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1.
BJU Int ; 114(6b): E70-E73, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24589330

ABSTRACT

OBJECTIVE: To report a simplified and effective method for substratification of M1 castrate-resistant prostate cancer (CRPC) by correlating progression-free (PFS) and overall survival (OS) with simple quantification of skeletal metastases. PATIENTS AND METHODS: In all, 561 men with M1 CRPC were studied longitudinally. Individual bone scan disease burden, quantified by counting bone metastasis number, was correlated with clinical outcome using specific threshold points of 1-4, 5-20 and >20 detectable lesions. RESULTS: Patients with a higher metastasis number had a shorter PFS and OS (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.7-2.4; P < 0.001). Patients with 1-4 metastases had much better PFS and OS than those with 5-20 metastases. The median PFS and OS in the latter was 10.9 (95% CI 8.4-12.8) and 22.1 (95% CI: 18.5-24.5) months, respectively. PFS and OS for patients with >20 metastases were shorter still [median 5.3 (95% CI 3.4-6.9) months and 13.3 (95% CI 11.3-17.6) months, respectively]. Dichotomising into cohorts with 1-4 and ≥5 metastases, the latter group had considerably poorer PFS [8.4 (95% CI 6.8-10.3) months; P < 0.001) and OS [18.7 (95% CI 17.5-22.1) months; P < 0.001]. CONCLUSIONS: Dichotomising patients with CRPC into cohorts with 1-4 or ≥5 skeletal metastases identifies a better and a worse cohort in a manner that is easy and clinically accessible. This simple method facilitates disease stratification and patient management, enabling clinicians to counsel patients more effectively about long-term outcomes and to help select intervention therapies more effectively.


Subject(s)
Bone Neoplasms/secondary , Prostatic Neoplasms, Castration-Resistant/pathology , Aged , Aged, 80 and over , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/mortality , Disease-Free Survival , Humans , Male , Middle Aged , Predictive Value of Tests , Proportional Hazards Models , Prostatic Neoplasms, Castration-Resistant/mortality , Radionuclide Imaging , Survival Rate
2.
Clin Drug Investig ; 32(3): 179-87, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22217154

ABSTRACT

BACKGROUND AND OBJECTIVES: Severe sepsis and septic shock have posed significant treatment challenges for many years. Recently, a number of circulating apoptosis biomarkers have emerged, such as full-length and caspase-cleaved cytokeratin 18 (CK18) and nucleosomal DNA (nDNA), that may be predictive of likely outcome. This non-interventional study aimed to assess the ability of enzyme-linked immunosorbent assays (ELISAs) for these biomarkers to provide clinically useful information to guide the management of sepsis. METHODS: This study was conducted in patients admitted to the intensive care unit with severe sepsis at five US centres. Blood samples for assessment of plasma levels of full-length CK18 (measured by the M65® ELISA) and caspase-cleaved CK18 (measured by the M30-Apoptosense® ELISA) and nDNA (measured by ELISA) were collected from patients within 2 hours of consent (baseline) and on days 2, 4 and 8. Blood samples from 17 healthy volunteers acted as controls. Levels of each biomarker were presented descriptively. RESULTS: A total of 22 patients (mean age 60 [range, 24-83] years; 50% male) were included in the study. The mean APACHE II score was 24.4 (range 7-50). One-third of patients had three organ system failures and over one-half had septic shock. Three patients died during the study. Full-length and caspase-cleaved CK18 levels decreased within 48 hours following initiation of treatment of sepsis in patients who survived, whereas increases were observed in the same timeframe in patients who died within 28 days of admission. Baseline nDNA and total soluble CK18 levels (caspase-cleaved and total intact) were significantly (p ≤ 0.05) higher in patients who required renal support than those who did not. CONCLUSIONS: Despite the small numbers of subjects assessed in the current study, these results confirm that measurement of apoptosis biomarkers may help to provide clinically useful information to manage sepsis and expedite development of novel therapeutics. However, further investigations to fully assess their prognostic value are required.


Subject(s)
DNA/blood , Keratin-18/blood , Nucleosomes/chemistry , Sepsis/blood , APACHE , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Pilot Projects , Prognosis , Sepsis/mortality
3.
Mol Cancer Ther ; 8(7): 1856-66, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19509270

ABSTRACT

Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC(50) range, 0.2-1.7 micromol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G(2)-M, S, and G(1) phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer(249)/Thr(252), for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.


Subject(s)
Antineoplastic Agents/pharmacology , CDC2 Protein Kinase/antagonists & inhibitors , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Imidazoles/pharmacology , Neoplasms/drug therapy , Pyrimidines/pharmacology , Xenograft Model Antitumor Assays , Animals , Blotting, Western , CDC2 Protein Kinase/metabolism , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 9/metabolism , Cyclin-Dependent Kinases/antagonists & inhibitors , Female , Humans , Mice , Mice, Nude , Neoplasms/metabolism , Neoplasms/pathology , Rats , Rats, Nude , Tumor Cells, Cultured
4.
Mol Cancer Ther ; 7(3): 455-63, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18347133

ABSTRACT

M30 and M65 are ELISAs that detect different circulating forms of cytokeratin 18. Using the aurora kinase inhibitor AZD1152 and the SW620 human colon cancer xenograft, experiments were conducted to qualify preclinically both assays as serologic biomarkers of cell death. Using two different apoptotic markers, the kinetics of cell death induced by AZD1152 was first characterized in vitro in three different cell lines and shown to peak 5 to 7 days after drug addition. Treatment of non-tumor-bearing rats with AZD1152 (25 mg/kg) produced no alterations in circulating baseline values of M30 and M65 antigens. In treated, tumor-bearing animals, M30 detected a 2- to 3-fold (P < 0.05) increase in plasma antigen levels by day 5 compared with controls. This correlated to a 3-fold increase in the number of apoptotic cells detected on day 5 in SW620 xenografts using immunohistochemistry. By contrast, M65 did not detect a drug-induced increase in circulating antigen levels at day 5. However, M65 plasma levels correlated to changes in tumor growth in control animals (r(2) = 0.93; P < 0.01) and also followed the magnitude of the temporal effect of AZD1152 on tumor growth. An intermediate but active dose of AZD1152 (12.5 mg/kg) produced a less significant increase in M30 plasma levels at day 5. It was also confirmed that the plasma profiles of M30 and M65 mirrored closely those measured in whole tumor lysates. We conclude that M30 is a pharmacodynamic biomarker of AZD1152-induced apoptosis in the SW620 xenograft model, whereas M65 is a biomarker of therapeutic response.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/blood , Enzyme-Linked Immunosorbent Assay/methods , Keratin-18/blood , Neoplasms, Experimental/pathology , Organophosphates/pharmacology , Quinazolines/pharmacology , Animals , Male , Rats , Rats, Nude
5.
Cancer Chemother Pharmacol ; 60(4): 479-88, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17143601

ABSTRACT

PURPOSE: AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t1/2 to be 1-3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (tmax), +/-6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity. RESULTS: Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807-S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807-S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK-PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249-T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose-response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively). CONCLUSIONS: The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.


Subject(s)
Cell Cycle/drug effects , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Hair/metabolism , Imidazoles/pharmacology , Leukocytes, Mononuclear/metabolism , Mouth Mucosa/metabolism , Pyrimidines/pharmacology , Biomarkers/analysis , Cell Proliferation/drug effects , Cross-Over Studies , Humans , Imidazoles/administration & dosage , Male , Placebos/administration & dosage , Pyrimidines/administration & dosage , Retinoblastoma Protein/analysis , Scalp
6.
Cancer Chemother Pharmacol ; 60(3): 391-8, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17115157

ABSTRACT

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. Tmax occurred between 0.5-3.0 hours with a relatively short plasma half-life of 1-3 h. The coefficient of variation of exposures within a dose level ranged from 22-71% (AUC) to 16-63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438's action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.


Subject(s)
Antineoplastic Agents/toxicity , Cyclin-Dependent Kinases/antagonists & inhibitors , Imidazoles/toxicity , Pyrimidines/toxicity , Adult , Antineoplastic Agents/pharmacokinetics , Cell Cycle/drug effects , Dose-Response Relationship, Drug , Double-Blind Method , Humans , Imidazoles/pharmacokinetics , Male , Middle Aged , Pyrimidines/pharmacokinetics , Reference Values , Safety
7.
Gastroenterology ; 124(1): 18-25, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12512025

ABSTRACT

BACKGROUND & AIMS: Central sensitization, an activity-dependent increase in spinal cord neuronal excitability, has been shown to contribute to esophageal pain hypersensitivity. Prostaglandin E2 (PGE(2)) is a mediator in both peripheral and central sensitization, in part via the prostaglandin E2 receptor-1 (EP-1), and may be a potential target for treating visceral pain. The purpose of this study was to determine whether acid-induced pain hypersensitivity within the non-acid-exposed esophagus (secondary hyperalgesia) is mediated by PGE(2) activation of the EP-1 receptor. METHODS: Twelve healthy male subjects participated in a randomized, placebo-controlled crossover study. Upper esophageal pain thresholds (PTs) to electrical stimulation were determined, and either the EP-1 antagonist ZD6416 or a placebo was orally administered. One-hour after dosing, acid or saline (0.15 mol/L) was infused into the lower esophagus for 30 minutes. Upper esophageal PT was monitored for 120 minutes after infusion. RESULTS: Except in 1 subject (who was excluded), the pH in the upper esophagus remained above 5 throughout all studies. In 8 subjects, ZD6416 attenuated the reduction in PT in the upper esophagus normally induced by acid infusion into the lower esophagus (area under curve [AUC]: -11.9 +/- 2.5 and 6.4 +/- 6.7 for placebo and ZD6416, respectively; P < 0.01). After saline infusion, the effects of ZD6416 and placebo were similar (AUC: 9.9 +/- 6 and 4.1 +/- 2, respectively; P = 0.8). Three subjects had no reduction in PT to acid infusion with placebo and were excluded at post hoc analysis. CONCLUSIONS: The attenuation of secondary esophageal hyperalgesia by ZD6416 suggests that PGE(2), via the EP-1 receptor, contributes to human visceral pain hypersensitivity.


Subject(s)
Acids/pharmacology , Pain Threshold/drug effects , Pain/physiopathology , Receptors, Prostaglandin E/metabolism , Viscera/drug effects , Viscera/physiopathology , Adult , Cross-Over Studies , Esophagus/drug effects , Esophagus/metabolism , Humans , Hydrogen-Ion Concentration/drug effects , Hyperalgesia/chemically induced , Hyperalgesia/physiopathology , Male , Middle Aged , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E, EP1 Subtype
8.
Pain ; 99(1-2): 323-31, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12237211

ABSTRACT

The reproducibility and tolerability of intradermal (i.d.) administration of capsaicin as a method for eliciting human pain was assessed in healthy male volunteers (n = 12). The primary endpoints for assessing pain were spontaneous pain response and areas of allodynia, pinprick hyperalgesia and neurogenic inflammation. These were recorded before, immediately after, and at regular intervals following each of four doses (250 microg) of capsaicin (two per trial day). Within- and between-subject variability to the technique was assessed by measuring the maximum recorded values (max), time to maximum value (t(max)) and area under the curve (AUC(0-1 h)) of each of the endpoints. Tolerability to the technique was addressed by recording adverse events. Reproducibility of the i.d. capsaicin model was demonstrated for each type of capsaicin-induced pain. Following each dose, the magnitude and profile of response and overall AUC values were similar for each parameter although some decrease in pinprick hyperalgesia was observed over time. For spontaneous pain, evidence of a period effect was observed in mean AUC data, with values increasing following the second dose of each trial day. This effect was confounded by the possibility of an arm effect, with the non-dominant arm appearing to be more sensitive to pain than the dominant arm. The data were not sufficient to confirm the existence of these effects. Between-subject variability and within-day, within-subject variability accounted for most of the variability observed in the trial. By optimising study design to eliminate these sources of variability, it was estimated that spontaneous pain and the area of allodynia would be the least variable endpoints. A positive correlation was found between the area of allodynia and area of pinprick hyperalgesia (r(2) = 0.835). Overall, the model was well tolerated with no reports of adverse events. We conclude that the tolerability profile, and variability of i.d. capsaicin-induced pain is acceptable for pharmacological profiling of novel anti-nociceptive agents, with limited number of subjects.


Subject(s)
Capsaicin/administration & dosage , Pain/chemically induced , Analysis of Variance , Arm , Capsaicin/adverse effects , Cross-Over Studies , Humans , Hyperalgesia/chemically induced , Injections, Intradermal , Male , Pain Measurement , Pain Threshold , Reproducibility of Results
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