Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin’s lymphoma: an in vitro and in vivo study
Summary Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin’s lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective...
Source: Investigational New Drugs - November 18, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies
Conclusions The MTD of this regimen is sorafenib 200 mg twice daily, days 3–6, 10–13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 18, 2015 Category: Drugs & Pharmacology Source Type: research

A phase II trial of ganetespib, a heat shock protein 90 Hsp90) inhibitor, in patients with docetaxel-pretreated metastatic castrate-resistant prostate cancer (CRPC)-a prostate cancer clinical trials consortium (PCCTC) study
Conclusions Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 18, 2015 Category: Drugs & Pharmacology Source Type: research

Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site
Conclusions Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 16, 2015 Category: Drugs & Pharmacology Source Type: research

Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts
We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28 days in response to 0.3 mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy ...
Source: Investigational New Drugs - November 12, 2015 Category: Drugs & Pharmacology Source Type: research

7-formyl-10-methylisoellipticine, a novel ellipticine derivative, induces mitochondrial reactive oxygen species (ROS) and shows anti-leukaemic activity in mice
In this study the anti-leukaemia effect of this compound was investigated in detail on an AML cell line, MV4-11. Over a period of 24 h 7-formyl-10-methyl isoellipticine at a concentration of 5 μM can kill up to 40 % of MV4-11 cells. Our research suggests that the cytotoxicity of 7-formyl-10-methylisoellipticine is partially mediated by an induction of mitochondrial reactive oxygen species (ROS). Furthermore, 7-formyl-10-methylisoellipticine demonstrated promising anti-tumour activity in an AML xenograft mouse model without causing toxicity, implying the potential of isoellipticines as novel chemotherapeut...
Source: Investigational New Drugs - November 12, 2015 Category: Drugs & Pharmacology Source Type: research

First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies
Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 10, 2015 Category: Drugs & Pharmacology Source Type: research

Identification of a novel compound (β-sesquiphellandrene) from turmeric ( Curcuma longa ) with anticancer potential: comparison with curcumin
Summary Considering that as many as 80 % of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, β-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, α-curcumene, ar-turmerone, α-turmerone, β-turmerone, and γ-turmerone, only SQP was foun...
Source: Investigational New Drugs - November 2, 2015 Category: Drugs & Pharmacology Source Type: research

Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients
Summary Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3–4 diarrhea. We performed systematic colonic biopsies in three patients with gr...
Source: Investigational New Drugs - October 22, 2015 Category: Drugs & Pharmacology Source Type: research

Effects of mTOR inhibitors and cytoskeletal-directed agents alone and in combination against normal and neoplastic hematopoietic cells in vitro
Summary The mechanistic target of rapamycin (mTOR) controls cell growth and enlargement and has been found to be aberrant in a wide variety of malignancies. Although mTOR is already an attractive antineoplastic target, overexpression or aberrant expression of mTOR may also provide an opportunity to further increase the size differential between malignant and normal cells, providing an opportunity to amplify and exploit cell size differences between neoplastic cells and their normal counterparts using physiochemical treatment modalities. Therefore, this study sought to quantify the concentration response and time c...
Source: Investigational New Drugs - October 22, 2015 Category: Drugs & Pharmacology Source Type: research

Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation
We report here the case of a heavily pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw impressive efficacy, with a long-term partial response along with CA125 reductions and symptom relief. Although this mutation is present in LGSOC at very a low incidence, we recommend routine testing for BRAF and other targetable mutations in this patient population, along with further evaluation in the increasingly popular basket trial approach. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 21, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors
Discussion The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 21, 2015 Category: Drugs & Pharmacology Source Type: research

Liver function assessment according to the Albumin–Bilirubin (ALBI) grade in sorafenib-treated patients with advanced hepatocellular carcinoma
Conclusion: Sorafenib may be indicated for all patients with advanced HCC and ALBI grade 1 and for some with ALBI grade 2. The subdivision of patients with ALBI grade 2 increases the utility of ALBI in identifying patients indicated for sorafenib therapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 14, 2015 Category: Drugs & Pharmacology Source Type: research

A phase II study evaluating axitinib in patients with unresectable, recurrent or metastatic head and neck cancer
Conclusion Treatment with single agent axitinib should be considered due to acceptable toxicity profile and favorable median overall survival compared to standard therapies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 10, 2015 Category: Drugs & Pharmacology Source Type: research

Fibrin gels loaded with cisplatin and cisplatin-hyaluronate complexes tested in a subcutaneous human melanoma model
Summary Fibrin gels are attractive biomaterials for local delivery of a variety of agents, from drugs to proteins. Similarly, polymer-anticancer-drug conjugates and nanoparticles are emerging as potential candidates for cancer treatment. Combining these different approaches, we have studied the efficacy of fibrin gels loaded with cisplatin (DDP) and a complex of DDP with hyaluronate (DDP-HA) for tumor growth inhibition in a melanoma model. Loaded gels prepared at relatively high fibrinogen concentration (22 mg/ml) showed good in vitro antiproliferative activities, prolonged release of the anticancer drug, and...
Source: Investigational New Drugs - October 7, 2015 Category: Drugs & Pharmacology Source Type: research

Histone deacetylase inhibitors and epigenetic regulation in lymphoid malignancies
Abstract A vast majority of lymphomas and leukaemias are results of translocations. These translocations produce various genetic and epigenetic changes that lead to oncogenesis. This opens an opportunity to use a relatively new class of anti-cancer agents, inhibitors of histone deacetylases (HDACi) to target lymphoid malignancies. Surprisingly, the rational basis for treatment of lymphomas with HDACi is far from clear, although some positive results have been obtained. Here we analyze the effect of histone deacetylase (HDAC) inhibitors on lymphoid malignancies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 30, 2015 Category: Drugs & Pharmacology Source Type: research

Erratum to: A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors
(Source: Investigational New Drugs)
Source: Investigational New Drugs - September 26, 2015 Category: Drugs & Pharmacology Source Type: research

Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients
Conclusion Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 19, 2015 Category: Drugs & Pharmacology Source Type: research

Blinatumomab for the treatment of acute lymphoblastic leukemia
Discussion and conclusions Blinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline setting and in combination with chemotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 17, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral gemcitabine prodrug, in patients with advanced solid tumors
Conclusions Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 16, 2015 Category: Drugs & Pharmacology Source Type: research

Phase 1 dose de-escalation trial of the endogenous folate [6R]-5,10-methylene tetrahydrofolate in combination with fixed-dose pemetrexed as neoadjuvant therapy in patients with resectable rectal cancer
Conclusions The results of this phase 1 study indicate that the estimated minimum tolerated dose of [6R]-MTHF was 100 mg/m2 once weekly in combination with pemetrexed 500 mg/m2. The low toxicity profile of [6R]-MTHF supports its further evaluation as a component of systemic chemotherapy in the management of colon and rectal cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

Evaluation of cytotoxic activity of titanocene difluorides and determination of their mechanism of action in ovarian cancer cells
Conclusion We anticipate that the presence of substituents on cyclopentadienyl ring(s) might play an important role in modulation of the activity of particular compounds. Titanocene difluorides exert comparable cytotoxic activity as cisplatin and are more efficient in cisplatin-resistant cell lines. Our results suggest potential utilization of these compounds especially in the treatment of cisplatin-resistant tumor cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

Topotecan plus cyclophosphamide in adults with relapsed or refractory pediatric-type sarcoma: a retrospective analysis from the German Sarcoma Medical Oncology Group (AIO)
Conclusions Limited activity was seen in adult pts with refractory or relapsed pediatric-type sarcomas with the regimen which has proven activity in pediatric patients. Adults with refractory small cell sarcoma appear to have a similar dismal outcome as seen in pts with common adult-type histologies; however, a subset of patients has achieved long-lasting remissions on TC resulting in long-term survival. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer
Conclusion The RD was determined to be 50 mg/m2/day of TAS-102 combined with 150 mg/m2 of irinotecan although further investigation to explore optimal regimen is warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 15, 2015 Category: Drugs & Pharmacology Source Type: research

A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort
Summary JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the ...
Source: Investigational New Drugs - September 14, 2015 Category: Drugs & Pharmacology Source Type: research

Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement–positive non–small cell lung cancer treated with alectinib
We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was th...
Source: Investigational New Drugs - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors
Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 4, 2015 Category: Drugs & Pharmacology Source Type: research

Long term exposure to antiangiogenic therapy, bevacizumab, induces osteonecrosis
Conclusions With an incidence of 4 out of 1000 patients osteonecrosis is a rare side effect of anti-angiogenic agent. With the increasing utilisation and duration of exposure of anti-VEGF therapy some rare side effect due to chronic ischemia may appear. The clinician should be aware about uncommon symptoms. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 27, 2015 Category: Drugs & Pharmacology Source Type: research

BRAF-mutated clear cell sarcoma is sensitive to vemurafenib treatment
We report a patient with a metastatic relapse of clear cell sarcoma, whose tumor harbored BRAF V600E mutation. Standard chemotherapy with doxorubicin and ifosfamide failed to slow the disease progression. Subsequent administration of vemurafenib (960 mg twice a day) resulted in complete tumor response after 8 weeks of treatment. Literature data on the use of vemurafenib and dabrafenib in non-melanoma BRAF-mutated tumors are reviewed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 19, 2015 Category: Drugs & Pharmacology Source Type: research

Ulcerative colitis in a patient with non-small-cell lung cancer receiving bevacizumab
Summary Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, is anticipated to prolong survival with inhibition of angiogenesis in patients with non-small-cell lung cancer. Rare life-threatening adverse events affecting the digestive tract have been reported, such as gastrointestinal hemorrhage and bowel perforation. A 62-year-old Japanese woman who was diagnosed as having stage IIIB (cT4N2M0) lung adenocarcinoma received chemotherapy with bevacizumab, pemetrexed and carboplatin every 3 weeks for four cycles, which resulted in a partial response, and then continued with mai...
Source: Investigational New Drugs - August 17, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies
This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies. Methods This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the c...
Source: Investigational New Drugs - August 15, 2015 Category: Drugs & Pharmacology Source Type: research

Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta
Conclusion These results suggest that CQ, alone or as an adjuvant therapeutic, could be used to inhibit the GBM malignant phenotype and could benefit GBM afflicted patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 14, 2015 Category: Drugs & Pharmacology Source Type: research

Subcellular localization of anthracyclines in cultured rat cardiomyoblasts as possible predictors of cardiotoxicity
In this study, we compared the cellular uptake, intracellular localization and cytotoxicity of two groups of anthracycline derivatives in cultured H9c2(2-1) rat cardiomyoblasts. The first group consisted of doxorubicin (DOX) and two of its derivatives containing a formamidino group (–N = CH–N
Source: Investigational New Drugs - August 14, 2015 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors
Conclusion APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m2 was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 14, 2015 Category: Drugs & Pharmacology Source Type: research

A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors
Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.) (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 11, 2015 Category: Drugs & Pharmacology Source Type: research

In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis
Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 5, 2015 Category: Drugs & Pharmacology Source Type: research

Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver
Conclusions HAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 5, 2015 Category: Drugs & Pharmacology Source Type: research

Generation and tumor recognition properties of two human monoclonal antibodies specific to cell surface anionic phospholipids
Summary Phosphatidylserine (PS) and other anionic phospholipids, which become exposed on the surface of proliferating endothelial cells, tumor cells and certain leukocytes, have been used as targets for the development of clinical-stage biopharmaceuticals. One of these products (bavituximab) is currently being investigated in Phase 3 clinical trials. There are conflicting reports on the ability of bavituximab and other antibodies to recognize PS directly or through beta-2 glycoprotein 1, a serum protein that is not highly conserved across species. Here, we report on the generation and characterization of two full...
Source: Investigational New Drugs - July 5, 2015 Category: Drugs & Pharmacology Source Type: research

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195
Summary Background SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. Methods Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating...
Source: Investigational New Drugs - July 5, 2015 Category: Drugs & Pharmacology Source Type: research

Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer
Conclusion This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 1, 2015 Category: Drugs & Pharmacology Source Type: research

P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib
Conclusion Thus, the brain penetration of palbociclib is restricted by P-gp and BCRP, which may restrict the efficacy against GBM and DIPG. Moreover, preclinical studies with this agent should be conducted at a more clinically relevant dose level. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 30, 2015 Category: Drugs & Pharmacology Source Type: research

Differential nucleobase protection against 5-fluorouracil toxicity for squamous and columnar cells: implication for tissue function and oncogenesis
Conclusion The directed application of the normal nucleobase uracil to the squamous cells of the oral mucosa and palms and soles together with the delivery of the normal nucleobase adenine to the columnar cells of the GI tract may enable the safe delivery of higher 5FU dose intensity. These results also suggest a feature of tissue function where squamous cells grow largely by recycling overlying tissue cell components. Columnar cells use absorbed surface nutrients for de novo growth. A disruption of this tissue function can result in growth derived from an underlying nutrient source. That change would also cause the l...
Source: Investigational New Drugs - June 30, 2015 Category: Drugs & Pharmacology Source Type: research

Cytotoxicity of anthraquinones from the roots of Pentas schimperi towards multi-factorial drug-resistant cancer cells
Conclusions Anthraquinones from Pentas schimperi and mostly 1 and 2 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug resistant cancers. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 27, 2015 Category: Drugs & Pharmacology Source Type: research

Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer
Summary Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxi...
Source: Investigational New Drugs - June 25, 2015 Category: Drugs & Pharmacology Source Type: research

Targeting the plasma membrane of neoplastic cells through alkylation: a novel approach to cancer chemotherapy
Conclusion Despite these compelling data, preliminary clinical trials for plasma membrane-directed agents have yet to be considered. Therefore, this review is intended for academics and clinicians to postulate a novel approach of chemotherapy; altering critical malignant cell signaling at the plasma membrane surface through alkylation, thereby inducing irreversible changes to functions needed for cell survival. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 23, 2015 Category: Drugs & Pharmacology Source Type: research

Three-dimensional and co-culture models for preclinical evaluation of metal-based anticancer drugs
Conclusion Taken together, our results demonstrate the advantages of spheroid-based assays and underline the necessity of using different experimental models for reliable preclinical investigations assessing and better predicting the anticancer potential of new compounds. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 21, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors
Conclusions The combination of ridaforolimus and vorinostat was tolerable at the recommended phase II dose. Two patients with papillary RCC experienced prolonged disease stabilization, thus further study of combined HDAC and mTOR inhibition in this population is warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 20, 2015 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose
Conclusion The MTD/RP2D of alisertib in East Asian patients (30 mg BID) was lower than in Western patients (50 mg BID), consistent with higher systemic exposures in the East Asian population. Alisertib was generally well tolerated and showed signs of antitumor activity in East Asian cancer patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 19, 2015 Category: Drugs & Pharmacology Source Type: research

Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079)
Conclusion The study was terminated due to the limited activity observed in this heavily pre-treated group of patients. Further studies are needed to elucidate the optimal way of selecting patients for AKT inhibitors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 19, 2015 Category: Drugs & Pharmacology Source Type: research

Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors
This study followed an accelerated titration design with a starting dose of 20 mg/m2/dose and a standard 3 + 3 dose escalation design for dose level 4 (120 mg/m2/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m2/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with d...
Source: Investigational New Drugs - June 18, 2015 Category: Drugs & Pharmacology Source Type: research