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Investigational New Drugs

Rafał Krętowski, Danuta Drozdowska, Beata Kolesińska, Zbigniew Kamiński, Justyna Frączyk, Marzanna Cechowska-Pasko
1,3,5-triazine is an important heterocyclic skeleton for mono, two or three 2-chloroethylamine groups. The study presented here provides novel information on cellular effects of 1,3,5-triazine with mono, two or three 2-chloroethylamine groups in glioblastoma LBC3, LN-18 and LN-229 cell lines. In our study, the most cytotoxic effect was observed in 1,3,5-triazine with three 2-chloroethylamine groups (12f compound). It has been demonstrated that 12f induce time- and dose-dependent cytotoxicity in all investigated glioma cell lines...
January 15, 2019: Investigational New Drugs
Philippe Collery, Vijay Veena, Adhikesavan Harikrishnan, Didier Desmaele
The rhenium(I)-diselenoether complex (Re-diSe) is a rhenium tricarbonyl-based drug chelated by a diselenoether ligand. In this work, we compared its inhibitory effects on the hormone-independent MDA-MB231cancer line and other different cancer cell lines after an exposure time of 72 h by MTT assays. The sensitivity of MDA-MB231 was in the same range than the hormone-dependent MCF-7 breast cancer, the PC-3 prostate and HT-29 colon cancer cells, while the A549 lung and the HeLa uterine cancer cells were less sensitive...
January 11, 2019: Investigational New Drugs
Rejitha Suraj, Jasim Al-Rawi, Christopher Bradley
Many compounds structurally similar to chromones have been developed to enhance the sensitizing effect of cancer cells to chemotherapeutic agents. Most of these compounds have been shown to promote this sensitization by targeting the repair pathways. One such compound is LTUR6, which enhances the sensitization of doxorubicin to colon cancer cells HT29, by inhibiting the phosphorylation of the double stranded break (DSB) repair enzyme AKT. The downstream regulatory targets of AKT that enhance doxorubicin mediated cytotoxicity in the presence of LTUR6 remains elusive...
January 10, 2019: Investigational New Drugs
Toshihiko Doi, Takeshi Aramaki, Hirofumi Yasui, Kei Muro, Masafumi Ikeda, Takuji Okusaka, Yoshitaka Inaba, Kenya Nakai, Hiroki Ikezawa, Ryo Nakajima
Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ≥20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escalation; ontuxizumab 2-12 mg/kg weekly) and part 2 (cohort-expansion; 4 or 8 mg/kg weekly, or 12 mg/kg biweekly)...
January 9, 2019: Investigational New Drugs
Tao Lv, Yujie Wang, Dan Ou, Peiyao Liu, Songbing Qin, Lidan Liu, Pengrong Lou, Xiaoshen Wang
Purpose The current standard treatment for locally advanced nasopharyngeal carcinoma (LANPC) is intensity-modulated radiation therapy (IMRT) plus cisplatin concurrent chemoradiotherapy (CCRT). However, this regimen has well-known hematological and gastrointestinal toxicities. Many studies have reported that S-1 was effective in the treatment of multiple solid cancers with mild toxicities. However, knowledge regarding IMRT plus S-1 CCRT in LANPC is lacking. Therefore, we conducted this prospective phase II trial to evaluate the efficacy and safety of this regimen in LANPC...
January 8, 2019: Investigational New Drugs
Titto Augustine, Radhashree Maitra, Jinghang Zhang, Jay Nayak, Sanjay Goel
Intended to explore synthetic lethality and develop better combinatorial regimens, we screened colorectal cancer (CRC) cells using poly ADP-ribose (PAR) polymerase (PARP) inhibitors and cytotoxic agents. We studied four PARP inhibitors and three DNA-damaging agents, and their combinations using sulforhodamine B assay. Rucaparib demonstrated the greatest synergy with irinotecan, followed by olaparib and PJ34. Rucaparib and irinotecan was further subjected to detailed examination to determine combination index (CI) and underlying mechanism of action...
January 5, 2019: Investigational New Drugs
I-Chen Sun
Drug lag, which delays patients' access to medicinal products, is typically associated with pharmaceutical regulations. To shorten drug lag, health authorities may establish new policies to liberalize the regulations, a step that is important in countries, such as Taiwan, with consumer demand for imported novel therapeutic agents. Taiwan's government enacted Articles 38-1 and 38-2 of Regulations for Registration of Medicinal Products to relax the regulatory barriers for new drug submission, thus conditionally exempting the requirement for the Certificate of Pharmaceutical Product (CPP)...
January 5, 2019: Investigational New Drugs
Fenghai Zhou, Fa Zhang, Chuan Zhou, Mengtian Liang, Zhonglin Cai, Haidi Lv, Wenjuan Li, Xupan Wei
The human embryonic lethal abnormal visual protein, HuR, belongs to the Hu family of RNA-binding proteins. Over the past two decades, HuR has been extensively associated with multiple biological characteristics of tumors, including tumor development and progression, angiogenesis, invasion, migration and prognosis, since this protein regulates the stability of cancer-associated target mRNAs due to its posttranscriptional regulatory mechanisms. A recent investigation of the multiple functions of HuR has provided emerging evidence of its role in drug resistance in various tumors...
January 5, 2019: Investigational New Drugs
Ya-Jen Chang, Chung-Li Ho, Kai-Hung Cheng, Wan-I Kuo, Wan-Chi Lee, Keng-Li Lan, Chih-Hsien Chang
Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188 Re achieved better therapeutic effect on lung cancer. Methods188 Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated...
January 5, 2019: Investigational New Drugs
Clinton Yam, Francisco J Esteva, Miral M Patel, Akshara S Raghavendra, Naoto T Ueno, Stacy L Moulder, Kenneth R Hess, Girish S Shroff, Silvia Hodge, Kimberly H Koenig, Mariana Chavez Mac Gregor, Robin L Griner, Sai-Ching J Yeung, Gabriel N Hortobagyi, Vicente Valero
Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer...
January 5, 2019: Investigational New Drugs
Huijun Zhao, Xuhong Zhao, Ting Lei, Man Zhang
Prostate-specific antigen (PSA) has been widely used as the unique serum biomarker for the diagnosis of prostate cancer (PCa). When PSA is moderately increased (e.g., 4-10 ng/ml), it is difficult to differentiate benign prostatic hyperplasia (BPH) from cancer. The diagnostic test (i.e., prostate biopsy) is invasive, adding pain and economic burden to the patient. Urine samples are more convenient, non-invasive and readily available than blood. We sought to determine whether ferritin might be the potential urinary biomarker in prostate cancer diagnosis...
January 4, 2019: Investigational New Drugs
Shaohua Ge, Haiyang Zhang, Ting Deng, Wu Sun, Tao Ning, Qian Fan, Yi Wang, Xinyi Wang, Qiumo Zhang, Zhengyang Zhou, Haiou Yang, Guoguang Ying, Yi Ba
Transforming growth factor-beta (TGF-β) signaling pathway plays pivotal roles in various types of cancer. TGF-β receptor 2 (TGFβR2) contains a kinase domain that phosphorylates and activates the downstream of the TGF-β signaling pathway. Our previous microarray analysis revealed marked changes in miR-181a expression in gastric cancers, and the bioinformatics analysis suggested that miR-181a negatively regulated TGFβR2. In order to verify the effect of miR-181a on TGFβR2 and clarify the influence of miR-181a on the migration and proliferation of gastric cancer, studies in gastric cancer cell lines and xenograft mouse models were carried out...
January 4, 2019: Investigational New Drugs
David C Smith, Rashmi Chugh, Amita Patnaik, Kyriakos P Papadopoulos, Min Wang, Ann M Kapoun, Lu Xu, Jakob Dupont, Robert J Stagg, Anthony Tolcher
Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds and selectively inhibits signaling via both Notch2 and Notch3, in adult patients with advanced malignancies. Methods Standard 3 + 3 design with tarextumab 0.5, 1, 2.5, or 5 mg/kg weekly, or 5, 7.5, or 10 mg/kg every other week, or 7.5 mg every 3 weeks. Dose-limiting toxicities (DLT) were assessed during the first 28 days...
December 28, 2018: Investigational New Drugs
Lisa Seitz, Lixia Jin, Manmohan Leleti, Devika Ashok, Jenna Jeffrey, Aimee Rieger, Renger G Tiessen, Gerhard Arold, Joanne B L Tan, Jay P Powers, Matthew J Walters, Joyson Karakunnel
Adenosine suppresses antitumor immune responses via A2a and A2b receptors expressed on intratumoral immune cells. This effect is mediated by increased cyclic adenosine 5'-monophosphate (AMP) levels and phosphorylation of cyclic AMP response element binding protein (CREB). We conducted a phase 1, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), including food effect (FE), and pharmacodynamics (PD) of oral AB928, a novel dual A2a R/A2b R antagonist, in healthy volunteers...
December 19, 2018: Investigational New Drugs
Theodoros N Teknos, J Grecula, A Agrawal, M O Old, E Ozer, R Carrau, S Kang, J Rocco, D Blakaj, V Diavolitsis, B Kumar, P Kumar, Q Pan, M Palettas, L Wei, R Baiocchi, P Savvides
Purpose Vorinostat is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium. The primary objective of this Phase I study was to determine the maximally tolerated dose (MTD) and safety of Vorinostat in combination with standard chemoradiation therapy treatment in HNSCC. Patients and Methods Eligible patients had pathologically confirmed Stage III, IVa, IVb HNSCC, that was unresectable or borderline resectable involving the larynx, hypopharynx, nasopharynx, and oropharynx...
December 19, 2018: Investigational New Drugs
Mariana Franzoni Maioral, Natália Marceli Stefanes, Álisson Bigolin, Gabriele Andressa Zatelli, Ana Cláudia Philippus, Miriam de Barcellos Falkenberg, Maria Cláudia Santos-Silva
Plants are important sources of biologically active compounds and they provide unlimited opportunities for the discovery and development of new drug leads, including new chemotherapeutics. Miconidin acetate (MA) is a hydroquinone derivative isolated from E. hiemalis. In this study we demonstrated that MA was cytotoxic against acute leukemia (AL), solid tumor cells and cancer stem cells, with the strongest effect exhibited against AL. Furthermore, it was non-cytotoxic against non-tumor cells and did not cause significant hemolysis...
December 19, 2018: Investigational New Drugs
Maurizio Viale, Rita Tosto, Valentina Giglio, Giuseppe Pappalardo, Valentina Oliveri, Irena Maric, Maria Addolorata Mariggiò, Graziella Vecchio
Polymeric cyclodextrin-based nanoparticles are currently undergoing clinical trials as nanotherapeutics. Using a non-covalent approach, we decorated two cross-linked cyclodextrin polymers of different molecular weights with an RGD peptide derivative to construct a novel carrier for the targeted delivery of doxorubicin. RGD is the binding sequence for the integrin receptor family that is highly expressed in tumour tissues. The assembled host-guest systems were investigated using NMR and DLS techniques. We found that, in comparison with free doxorubicin or the binary complex doxorubicin/cyclodextrin polymer, the RGD units decorating the cyclodextrin-based nanosystems improved the selectivity and cytotoxicity of the complexed doxorubicin towards cultured human tumour cell lines...
December 17, 2018: Investigational New Drugs
Alexandra Leary, Christophe Le Tourneau, Andrea Varga, Marie-Paule Sablin, Carlos Gomez-Roca, Nicolas Guilbaud, Aurelie Petain, Mariya Pavlyuk, Jean-Pierre Delord
Purpose To determine the maximum tolerated dose (MTD) of F14512, a topoisomerase II inhibitor designed to target cancer cells through the polyamine transport system, (three-hour daily infusion given for 3 consecutive days every 3 weeks) in platinum-refractory or resistant ovarian cancer. Other objectives were safety, pharmacokinetics (PK), PK/pharmacodynamics relationship, and efficacy. Methods This was an open-label, dose-escalation, multicenter phase I study. Results Eleven patients were enrolled and were treated at dose levels (DLs) of 10 and 5 mg/m2 /day...
December 14, 2018: Investigational New Drugs
Evelien A W Smits, José A Soetekouw, Ebel H E Pieters, Coen J P Smits, Nicolette de Wijs-Rot, Herman Vromans
Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied...
December 13, 2018: Investigational New Drugs
Blair P Curless, Nne E Uko, Diane F Matesic
Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation...
December 13, 2018: Investigational New Drugs
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