PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (517)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
more »
1.  TARGETED THERAPY IN CANCER 
Cancer chemotherapy and pharmacology  2015;76(6):1113-1132.
Purpose
To describe the emergence of targeted therapies that have led to significant breakthroughs in cancer therapy and completed or ongoing clinical trials of novel agents for the treatment of patients with advanced cancer.
Methods
The literature was systematically reviewed, based on clinical experience and the use of technologies that improved our understanding of carcinogenesis.
Results
Genomics and model systems have enabled the validation of novel therapeutic strategies. Tumor molecular profiling has enabled the reclassification of cancer, and elucidated some mechanisms of disease progression or resistance to treatment, the heterogeneity between primary and metastatic tumors, and the dynamic changes of tumor molecular profiling over time. Despite the notable technologic advances, there is a gap between the plethora of preclinical data and the lack of effective therapies, which is attributed to suboptimal drug development for “driver” alterations of human cancer, the high cost of clinical trials and available drugs, and limited access of patients to clinical trials. Bioinformatic analyses of complex data to characterize tumor biology, function, and the dynamic tumor changes in time and space may improve cancer diagnosis. The application of discoveries in cancer biology in clinic holds the promise to improve the clinical outcomes in a large scale of patients with cancer. Increased harmonization between discoveries, policies, and practices will expedite the development of anticancer drugs and will accelerate the implementation of precision medicine.
Conclusions
Combinations of targeted, immunomodulating, antiangiogenic, or chemotherapeutic agents are in clinical development. Innovative adaptive study design is used to expedite effective drug development.
doi:10.1007/s00280-015-2861-1
PMCID: PMC4998041  PMID: 26391154
Targeted therapy; Molecular alterations; Bioinformatics; Precision medicine; Big data analysis
2.  Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy 
Cancer chemotherapy and pharmacology  2015;76(6):1297-1307.
Purpose
Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One model for the mechanism of anthracycline induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant cardioprotective schemes.
Methods
Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted and effects on cell death were assessed.
Results
Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity.
Conclusions
Our findings point towards revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.
doi:10.1007/s00280-015-2879-4
PMCID: PMC4651800  PMID: 26515054
Anthracyclines; cardiotoxicity; oxidative stress; cell death
3.  Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 
Cancer Chemotherapy and Pharmacology  2016;78(6):1269-1281.
Purpose
Tumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.
Methods
In vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.
Results
The combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.
Conclusion
These studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-016-3186-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-016-3186-4
PMCID: PMC5114336  PMID: 27837257
PI3K; MEK; Combination; Synergy; Colorectal cancer
4.  Pharmcodynamics (PD) and Pharmacokinetics (PK) of E7389 (Eribulin, Halichondrin B Analog) During a Phase I Trial in Patients with Advanced Solid Tumors: A California Cancer Consortium Trial 
Background
The California Cancer Consortium completed a Phase I trial of E7389 (eribulin mesylate), an analog of the marine natural product halichondrin B. This trial was to determine the pharmacodynamics, pharmacokinetics, and MTD of E7389 administered by bolus injection weekly for three weeks out of four.
Methods
This trial included a rapid titration design. Real-time pharmacokinetics were utilized to guide dose escalation. Initially, single patient cohorts were enrolled with intra- and inter-patient dose-doubling. The second phase was a standard 3 + 3 dose escalation schedule. At the MTD, a cohort of patients was enrolled for target validation studies (separate manuscript). The starting dose was 0.125 mg/m2, and doses were doubled within and between patients in the first phase. Blood and urine sampling for E7389 pharmacokinetics was performed on doses 1 and 3 of cycle 1. Levels were determined using a LC/MS/MS assay.
Results
40 patients were entered. Thirty-eight were evaluable for toxicity, thirty-five for response. The rapid escalation ended with a grade 3 elevation of alkaline phosphatase at 0.5 mg/m2/wk. The second phase ended at 2.0 mg/m2/wk with dose-limiting toxicities of grade 3 and 4 febrile neutropenia. Other toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/wk. Responses included 4 partial responses, (lung cancer [2], urothelial [1], and melanoma [1]).
Conclusions
E7389 was well-tolerated in this trial with the major toxicity being myelosuppression. PD shows that E7389 induces significant morphologic changes (bundle formation) in the microtubules of peripheral blood mononuclear cells and tumor cells in vivo. The data suggest that lower intra-tumoral levels of β-tubulin III or higher intra-tumoral levels of MAP4 may correlate with response to E7389, while lower intra-tumoral levels of stathmin may be associated with progression. PK data reveals that E7389 exhibits a tri-exponential elimination from the plasma of patients receiving a rapid i.v. infusion. At sub-toxic doses, plasma concentrations of E7389 are maintained well above the levels required for activity in vitro for > 72 hours.
doi:10.1007/s00280-015-2868-7
PMCID: PMC4694049  PMID: 26362045
5.  A phase I pharmacokinetic and safety study of cabazitaxel in adult cancer patients with normal and impaired renal function 
Cancer Chemotherapy and Pharmacology  2016;78(6):1185-1197.
Purpose
Limited data are available on cabazitaxel pharmacokinetics in patients with renal impairment. This open-label, multicenter study assessed cabazitaxel in patients with advanced solid tumors and normal or impaired renal function.
Methods
Cohorts A (normal renal function: creatinine clearance [CrCL] >80 mL/min/1.73 m2), B (moderate renal impairment: CrCL 30 to <50 mL/min/1.73 m2) and C (severe impairment: CrCL <30 mL/min/1.73 m2) received cabazitaxel 25 mg/m2 (A, B) or 20 mg/m2 (C, could be escalated to 25 mg/m2), once every 3 weeks. Pharmacokinetic parameters and cabazitaxel unbound fraction (F U) were assessed using linear regression and mixed models. Geometric mean (GM) and GM ratios (GMRs) were determined using mean CrCL intervals (moderate and severe renal impairment: 40 and 15 mL/min/1.73 m2) versus a control (90 mL/min/1.73 m2).
Results
Overall, 25 patients received cabazitaxel (median cycles: 3 [range 1–20]; Cohort A: 5 [2–13]; Cohort B: 3 [1–15]; and Cohort C: 5 [1–20]), of which 24 were eligible for pharmacokinetic analysis (eight in each cohort). For moderate and severe renal impairment versus normal renal function, GMR estimates were: clearance normalized to body surface area (CL/BSA) 0.95 (90% CI 0.80–1.13) and 0.89 (0.61–1.32); area under the curve normalized to dose (AUC/dose) 1.06 (0.88–1.27) and 1.14 (0.76–1.71); and F U 0.99 (0.94–1.04) and 0.97 (0.87–1.09), respectively. Estimated slopes of linear regression of log parameters versus log CrCL (renal impairment) were: CL/BSA 0.06 (−0.15 to 0.28); AUC/dose −0.07 (−0.30 to 0.16); and F U 0.02 (−0.05 to 0.08). Cabazitaxel safety profile was consistent with previous reports.
Conclusions
Renal impairment had no clinically meaningful effect on cabazitaxel pharmacokinetics.
doi:10.1007/s00280-016-3175-7
PMCID: PMC5114328  PMID: 27796539
Cabazitaxel; Renal impairment; Pharmacokinetics; Phase I; Advanced solid tumors
6.  Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial 
Cancer Chemotherapy and Pharmacology  2016;78(6):1175-1184.
Purpose
Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.
Methods
We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.
Results
Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m2) than older children (26.6 ± 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.
Conclusion
In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-016-3174-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-016-3174-8
PMCID: PMC5114325  PMID: 27770238
Doxorubicin; Cancer; Children; Pharmacokinetic; Cardiotoxicity
7.  A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma 
Cancer Chemotherapy and Pharmacology  2016;78(5):1041-1049.
Purpose
Consolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy.
Methods
In this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m2 on days 1 and 15), lenalidomide (10 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15 and 22).
Results
The overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs.
Conclusion
Our sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.
doi:10.1007/s00280-016-3163-y
PMCID: PMC5083756  PMID: 27738809
Multiple myeloma; Consolidation/maintenance; Bortezomib; Lenalidomide; Dexamethasone; VRD
8.  Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study 
Cancer Chemotherapy and Pharmacology  2016;78(5):1003-1011.
Purpose
Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia’s formula (QTcF).
Methods
Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points. Absence of clinically relevant QTcF effect was shown if the 95 % upper confidence bound (UCB) for the mean ∆∆QTcF was <10 ms for all time points. An exposure–response analysis was also performed.
Results
Forty-seven patients were enrolled. Maximum mean ∆∆QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean ∆∆QTcF was 3.6 ms, with a 95 % UCB of 6.1 ms. No patient had a QTcF value >480 ms or change from baseline in QTcF interval >30 ms. Treatment-emergent adverse events (TEAEs) were experienced by 36.2, 48.9, and 47.8 % of patients while receiving veliparib 200 mg, veliparib 400 mg, and placebo, respectively. Most common TEAEs were nausea (12.8 %) and myalgia (8.5 %) after veliparib 200 mg, nausea (8.5 %) and vomiting (8.5 %) after veliparib 400 mg, and nausea (6.5 %) after placebo.
Conclusions
Single-dose veliparib (200 mg or 400 mg) did not result in clinically significant QTc prolongation and was well tolerated in patients with advanced solid tumors.
doi:10.1007/s00280-016-3156-x
PMCID: PMC5083757  PMID: 27709282
Veliparib; Poly(ADP-ribose) polymerase; PARP inhibitor; QT interval; ECG; Solid tumor
9.  Oral and intravenous pharmacokinetics of 5-fluoro-2’-deoxycytidine and THU in cynomolgus monkeys and humans 
Introduction
5-Fluoro-2’-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907).
Methods
Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability.
Results
After IV FdCyd and THU administration, FdCyd Cmax and AUC increased with dose. FdCyd half-life ranged between 22–56 min, clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9–25% and increased with increasing THU dose. PO bioavailability of THU was less than 5%, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10%) and THU (4.1%).
Conclusion
Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1% to 24%. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times 3 at the beginning of the first and second weeks of a 28 day cycle.
doi:10.1007/s00280-015-2857-x
PMCID: PMC4573928  PMID: 26321472
fluorodeoxycytidine; tetrahydouridine; toxicokinetics; toxicity; monkeys; DNA methylation inhibitor
10.  Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib 
Purpose
Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib.
Methods
Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC).
Results
Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure.
Conclusion
CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.
doi:10.1007/s00280-015-2856-y
PMCID: PMC4577782  PMID: 26330331
Erlotinib; Drug interaction; AIDS; Ritonavir; Efavirenz
11.  In vitro cytotoxicity and in vivo efficacy, pharmacokinetics and metabolism of pyrazole-based small-molecule inhibitors of Mdm2/4-p53 interaction 
Purpose
The interaction of p53, with its negative regulators Mdm2/4 has been widely studied [1]. In p53+/+ cells, expression of Mdm2/4 leads to p53 turnover, inhibition of downstream transcription, decreasing cell cycle arrest or apoptosis. We report in vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of YH264, YH263 and WW751, three proposed small molecule inhibitors of the Mdm2/4-p53 interaction.
Methods
MTT cytotoxicity assays were performed and alterations in proteins were examined using Western blots. Mice were dosed 150 mg/kg YH264 or YH263 iv or po QDx5. Mice were iv dosed 88 mg/kg, 57 mg/kg, or 39 mg/kg WW751 for three, five, or five days. YH264, YH263 and WW751 and metabolites were quantitated by LC-MS/MS.
Results
IC50 values for YH264, YH263 and WW751 against p53 wild type HCT 116 cells after 72 h of incubation were 18.3 ± 2.3 μM, 8.9 ± 0.6 μM, and 3.1 ± 0.2 μM respectively. Only YH264 appeared to affect p53 expression in vitro. None of the compounds affected the growth of HCT 116 xenografts in C.B-17 SCID mice. YH264 plasma half-life was 147 min; YH263 plasma half-life was 263 min; and WW751 plasma half-life was less than 120 min.
Conclusions
Despite dosing the mice at the maximum soluble doses, we could not achieve tumor concentrations equivalent to the intracellular concentrations required to inhibit cell growth in vitro. YH263 and WW751 do not appear to affect p53/Mdm2 and none of the three were active in a subcutaneous HCT116 p53+/+ xenograft model.
doi:10.1007/s00280-015-2791-y
PMCID: PMC5033042  PMID: 26050209
12.  Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients 
Cancer Chemotherapy and Pharmacology  2016;78(5):1093-1096.
Purpose
Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity.
Methods
We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy.
Results
We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B12 deficiency is common in pediatric leukemia patients.
Conclusions
Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate-induced neurotoxic effects.
doi:10.1007/s00280-016-3153-0
PMCID: PMC5083755  PMID: 27659182
Neurotoxicity; Hematology; Methotrexate; Nitrous oxide; Leukemia; Toxicity
13.  Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague–Dawley rats 
Purpose
Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.
Methods
Male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.
Results
All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.
Conclusions
Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-016-3150-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-016-3150-3
PMCID: PMC5040744  PMID: 27590707
Intestinal permeability; Chemotherapy; 5-Fluorouracil; Oxaliplatin; Irinotecan
14.  Characterization of the metabolism of benzaldehyde dimethane sulfonate (NSC 281612, DMS612) 
Introduction
Benzaldehyde dimethane sulfonate (BEN, DMS612, NSC281612) is a bifunctional alkylating agent currently in clinical trials. We previously characterized the degradation products of BEN in plasma and blood. The conversion of BEN to its carboxylic acid analogue (BA) in whole blood, but not plasma, suggests that an enzyme in RBCs may be responsible for this conversion. BEN conversion to BA was observed in renal carcinoma cells and appeared to correlate with IC50. To better understand the pharmacology of BEN we aimed to evaluate the metabolism and enzymes potentially responsible for the conversion of BEN to BA.
Methods
Human red blood cells (RBC) were used to characterize kinetics and susceptibility to enzyme specific inhibitors. Recombinant enzymes were used to confirm metabolism of BEN to BA. Analytes were quantitated with established LC-MS/MS methods.
Results
Average apparent Vmax and Km were 68 ng/mL•min-1•[10% RBC]−1 and 373 ng/mL, respectively. The conversion of BEN to BA in RBC was not inhibited by carbon monoxide, nitrogen gas or menadione, an inhibitor of aldehyde oxidase. The conversion was inhibited by disulfiram, an inhibitor of ALDH. Of available ALDH isoforms ALDH1A1, ALDH3A1, ALDH2, and ALDH5A1, only ALDH1A1 converted BEN to BA.
Conclusion
The activating conversion of BEN to BA is not mediated by CYP450 enzymes or aldehyde oxidase but by ALDH1A1. This enzyme, a potential stem cell marker, may be a candidate biomarker for clinical activity of BEN.
doi:10.1007/s00280-015-2828-2
PMCID: PMC4545378  PMID: 26193988
BEN Metabolism; Alkylators; Degradation; Renal Cell Carcinoma; HPLC; Mass spectrometry; Metabolism; Aldehyde Dehydrogenase; Stability; Cell lines; Cancer
15.  Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma 
Purpose
Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known.
Methods
For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I–III disease.
Results
Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30–0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95 % CI 1.12–2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65–0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98).
Conclusions
Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma.
doi:10.1007/s00280-015-2788-6
PMCID: PMC4811030  PMID: 26126726
Pancreatic adenocarcinoma; Family history; BRCA; Chemotherapy; Survival
16.  Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies 
Cancer chemotherapy and pharmacology  2015;75(5):1047-1055.
Purpose
Combination therapy with trabectedin and docetaxel was evaluated in patients with advanced malignancies.
Methods
In this open-label phase 1 study, docetaxel (60 or 75 mg/m2; 1-h intravenous infusion) was given on day 1 of a 21-day cycle in combination with escalating doses of trabectedin (0.4–1.3 mg/m2 by 3-h intravenous infusion, 1 h after docetaxel) and prophylactic granulocyte colony-stimulating factor (G-CSF). Maximum tolerated dose (MTD) as primary objective and safety, plasma pharmacokinetics, and antitumor activity as secondary objectives were assessed.
Results
Patients (N = 49) received a median of four cycles of treatment. MTD was 1.3 mg/m2 trabectedin and 60 mg/m2 docetaxel for patients with limited and 1.1 mg/m2 trabectedin and 60 mg/m2 docetaxel for patients with unlimited prior chemotherapy. Dose-limiting toxicities (during cycle 1) included elevated alanine aminotransferase (ALT) and fatigue in patients with limited prior chemotherapy and elevated ALT and febrile neutropenia in those with unlimited prior chemotherapy. The most common drug-related adverse events were nausea (65 %), fatigue (63 %), and neutropenia (53 %). One patient achieved a complete response. Thirty patients had stable disease, and 11 had stable disease for ≥6 months. Pharmacokinetic results for trabectedin plus docetaxel were similar to those previously reported for the single agents.
Conclusion
In patients with previously treated, advanced malignancies, the combination of therapeutic doses of trabectedin and docetaxel showed clinical activity and was tolerable with prophylactic G-CSF, with no evidence of clinically important drug interactions.
doi:10.1007/s00280-015-2705-z
PMCID: PMC4978949  PMID: 25791363
Advanced malignancies; Combination chemotherapy; Docetaxel; Ovarian cancer; Sarcoma; Trabectedin
17.  The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation 
The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phospho-Thr288-Aurora-A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phospho-Thr288-Aurora–A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phospho-Thr288-Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biological response modifiers in glioblastoma patients.
doi:10.1007/s00280-014-2430-z
PMCID: PMC4975936  PMID: 24627220
MLN8237; alisertib; glioblastoma; neurospheres; Aurora-A; temozolomide; radiation
21.  The molecular mechanism of action of superactive human leptin antagonist (SHLA) and quadruple leptin mutein Lan-2 on human ovarian epithelial cell lines 
Introduction
A number of leptin receptor antagonists have been synthesised for therapeutic use, with pre-clinical tests suggesting their future use in anticancer therapy. To our knowledge, there are no data concerning the possible application of leptin receptor blockers in ovarian cancer.
Methods
In this study, we evaluated two leptin receptor antagonists: superactive human leptin antagonist (SHLA) and quadruple leptin mutein, Lan-2 (L39A/D40A/F41A/I42A), on cell proliferation (Alamar Blue test, BrdU assay), cell cycle gene (qPCR) and protein expression (Western blot) and cell signalling pathways (Western blot) in three different types of cell lines: OVCAR-3, CaOV-3 and HOSEpiC.
Results
Both receptor blockers had no effect on non-cancerous HOSEpiC cell line proliferation; however, both reversed the stimulatory effect of leptin on CaOV-3 cell line proliferation to control levels and to below control levels in OVCAR-3 cells. In metastatic carcinoma CaOV-3, both ObR antagonists had an inhibitory effect on the cdk2/cyclin D1 complex, while in serous carcinoma, OVCAR-3, they only had an effect on cdk2 and cdk4 protein expression. SHLA had an inhibitory effect on all investigated signalling pathways in OVCAR-3, while only on Stat3 in CaOV-3. Lan-2 had an inhibitory effect on Stat3 and ERK1/2 in CaOV-3, while in OVCAR-3 it only affected Akt protein phosphorylation.
Conclusion
Based on these results, we conclude that SHLA and Lan-2 are promising leptin receptor inhibitors which could be used to block leptin activity, eliminating its negative effects on activities related to carcinogenesis. However, the selection of a specific antagonist should be related to tumour type.
doi:10.1007/s00280-016-3113-8
PMCID: PMC5010610  PMID: 27480179
Ovarian cell lines; ObR antagonists; Cell cycle; Signalling pathways
22.  Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network 
Purpose
To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients.
Methods
A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists.
Results
In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy’s law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib.
Conclusions
Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.
doi:10.1007/s00280-016-3112-9
PMCID: PMC5010603  PMID: 27438066
Hepatotoxicity; Liver chemistry; Renal cell carcinoma; Pazopanib; Anti-VEGF
23.  Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours 
Purpose
This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed.
Methods
In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation.
Results
Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response.
Conclusions
Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies.
Clinical trial registration number
NCT01813474.
doi:10.1007/s00280-016-3106-7
PMCID: PMC5010592  PMID: 27422301
Olaparib; Poly(ADP-ribose) polymerase inhibitors; Clinical trial, Phase I; Safety; Solid tumours
24.  Lack of pharmacokinetic drug–drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors 
Purpose
The objective of this phase II study was to evaluate pharmacokinetic interaction potential between ramucirumab and paclitaxel in patients with advanced cancer.
Methods
This study was designed to assess 2-way pharmacokinetic drug–drug interactions between ramucirumab and paclitaxel. Twenty-four patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m2 was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15). Patients could continue to receive combination therapy with ramucirumab and paclitaxel. In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle. Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel.
Results
Concomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0–∞) and 0.97 (90 % CI 0.83, 1.13) for Cmax. In addition, similar ramucirumab pharmacokinetic characteristics were observed with or without paclitaxel administration. The ratios of geometric LS means of AUC(0–∞) and Cmax of ramucirumab (with paclitaxel vs. alone) were 1.00 (90 % CI 0.84, 1.19) for AUC(0–∞) and 1.07 (90 % CI 0.93, 1.24) for Cmax, respectively.
Conclusions
Concomitant paclitaxel administration is unlikely to affect the pharmacokinetics of ramucirumab, and vice versa. The incidence and severity of adverse events were consistent with the known safety profiles of paclitaxel and ramucirumab.
doi:10.1007/s00280-016-3098-3
PMCID: PMC4965482  PMID: 27379498
Ramucirumab; Paclitaxel; Pharmacokinetics; Drug–drug interactions; Cancer
25.  Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients 
Purpose
Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine’s metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4+ and CD8+ cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients.
Methods
Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine – F-ara-A area under the curve (AUC) and the ratio of circulating CD4+ and CD8+ cells (CD4+/CD8+ ratio) after fludarabine administration – in 102 patients; F-ara-ATP accumulation rate in enriched CD4+ and CD8+ cells was evaluated in 34 and 36 patients, respectively.
Results
Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8+ cells). Circulating CD8+ cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4+ (R2=0.01) and CD8+ cells (R2=0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T-cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality).
Conclusions
Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.
doi:10.1007/s00280-015-2768-x
PMCID: PMC4489995  PMID: 25983023
Fludarabine; biomarkers; nucleoside analogs; pharmacokinetics; pharmacodynamics; hematopoietic cell transplantation

Results 1-25 (517)