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1.  A Phase I and Pharmacologic Study of the Combination of Bortezomib and Pegylated Liposomal Doxorubicin in Patients with Refractory Solid Tumors 
Purpose
Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We therefore conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.
Methods
Patients received bortezomib, 0.9-1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.
Results
A total of 37 patients with 4 median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1/6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1/6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.
Conclusions
A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
doi:10.1007/s00280-008-0716-8
PMCID: PMC4312589  PMID: 18327587
phase I; proteasome inhibition; bortezomib; pegylated liposomal doxorubicin; breast cancer
2.  Genetic Heterogeneity Beyond CYP2C8*3 Does Not Explain Differential Sensitivity to Paclitaxel-Induced Neuropathy 
Purpose
The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics.
Methods
Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C8*2, *3 or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN.
Results
412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR=1.722, p=0.018), however, the influence of the *2 and *4 SNPs were not independently significant (*2: p=0.847, *4: p=0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p=0.0008) but not in the non-Caucasian replication group (p=0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN.
Conclusions
The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3.
doi:10.1007/s10549-014-2910-1
PMCID: PMC4256153  PMID: 24706167
paclitaxel; pharmacogenetics; breast cancer; chemotherapy-induced peripheral neuropathy; ABCG1; Affymetrix DMET™ Plus; CYP2C8; race
3.  A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors 
Oncotarget  2014;5(18):8136-8146.
Background
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod.
Methods
Docetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured.
Results
Twenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted.
Conclusions
Docetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.
PMCID: PMC4226672  PMID: 25327557
Indoximod; 1-methyl-D-tryptophan; immunomodulator; docetaxel; indoleamine 2, 3 dioxygenase
4.  Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study 
Journal of Clinical Oncology  2011;29(24):3232-3239.
Purpose
We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism.
Patients and Methods
One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later.
Results
As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (−0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower.
Conclusion
This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
doi:10.1200/JCO.2010.31.4427
PMCID: PMC3158597  PMID: 21768473
5.  Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors 
Purpose
Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
Methods
In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3–6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
Results
Sixty-one patients received 5, 10, 20, 30 or 40 mg once daily for 7 days; 25, 35, 45 or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70 or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7–21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose-proportional, and terminal half-life was 30-40 hours. Three patients had stable disease for >6 cycles.
Conclusions
MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
doi:10.1007/s00280-010-1377-y
PMCID: PMC3026871  PMID: 20607239
MLN8054; Aurora A kinase; dose-limiting toxicity; pharmacokinetics; pharmacodynamics
6.  Phase I Study and Biomarker Analysis of Lapatinib and Concurrent Radiation for Locally Advanced Breast Cancer 
The Oncologist  2012;17(12):1496-1503.
This article describes a phase I dose-escalation study that assessed the toxicity and safety of combining daily lapatinib with radiation therapy for patients with unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer.
Purpose.
This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways.
Methods.
Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry.
Results.
Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per Response Evaluation Criteria in Solid Tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation.
Conclusions.
The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.
doi:10.1634/theoncologist.2012-0256
PMCID: PMC3528381  PMID: 23006498
Breast neoplasms; Radiotherapy; Combined modality therapy; Biological markers
7.  CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel 
Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response + partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1 % to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7 %) had higher rates of cCR (55 % vs. 23 %; OR = 3.92 [95 % CI: 1.46–10.48], corrected p = 0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22 % vs. 8 %; OR = 3.13 [95 % CI: 0.89–11.01], uncorrected p = 0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.
doi:10.1007/s10549-012-2054-0
PMCID: PMC3727245  PMID: 22527101
Paclitaxel; CYP2C8*3; Pharmacogenetics; Neoadjuvant breast cancer therapy; Clinical complete response
8.  A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors 
Investigational new drugs  2010;29(5):978-983.
Summary
Purpose
Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway.
Methods
This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors.
Results
Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m2 IV day 1 and erlotinib 75 mg PO days 2–21 (“continuous erlotinib”) in 21 day cycles, two of four patients experienced DLTs. At dose level -1 (vinflunine 250 mg/m2 every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to “intermittent erlotinib” dosing: vinflunine day 1 and erlotinib days 2–15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥6 cycles. All were treated in the continuous erlotinib group.
Conclusions
Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.
doi:10.1007/s10637-010-9427-1
PMCID: PMC2988886  PMID: 20387090
Influnine; Erlotinib; Phase I; Safety and toxicity
9.  A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients 
Introduction
Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases.
Methods
A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin.
Results
Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42-73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1-4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level -1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT.
Conclusions
The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m2 every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously.
doi:10.1016/j.lungcan.2010.05.022
PMCID: PMC2978774  PMID: 20580118
Sorafenib; non-small cell lung cancer; small cell lung cancer; safety and toxicity; phase I
10.  Phase I trial of vinflunine and pemetrexed in refractory solid tumors 
Investigational new drugs  2009;29(1):131-136.
Summary
Background
Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors.
Methods
A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m2 was given with vinflunine 280 mg/m2 (cohort 1), 300 mg/m2 (cohort 2) or 320 mg/m2 (cohort 3) on day 1 of a 21-day cycle.
Results
19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1–6) prior therapies. DLT occured 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively.
Conclusions
Based on this experience we recommend vinflunine 300 mg/m2 and pemetrexed 500 mg/m2 in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.
doi:10.1007/s10637-009-9344-3
PMCID: PMC3143820  PMID: 19830387
Phase I; Vinflunine; Pemetrexed; Vinca alkaloid
11.  The warfarin–cranberry juice interaction revisited: A systematic in vitro–in vivo evaluation 
Background
Cranberry products have been implicated in several case reports to enhance the anticoagulant effect of warfarin. The mechanism could involve inhibition of the hepatic CYP2C9-mediated metabolic clearance of warfarin by components in cranberry. Because dietary/natural substances vary substantially in bioactive ingredient composition, multiple cranberry products were evaluated in vitro before testing this hypothesis in vivo.
Methods
The inhibitory effects of five types of cranberry juices were compared with those of water on CYP2C9 activity (S-warfarin 7-hydroxylation) in human liver microsomes (HLM). The most potent juice was compared with water on S/R-warfarin pharmacokinetics in 16 healthy participants given a single dose of warfarin 10 mg.
Results
Only one juice inhibited S-warfarin 7-hydroxylation in HLM in a concentration-dependent manner (P < 0.05), from 20% to >95% at 0.05% to 0.5% juice (v/v), respectively. However, this juice had no effect on the geometric mean AUC0–∞ and terminal half-life of S/R-warfarin in human subjects.
Conclusions
A cranberry juice that inhibited warfarin metabolism in HLM had no effect on warfarin clearance in healthy participants. The lack of an in vitro–in vivo concordance likely reflects the fact that the site of warfarin metabolism (liver) is remote from the site of exposure to the inhibitory components in the cranberry juice (intestine).
doi:10.2147/JEP.S11719
PMCID: PMC2943398  PMID: 20865058
warfarin; cranberry; interaction; CYP2C9; metabolism; inhibition
12.  Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane®) on three treatment schedules in patients with solid tumors 
Purpose
Albumin-bound paclitaxel, ABI-007 (Abraxane ®), has a different toxicity profile than solvent-based paclitaxel, including a lower rate of severe neutropenia. The combination of ABI-007 and carboplatin may have significant activity in a variety of tumor types including non-small and small cell lung cancer, ovarian cancer, and breast cancer. The purpose of this study was to determine the maximum tolerated dose (MTD) of ABI-007, on three different schedules in combination with carboplatin.
Methods
Forty-one patients with solid tumors were enrolled, and received ABI-007 in combination with carboplatin AUC of 6 on day 1. Group A received ABI-007 at doses ranging from 220 to 340 mg/m2 on day 1 every 21 days; group B received ABI-007 at 100 or 125 mg/m2 on days 1, 8, and 15 every 28 days; and group C received ABI-007 125 or 150 mg/m2 on days 1 and 8 every 21 days. Dose-limiting toxicities were assessed after the first cycle. Doses were escalated in cohorts of three to six patients. Fifteen patients participated in a pharmacokinetic study investigating the effects of the sequence of infusion. ABI-007 was infused first followed by carboplatin in cycle 1, and vice versa in cycle 2.
Results
The MTD of ABI-007 in combination with carboplatin was 300, 100, and 125 mg/m2 in groups A, B, and C, respectively. Myelosuppression was the primary dose limiting toxicity. No unexpected or new toxicities were reported. Sequence of infusion did not affect either the pharmacokinetics of ABI-007 or the degree of neutropenia. Responses were seen in melanoma, lung, bladder, esophageal, pancreatic, breast cancer, and cancer of unknown primary.
Conclusions
The recommended dose for phase II studies of ABI-007 in combination with carboplatin (AUC of 6) is 300, 100, 125 mg/m2 for the schedules A, B, and C, respectively. The combination of ABI-007 and carboplatin is well tolerated and active in this heavily pretreated patient population.
doi:10.1007/s00280-007-0423-x
PMCID: PMC2860386  PMID: 17285317
Dose-limiting toxicity; Maximum tolerated dose; Melanoma; Non-small-cell lung cancer; Small-cell lung cancer; Clinical trial
13.  Phase I Trial of Nanoparticle Albumin-Bound Paclitaxel in Combination with Gemcitabine in Patients with Thoracic Malignancies 
Background
Nab-paclitaxel has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose and dose limiting toxicities (DLT) of nab-paclitaxel in combination with gemcitabine.
Methods
Patients were required to have a performance status of 0 to 1, ≤three prior cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received gemcitabine 1000 mg/m2 on days 1, 8 in all cohorts, and nab-paclitaxel at doses of 260, 300, 340 mg/m2 every 21 days depending on the treatment cohort (1 cycle = 21 days). DLT were assessed after the first cycle, and doses were escalated in cohorts of 3 to 6 patients.
Results
Eighteen patients were consented and 15 patients are evaluable [median age 62 years (range, 35–75); median number of prior treatments 3 (range, 1–4); tumor types: non-small cell lung cancer (NSCLC) (n = 8), small cell lung cancer (SCLC) (n = 6), and esophageal cancer (n = 1)]. At a nab-paclitaxel dose of 300 mg/m2, 1 of 6 pts experienced a DLT (omission of day 8 gemcitabine due to absolute neutrophil count <500), and at an nab-paclitaxel dose of 340 mg/m2 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Responses were observed in NSCLC and SCLC.
Conclusions
The maximum tolerated dose of nab-paclitaxel is 300 mg/m2 in combination with gemcitabine 1000 mg/m2 on days 1, 8 every 21 days. This combination demonstrated activity in previously treated NSCLC and SCLC patients.
doi:10.1097/JTO.0b013e31816de2a7
PMCID: PMC2860395  PMID: 18449006
Abraxane; Non-small cell lung cancer; Small cell cancer; Esophageal cancer; ABI-007; Taxane
14.  IDENTIFICATION OF A CRANBERRY JUICE PRODUCT THAT INHIBITS ENTERIC CYP3A-MEDIATED FIRST-PASS METABOLISM IN HUMANS 
An in vivo study in rats demonstrated a cranberry juice product to inhibit the intestinal first-pass metabolism of the CYP3A substrate nifedipine. However, a clinical study involving the CYP3A probe substrate, midazolam, and a different cranberry juice product demonstrated no interaction. Since the composition of bioactive components in natural products can vary substantially, a systematic in vitro-in vivo approach was taken to identify a cranberry juice capable of inhibiting enteric CYP3A in humans. First, the effects of five cranberry juices, coded A-E, were evaluated on midazolam 1'-hydroxylation activity in human intestinal microsomes. Juice E was the most potent, ablating activity at 0.5% juice (v/v) relative to control. Second, juice E was fractionated to generate hexane-, chloroform-, butanol-, and aqueous-soluble fractions. The hexane- and chloroform-soluble fractions at 50 μg/ml were the most potent, inhibiting by 77% and 63%, respectively, suggesting that the CYP3A inhibitors reside largely in these more lipophilic fractions. Finally, juice E was evaluated on the oral pharmacokinetics of midazolam in 16 healthy volunteers. Relative to water, juice E significantly increased the geometric mean AUC0-∞ of midazolam by ∼30% (p=0.001), decreased the geometric mean 1'-hydroxymidazolam-to-midazolam AUC0-∞ ratio by ∼40% (p<0.001), and had no effect on geometric mean terminal half-life, indicating inhibition of enteric, but not hepatic, CYP3A-mediated first-pass metabolism of midazolam. This approach both demonstrated a potential drug interaction liability with cranberry juice and substantiated that rigorous in vitro characterization of dietary substances is required prior to initiation of clinical drug-diet interaction studies.
doi:10.1124/dmd.108.024968
PMCID: PMC2650736  PMID: 19114462
15.  The role of the ubiquitination-proteasome pathway in breast cancer: Applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer 
Breast Cancer Research  2002;5(1):1-7.
The ubiquitin-proteasome pathway is responsible for most eukaryotic intracellular protein degradation. This pathway has been validated as a target for antineoplastic therapy using both in vitro and preclinical models of human malignancies, and is influenced as part of the mechanism of action of certain chemotherapeutic agents. Drugs whose primary action involves modulation of ubiquitin-proteasome activity, most notably the proteasome inhibitor PS-341, are currently being evaluated in clinical trials, and have already been found to have significant antitumor efficacy. On the basis of the known mechanisms by which these agents work, and the available clinical data, they would seem to be well suited for the treatment of breast neoplasms. Such drugs, alone and especially in combination with current chemotherapeutics, may well represent important advances in the therapy of patients with breast cancer.
doi:10.1186/bcr460
PMCID: PMC154126  PMID: 12559038
chemotherapy; neoplasm; NF-κB; p44/42 MAPK; proteasome; PS-341; ubiquitin

Results 1-15 (15)