 500 mg or 250 mg. The follow-up period ranged from 5.9 to 21.3 months (median, 14.0 months). None of the patients achieved a complete response (CR). Nevertheless, a partial response (PR), stable disease (SD) an d progressive disease (PD) were observed i...
Source: Investigational New Drugs - October 21, 2019 Category: Drugs & Pharmacology Source Type: research

Impact of l -carnitine on imatinib-related muscle cramps in patients with gastrointestinal stromal tumor
This study aims to assess the impact ofl-carnitine on relieving cramps in patients with GIST taking imatinib.Materials and methods We reviewed our prospective database for patients with GIST who tookl-carnitine (500-mg tablet, 2 –3 times daily) for muscle cramps in Asan Medical Center. The assessment tool included severity by the numeric rating scale (NRS), frequency, duration of cramps, and questionnaire for the disturbance in basic activities of daily living (ADL), instrumental ADL (iADL), outdoor activity, or sleeping before and afterl-carnitine treatment.Results We examined 42 patients [median age: 60 (range: 17 ...
Source: Investigational New Drugs - October 18, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery and evaluation of Atopaxar hydrobromide, a novel JAK1 and JAK2 inhibitor, selectively induces apoptosis of cancer cells with constitutively activated STAT3
In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 14, 2019 Category: Drugs & Pharmacology Source Type: research

Mass balance and metabolite profiling of 14 C-guadecitabine in patients with advanced cancer
Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 11, 2019 Category: Drugs & Pharmacology Source Type: research

The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling
SummaryNon-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit...
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

A mediator of phosphorylated Smad2/3, evodiamine, in the reversion of TAF-induced EMT in normal colonic epithelial cells
Conclusion Based on our observations, evodiamine can reverse the TAF-induced EMT-like phenotype in colon epithelial cells, which may be associated with its mediation of phosphorylated Smad2 and Smad3 expression. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

The drug lag and associated factors for orphan anticancer drugs in Japan compared to the United States
SummaryThe approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orpha...
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma
SummaryCancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo phar...
Source: Investigational New Drugs - September 6, 2019 Category: Drugs & Pharmacology Source Type: research

Osimertinib in a patient with non-small cell lung cancer and renal failure undergoing hemodialysis: a case report
SummaryOsimertinib is a key drug for cancer patients withEGFR mutations. However, there is little information about its safety in cancer patients who require hemodialysis (HD) for chronic renal failure, despite notable increases in their numbers. Herein, we examined osimertinib safety in such a patient via pharmacokinetics analysis. A 66-year-old man was diagnosed with relapsed stage IV non-small cell lung cancer with anEGFR mutation in exon 21 (L858R) 2  years after stereotactic body radiotherapy. He was undergoing HD three times a week owing to worsening diabetic nephropathy. We administered osimertinib (80 mg/...
Source: Investigational New Drugs - September 5, 2019 Category: Drugs & Pharmacology Source Type: research

Radiosensitizing effects of trabectedin on human A549 lung cancer cells and HT-29 colon cancer cells
Conclusion The results of this study underline the antitumor activity of trabectedin at low nanomolar concentrations. We demonstrated that trabectedin enhanced radiation response in human lung (A549) cancer cells and colon (HT-29) cancer cells. Further studies are necessary to examine trabectedin as a potential candidate for future applications in radiotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 3, 2019 Category: Drugs & Pharmacology Source Type: research

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors
Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 30, 2019 Category: Drugs & Pharmacology Source Type: research

The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma
In this study, we found that the mTORC1 pathway was hyperactive in RCC. Immunohistochemistry and western blot analysis showed that phosphorylation of the mTORC1 substrate 4EBP1 at threonine 37/46 increased in RCC tissues compared with that in normal renal tissues. It was also found that mTORC1 inhibitor everolimus suppressed glucose consumption, lactate production, and multiple catalytic enzymes involved in glycolysis in 786-O and ACHN cells, but the accumulation of HIF1 α induced by CoCl2 blocked the inhibitory effect of everolimus on aerobic glycolysis. Interestingly, western blot and metabolite analysis showed tha...
Source: Investigational New Drugs - August 28, 2019 Category: Drugs & Pharmacology Source Type: research

Effects of salinomycin and niclosamide on small cell lung cancer and small cell lung cancer circulating tumor cell lines
In conclusion, the SCLC CTCs established from patients with relapsed disease lack a typical CSC phenotype in respect to chemosensitivity to CSC-selective drugs, surface markers, expression of pluripotent stem cell and transcription factors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 24, 2019 Category: Drugs & Pharmacology Source Type: research

Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours
Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highly expressed in ACC patients, and STMN1 silencing reduces the clonogenicity and migration of ACC cell lines. However, the prognostic significance of STMN1 and its therapeutic potential remain undefined in ACC. In the present study,STMN1 mRNA levels were significantly higher (p 
Source: Investigational New Drugs - August 22, 2019 Category: Drugs & Pharmacology Source Type: research

Benzothiazole derivative bearing amide moiety induces p53-mediated apoptosis in HPV16 positive cervical cancer cells
SummaryIn our previous study, we screened the anti-cancer properties of 10 benzothiazole derivatives in cervical cancer cell lines. In the present study, we aimed to delineate the mechanism of the apoptotic pathway (whether intrinsic or extrinsic) following the treatment of N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-chloro-2-methoxybenzamide (named as A-07) on cervical cancer cell lines. Cellular stress by reactive oxygen species was measured using DCFDA dye by flowcytometry. Protein expression and localization was checked by immunofluorescence for γH2A.X, TP53, and CASP-3. Expression profiles of BAX and BCL-2 was done by ...
Source: Investigational New Drugs - August 20, 2019 Category: Drugs & Pharmacology Source Type: research

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy
SummaryPurpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer.Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5  g/day for 14 days (Group A,N = 20) or not (Group B,N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and apr...
Source: Investigational New Drugs - August 19, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of enfortumab vedotin in Japanese patients with locally advanced or metastatic urothelial carcinoma
SummaryLocally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody –drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible f or cisplatin, were randomized 1:1 t...
Source: Investigational New Drugs - August 14, 2019 Category: Drugs & Pharmacology Source Type: research

Identification of HGF as a novel target of miR-15a/16/195 in gastric cancer
Conclusions miR-15a/16/195 suppresses tumorigenesis by targeting HGF and may have a potential therapeutic application in the clinical treatment of GC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 14, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug
SummaryGlioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS). Effective treatments remain limited. Therefore, novel chemotherapy drugs with high efficiency and few adverse effects are urgently needed. Histone deacetylase (HDAC) and serum and glucocorticoid-regulated protein kinase 1 (SGK1) are targets for the prevention and treatment of GBM. Rhein has antitumor and SGK1 suppression effects, although its biological activity is limited by poor bioavailability. To improve the drug-like properties of rhein, we constructed a novel rhein-hydroxyethyl hydroxamic acid derivative (SYSU...
Source: Investigational New Drugs - August 14, 2019 Category: Drugs & Pharmacology Source Type: research

Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors
Conclusion These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 11, 2019 Category: Drugs & Pharmacology Source Type: research

A randomized phase 2 trial of apatinib vs observation as maintenance treatment following first ­line induction chemotherapy in extensive­ stage small cell lung cancer
Conclusion Apatinib combination/maintenance therapy showed promising efficacy and safety to extend OS/PFS in ED-SCLC and will be a potent therapeutic option in future practice. Although the scale of this study is small, further research on large sample sizes is needed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 9, 2019 Category: Drugs & Pharmacology Source Type: research

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001)
SummaryObjectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients.Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monot...
Source: Investigational New Drugs - August 7, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Inhibitory effects of tea polyphenols by targeting cyclooxygenase-2 through regulation of nuclear factor kappa B, Akt and p53 in rat mammary tumors
The authors regret to inform that there were unknowing errors in figures. The corrected images are given below. These figures are not affecting the results and conclusion of the manuscript. Hence, the text in original paper remains unchanged. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 7, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors
Conclusion The combination of AT-101 at 40  mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 6, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the anti-endothelin B receptor antibody-drug conjugate DEDN6526A in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma
Conclusion DEDN6526A administered at the RP2D of 2.4  mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. ClinicalTrials.gov identifier: NCT01522664. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 5, 2019 Category: Drugs & Pharmacology Source Type: research

Efficacy of immune checkpoint blockade in MUTYH -associated hereditary colorectal cancer
SummaryColorectal carcinomas (CRCs) caused by hereditary biallelicMUTYH gene mutations are characterized by elevated mutation load and high lymphocyte infiltration. Given that these tumor features are associated with the response to immune checkpoint inhibitors, we administered nivolumab to a CRC patient who carried two inactiveMUTYH alleles (p.Y179C and p.G396D) and previously experienced failure of chemotherapy. This experimental treatment resulted in a pronounced tumor response. We further compared tumor lymphocyte infiltration inMUTYH-associated (n = 3), high-level microsatellite instability (MSI-H,n&thin...
Source: Investigational New Drugs - August 3, 2019 Category: Drugs & Pharmacology Source Type: research

Ibrutinib as a potential therapeutic option for HER2 overexpressing breast cancer – the role of STAT3 and p21
In this study, we have performed a kinome array analysis of ibrutinib treatment in two HER2 overexpressing breast ca ncer cell lines. Our analysis shows that ibrutinib induces changes in nuclear morphology and causes apoptosis via caspase-dependent extrinsic apoptosis pathway with the activation of caspases-8, caspase-3, and cleavage of PARP1. We further show that phosphorylated STAT3Y705 is upregulated and phosphorylated p21T145 is downregulated upon ibrutinib treatment. We propose that STAT3 upregulation is a passive response as a result of induction of DNA damage and downregulation of phosphorylated p21 is promoting cel...
Source: Investigational New Drugs - August 2, 2019 Category: Drugs & Pharmacology Source Type: research

E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases
SummaryMalignant melanoma (MM) exhibits a high propensity for central nervous system dissemination with ~50% of metastatic MM patients developing brain metastases (BM). Targeted therapies and immune checkpoint inhibitors have improved overall survival for MM patients with BM. However, responses are usually of short duration and new agents that effectively penetrate the blood brain barrier (BBB) are needed. Here, we report a MM patient with BM who experienced an exceptional response to E6201, an ATP-competitive MEK1 inhibitor, on a Phase 1 study, with ongoing near-complete response and overall survival extending beyond 8 &n...
Source: Investigational New Drugs - July 13, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors
Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 13, 2019 Category: Drugs & Pharmacology Source Type: research

Phase 1b study of a small molecule antagonist of human chemokine (C-C motif) receptor 2 (PF-04136309) in combination with nab-paclitaxel/gemcitabine in first-line treatment of metastatic pancreatic ductal adenocarcinoma
Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine.ClinicalTrials.gov identifier: NCT02732938. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 12, 2019 Category: Drugs & Pharmacology Source Type: research

Dirty deeds done dirt cheap: sensitization of prostate cancer cells to abiraterone treatment using hydroxylated polychlorinated biphenyls
SummaryEffective targeting of androgen biosynthesis by the 17 α-hydroxylase/17,20-lyase inhibitor abiraterone prolongs survival in a variety of prostate cancer patients. However, resistance to abiraterone treatment occurs frequently and the development of new drugs supporting or complementing abiraterone therapy is urgently needed. We recently reported antipr oliferative and proapoptotic effects of hydroxylated polychlorinated biphenyls (PCBs) on various blood cell lines in vitro. Here we report the biological evaluation of the PCB28 derived OH-metabolites 3-OHCB28 or 3′-OHCB28 in prostate cancer cells. Dependi...
Source: Investigational New Drugs - July 11, 2019 Category: Drugs & Pharmacology Source Type: research

TS-1 add-on therapy in Japanese patients with triple-negative breast cancer after neoadjuvant or adjuvant chemotherapy: a feasibility study
Conclusions The 365-day cumulative rate of TS-1 administration in TNBC patients was comparable to that in gastric cancer patients despite previous chemotherapy with anthracyclines and/or taxanes. TAT was feasible for TNBC patients after standard primary therapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 10, 2019 Category: Drugs & Pharmacology Source Type: research

Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2 V617F cells
In conclusion, ruxolitinib induces autophagy in JAK2V617F cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2V617F-mutated MPNs. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 8, 2019 Category: Drugs & Pharmacology Source Type: research

Design, synthesis, and biological activity of TLR7-based compounds for chemotherapy-induced alopecia
SummaryHair loss is a common dermatosis symptom and side-effect in cancer chemotherapeutics. Imiquimod application at mid and late telogen activated the hair follicle stem cells leading to premature hair cycle entry. Based on quinoline structure, a newly synthesized compound 6b displayed proliferation activity in vitro and in vivo through branch chain replacement and triazole ring cyclization. Toll-like receptors (TLRs) are also critical mediators of the immune system, and their activation is linked to various diseases. The present study aimed to expand new agonists within co-crystallization of TLR7 (PDB code: 5GMH); howev...
Source: Investigational New Drugs - July 4, 2019 Category: Drugs & Pharmacology Source Type: research

T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting
In conclusion, B7-H3Bi-Ab enhances the ability of T cells to kill hematologic tumor cells, and B7-H3 may serve as a novel target for immunotherapy against hematologic malignancy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

LncRNA differentiation antagonizing non-protein coding RNA promotes proliferation and invasion through regulating miR-135a/NLRP37 axis in pancreatic cancer
Conclusion DANCR promoted proliferation and invasion through the regulating of miR-135a / NLRP3 axis in pancreatic cancer cell. Our results suggest that DANCR may be a potential target for the therapy of pancreatic cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction
SummaryThe bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no s...
Source: Investigational New Drugs - July 3, 2019 Category: Drugs & Pharmacology Source Type: research

In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101
SummaryOsteosarcoma (OS) is the most common primary malignant bone tumor and mainly affects children and adolescents. The OS five-year survival rate remains very low. Thus, novel therapeutic protocols for the treatment of OS are needed. Several approaches targeting deregulated signaling pathways have been proposed. The antitumoral effects of polyphenols, which are naturally occurring compounds with potent antioxidant and anti-inflammatory activity, have been investigated in different tumors. Gossypol, which is a natural polyphenolic aldehyde isolated from the seeds of the cotton plant, has been shown to exert antitumoral a...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Retrospective comparison of nab-paclitaxel plus ramucirumab and paclitaxel plus ramucirumab as second-line treatment for advanced gastric cancer focusing on peritoneal metastasis
Conclusion This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Xanthan gum-based hydrogel containing nanocapsules for cutaneous diphenyl diselenide delivery in melanoma therapy
SummaryThe aim of this study was to further evaluate the antitumoral effect of (PhSe)2-loaded polymeric nanocapsules (NC (PhSe)2) against a resistant melanoma cell line (SK-Mel-103) and develop a xanthan gum-based hydrogel intending the NC (PhSe)2 cutaneous application. For the in vitro evaluation, cells were incubated with free (PhSe)2 or NC (PhSe)2 (0.7 –200 μM) and after 48 h the MTT assay, propidium iodide uptake (necrosis marker) and nitrite levels were assessed. The hydrogels were developed by thickening of the NC (PhSe)2 suspension or (PhSe)2 solution with xanthan gum and characterized in terms of...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Dual functionality of the antimicrobial agent taurolidine which demonstrates effective anti-tumor properties in pediatric neuroblastoma
SummaryHigh-risk, relapsed and refractory neuroblastoma are associated with poor 5-years survival rates, demonstrating the need for investigational therapeutic agents to treat this disease. Taurolidine is derived from the aminosulfoacid taurine and has known anti-microbial and anti-inflammatory properties. Taurolidine has also demonstrated anti-neoplastic effects in a range of cancers, providing the rationale to investigate the activity of taurolidine against neuroblastoma in preclinical studies. We investigated the in vitro activity of taurolidine against neuroblastoma using the alamar blue cytotoxicity assay, phase-contr...
Source: Investigational New Drugs - July 2, 2019 Category: Drugs & Pharmacology Source Type: research

Targeting ROS overgeneration by N-benzyl-2-nitro-1-imidazole-acetamide as a potential therapeutic reposition approach for cancer therapy
Conclusion The current findings indicate that BZN acts as a tumor growth inhibitor and anti-angiogenic agent by ROS overgeneration, which interact with DNA causing damage and triggering apoptosis. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 1, 2019 Category: Drugs & Pharmacology Source Type: research

Vitamin K 3 thio-derivative: a novel specific apoptotic inducer in the doxorubicin-sensitive and -resistant cancer cells
In conclusion, the synthetic vitamin K3 thio-derivative (VKT-1) inhibited doxorubicin-sensitive and -resistant tumor cells by cell arrest, apoptosis induction, as well as, migration inhibition, and microtubule deterioration of U2OS-GFP- α-tubulin cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 29, 2019 Category: Drugs & Pharmacology Source Type: research

Evaluation of absorption, distribution, metabolism, and excretion of [ 14 C]-rucaparib, a poly(ADP-ribose) polymerase inhibitor, in patients with advanced solid tumors
SummaryRucaparib, a poly(ADP-ribose) polymerase inhibitor, is licensed for use in recurrent ovarian, fallopian tube, or primary peritoneal cancer. We characterized the absorption, distribution, metabolism, and elimination of rucaparib in 6 patients with advanced solid tumors following a single oral dose of [14C]-rucaparib 600  mg (≈140 μCi). Total radioactivity (TRA) in blood, plasma, urine, and feces was measured using liquid scintillation counting. Unchanged rucaparib concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry. Maximum concentration (Cma...
Source: Investigational New Drugs - June 27, 2019 Category: Drugs & Pharmacology Source Type: research