Sridhar Mani

..This is the first demonstration of a chemical analog of a PXR inhibitor that retains activity against activated PXR. Furthermore, in contrast with ketoconazole, 3 is less toxic in human cell lines and has negligible CYP450 activity...

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..It appears to be a suitable candidate for third-line monotherapy and beyond for locally advanced and metastatic breast cancer. This review will focus on published and peer-reviewed data on breast cancer...

..This report describes studies undertaken to explore the characteristics of hPXR stimulation and mechanisms of drug-receptor interactions in vitro with new anti-tubulin drugs...

..Our study warrants further exploration of efficacy in a Phase II and/or Phase III clinical trial setting...

..The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil...

..The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks...

..In the current study, a new expanded evaluation of drug target effect was undertaken...

..To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer...

..g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy...

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..Preclinical studies have demonstrated synergistic antitumor activity when GEM231 is combined with docetaxel. This trial assesses the safety of this combination...

..We conducted a study to identify a safe dose and potential drug-drug interactions of this combination...

..The synergy of Flavopiridol and UCN-01 are selectively toxic to survivin-overexpressing cell lines and the mechanism of toxicity involves caspase-dependent cell death...

..To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma...

..Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas...

..5 weeks (range 14.5-28+). Edrecolomab and capecitabine may be safely given in combination to patients with advanced or metastatic adenocarcinoma. Clinical activity is seen in this heavily pretreated patient population...

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..To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma...

..Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine...

..Five partial responses were observed. Pharmacokinetic modulation of irinotecan with cyclosporine and phenobarbital has been demonstrated; further studies are necessary to evaluate whether this strategy improves the therapeutic index...

..We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma...

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..We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand...

..Thus, UCN-01 was effective at inducing apoptosis in neuroblastoma cell lines...

..We are in the process to explore the molecular mechanism of action of oxazine derivative compounds on hypoxia tumor cells...

..There is now considerable data regarding the efficacy of the epothilones in human beings and discodermolide holds such promise, as well...

..This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies...

..The docetaxel dose can be safely escalated to 145 mg/m(2) every 21 d with GCSF support, a 45% increase above the standard recommended phase II dose. Further studies will clarify the role of dose-intensified docetaxel...

..Because the orphan receptor, pregnenolone X-receptor (PXR), coordinately regulates the expression of paclitaxel metabolizing and transport enzymes, controlling this process could improve therapeutic outcome...

..Because cdk inhibitors have not been used for preclinical or clinical testing on rhabdoid tumors, we investigated the effect of flavopiridol, a pan-cdk inhibitor with promising clinical activity, on rhabdoid tumors...

..However, in the era of 'targeted' or seemingly 'less toxic' therapy, these interactions are more commonly flagged and contribute significantly towards poor 'quality of life' and medical fatalities...

..These studies provide the basis for development of novel small molecule inhibitors of PXR with the ultimate goal of clinical applications toward preventing drug-drug interactions...

..The combination of irinotecan 275 mg/m(2) and capecitabine 2,300 mg/d represents a safe, favorable, and convenient outpatient regimen warranting further phase II evaluation...

..The pharmacokinetics of MGd were also evaluated...

..To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4...

..Alternative dosing schedules should include intermittent administration to minimize cumulative toxicity. Additional studies using intermittent continuous infusion schedules of GEM231 are warranted...

..Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted...

..Clinical studies demonstrate significant activity of ixabepilone monotherapy in these heavily pretreated patients. The toxicity profile of ixabepilone seems to be similar to that of taxanes and manageable by supportive methods...

..This rationale becomes even more striking when one observes overexpression of Bcl2 in 70% of breast cancer, 30-60% of prostate cancer, 80% of B-cell lymphomas, 90% of colorectal adenocarcinomas, and many other forms of cancer...

..This drug has demonstrated promising antitumor activity in Phase II trials in several solid tumors and definitive Phase III studies to demonstrate clinical benefit have completed accrual...

..It induces cytopathic and anti-cancer effects in cells with an activated ras pathway due to inhibition of the dsRNA-activated protein kinase...

..Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations...

..To evaluate the safety and efficacy of a five-day regimen of oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients with metastatic colorectal cancer (CRC)...

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..The recommended phase II dose is 256 mg/m(2)/d. Rapid dose escalation with single patient cohorts was a safe and efficient method of conducting this phase I trial...

..Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer...

..CONCLUSION: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated...

..CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation...

..Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions...

..Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation...

..Cyclin D1 overexpression results in combination drug resistance. In addition, inhibition of Akt may prove to be a useful therapeutic strategy in combination with flavopiridol...

..Collectively, these results suggest that the CSB gene product may be viewed as an anti-cancer target...

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..Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC...

..While the application of antisense technology to the treatment of human cancer is conceptually straightforward, in practice there are many complicated, mechanistically based questions that must be considered...

..We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy...

..Grade 3/4 nonhematologic toxicities were minimal. We conclude that fixed dose rate gemcitabine results in significant myelosuppression and has minimal activity in patients with biliary tree carcinoma...

..Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics...

..In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs...

..This class of agents is suitable for development as chemical probes of PXR function as well as potential PXR-directed therapeutics...

..UFT 300 mg/m2/day and leucovorin 90 mg/day could be administered safely to patients with advanced biliary cancer with good performance status; however, this combination and schedule of 28-day administration has no activity in this disease...

..Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application...

..This regimen and sequence is worthy of further study especially in combination with colony stimulating factors, however, its tolerability may be most applicable for patients who have had minimal prior therapy...

..The article discusses the current knowledge of the biology of this lethal disease, its impact on treatment options, and explores novel therapeutic modalities that are likely to improve outcomes and survival for patients in the future...

..Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested...

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..Other uses are being tested, such as imatinib for gastrointestinal stromal tumor. These compounds will alter cancer care as adjuncts to currently available treatment options...

..Bone marrow suppression, which may be cumulative, is the dose-limiting toxicity of the combination. Prolonged AGT suppression is likely attributable primarily to the effect of O6-benzyl-8-oxoguanine...

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..Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted...

..These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs...

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..This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population...

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..To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function...

..These data suggest that dose reductions of single-agent oxaliplatin are not necessary in patients with CrCLs >20 mL/min...

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..Thus, we evaluated the disposition of 9NC and 9AC after administration of 9NC under fasting conditions and after a standard meal...

..The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2 on the pharmacokinetic disposition of 9NC and 9AC...

..These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists...

..To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population...

..To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung...

..Our results show that autoantibody ECPKA is a universal serum biomarker for cancers of various cell types...

..The integrated treatment was well tolerated in patients with predominantly prior treatment-refractory solid tumors. Controlled prospective clinical trials have been initiated to more fully define the therapeutic contribution of TNFerade...

..8 microM), that seems to be a PXR antagonist in vitro. These observations are important for predicting whether further molecules may interact with PXR as antagonists in vivo with potential therapeutic applications...

..These studies will be vital for the generation on non-toxic compounds that antagonize PXR function - a tool necessary to probe PXR function in cells. ..

..These studies will be vital for the generation on non-toxic compounds that antagonize PXR function - a tool necessary to probe PXR function in cells. ..