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Biomedical subjects

Julian Adams

Publications and source records attributed to Julian Adams.

At least 19 recordsLinked to original sources
PubMed2006

Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma.

PURPOSE: Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients. METHODS: Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4. RESULTS: Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade > or = 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study. CONCLUSION: Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

Adult↗
PubMed2005

Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma.

PURPOSE: To examine the effects the proteasome inhibitor bortezomib (VELCADE) on transcription factor nuclear factor-kappaB (NF-kappaB) and target genes and the feasibility of combination therapy with reirradiation in patients with recurrent head-and-neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: The tolerability and response to bortezomib 0.6 mg/m2 and 0.9 mg/m2 given twice weekly concurrent with daily reirradiation to 50-70 Gy was explored. Blood proteasome inhibition and NF-kappaB-modulated cytokines and factors were measured. Proteasome inhibition, nuclear localization of NF-kappaB phospho-p65, apoptosis, and expression of NF-kappaB-modulated mRNAs were compared in serial biopsies from accessible tumors. RESULTS: The maximally tolerated dose was exceeded, and study was limited to 7 and 2 patients, respectively, given bortezomib 0.6 mg/m2 and 0.9 mg/m2/dose with reirradiation. Grade 3 hypotension and hyponatremia were dose limiting. Mucositis was Grade 3 or less and was delayed. The mean blood proteasome inhibition at 1, 24, and 48 h after 0.6 mg/m2 was 32%, 16%, and 7% and after 0.9 mg/m2 was 56%, 26%, and 14%, respectively. Differences in proteasome and NF-kappaB activity, apoptosis, and expression of NF-kappaB-modulated cell cycle, apoptosis, and angiogenesis factor mRNAs were detected in 2 patients with minor tumor reductions and in serum NF-kappaB-modulated cytokines in 1 patient with a major tumor reduction. CONCLUSIONS: In combination with reirradiation, the maximally tolerated dose of bortezomib was exceeded at a dose of 0.6 mg/m2 and the threshold of proteasome inhibition. Although this regimen with reirradiation is not feasible, bortezomib induced detectable differences in NF-kappaB localization, apoptosis, and NF-kappaB-modulated genes and cytokines in tumor and serum in association with tumor reduction, indicating that other schedules of bortezomib combined with primary radiotherapy or reirradiation may merit future investigation.

Adult↗
PubMed2005

Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling.

Constitutive activation of the NF-kappaB pathway is required for survival of the activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL). Here we show that a small molecule IkappaB kinase (IKK) inhibitor, PS-1145, and related compounds are toxic for ABC DLBCL cell lines but not for cell lines derived from the other prevalent form of DLBCL, germinal center B cell-like DLBCL. Treatment of ABC lines with these inhibitors rapidly induced a series of gene expression changes that were attributable to cessation of constitutive IKK activity, similar to changes induced by acute expression of genetic inhibitors of NF-kappaB, confirming the effectiveness and specificity of this compound. Before cell death, inhibition of IKK also induced features of apoptosis and an arrest in the G1 phase of the cell cycle. To test further the specificity of this toxicity, an inducible form of NF-kappaB was created by fusing the p65 NF-kappaB subunit with the ligand-binding domain of the estrogen receptor (p65-ERD). In the presence of tamoxifen, p65-ERD reversed the toxicity of IKK inhibition and restored expression of many NF-kappaB target genes. Another subgroup of DLBCL, primary mediastinal B-cell lymphoma (PMBL), also expresses NF-kappaB target genes, and treatment of a PMBL cell line with an IKK inhibitor was toxic and induced gene expression changes of a distinct group of NF-kappaB target genes. These studies validate the NF-kappaB pathway as a promising therapeutic target in ABC DLBCL, PMBL, and other lymphomas that depend on the activity of NF-kappaB for survival and proliferation.

Antineoplastic Agents↗
PubMed2004

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Adult↗
PubMed2004

Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma.

PURPOSE: To determine the antitumor activity of the novel proteasome inhibitor bortezomib in patients with indolent and mantle-cell lymphoma (MCL). PATIENTS AND METHODS: Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/microL (500/microL if documented bone marrow involvement); and platelet count more than 50,000/microL. RESULTS: Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7). CONCLUSION: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.

Adult↗
PubMed2004

Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Adult↗
PubMed2004

Delayed treatment of ischemia/reperfusion brain injury: extended therapeutic window with the proteosome inhibitor MLN519.

BACKGROUND AND PURPOSE: Clinical development of novel neuroprotection therapies for the treatment of brain injury has been unsuccessful. One critical limitation is the lack of a viable therapeutic treatment window (TW). In this study, we evaluated the neuroprotection TW for the proteosome inhibitor MLN519 after ischemia/reperfusion brain injury in rats as related to its antiinflammatory mechanism. METHODS: Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), followed by 70 hours of reperfusion and recovery. MLN519 was administered after injury (starting 6 to 12 hours after MCAo) to evaluate the full TW. Brain infarction, neuronal degeneration, neurological recovery, leukocyte infiltration, and inflammatory gene mRNA levels were assessed. RESULTS: Core infarct volume in vehicle-treated rats (216+/-25 mm3) was reduced with delayed MLN519 treatments of 6, 8, or 10 hours after injury (45+/-13, 86+/-28, and 150+/-27 mm3, respectively, P<0.05) and was associated with reductions in neuronal and axonal degeneration. MLN519-treated rats had reduced brain mRNA levels of TNF-alpha (46%, P<0.05), ICAM-1 (58%, P<0.05), IL-6 (58%, P<0.05), and E-selectin (72%, P<0.05) at 24 hours after injury. Furthermore, MLN519 treatment reduced leukocyte infiltration by 32% to 80% (P<0.05) in ischemic brain regions. CONCLUSIONS: Neuroprotection treatment with MLN519 provides an extended TW of up to 10 hours after ischemia/reperfusion brain injury, in part by attenuating the inflammatory response. As such, the delayed onset of brain inflammation after an ischemic injury offers a prime target for extending the neuroprotective TW with compounds such as MLN519, used either alone or possibly as an adjunctive therapy with thrombolytic agents.

Acetylcysteine↗
PubMed2004

Microbial evolution in laboratory environments.

The classical model of evolutionary change in microbial populations is evaluated in terms of recent evidence obtained from genetic and molecular analysis of evolving laboratory populations in simple, defined homogeneous environments. Patterns of change are observed which cannot be predicted from the classical model. These observations highlight the value of the study of evolving laboratory populations, which allow a degree of analysis typically not possible for natural populations.

Biomarkers↗
PubMed2004

The development of proteasome inhibitors as anticancer drugs.

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.

Antineoplastic Agents↗
PubMed2004

Ty1 insertions in intergenic regions of the genome of Saccharomyces cerevisiae transcribed by RNA polymerase III have no detectable selective effect.

The retrotransposon Ty1 of Saccharomyces cerevisiae inserts preferentially into intergenic regions in the vicinity of RNA polymerase III-transcribed genes. It has been suggested that this preference has evolved to minimize the deleterious effects of element transposition on the host genome, and thus to favor their evolutionary survival. This presupposes that such insertions have no selective effect. However, there has been no direct test of this hypothesis. Here we construct a series of strains containing single Ty1 insertions in the vicinity of tRNA genes, or in the rDNA cluster on chromosome XII, which are otherwise isogenic to strain 337, containing zero Ty1 elements. Competition experiments between 337 and the strains containing single Ty1 insertions revealed that in all cases, the Ty1 insertions have no selective effect in rich medium. These results are thus consistent with the hypothesis that the insertion site preference of Ty1 elements has evolved to minimize the deleterious effects of transposition on the host genome.

Base Sequence↗
PubMed2004

Development of the proteasome inhibitor Velcade (Bortezomib).

The dipeptide boronic acid analogue VELCADE (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib--mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.

Boronic Acids↗
PubMed2004

Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site.

AMP-activated protein kinase (AMPK) is a alphabetagamma heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the alpha subunit and by AMP allosteric control previously thought to be mediated by both alpha and gamma subunits. Here we present evidence that adjacent gamma subunit pairs of CBS repeat sequences (after Cystathionine Beta Synthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the gamma(1) CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast gamma homolog, snf4 contains a His151Gly substitution, and when this is introduced into gamma(1), AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in gamma(1) corresponds to the site of mutation in human gamma(2) and pig gamma(3) genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the alpha and gamma subunits and that AMP functions to derepress AMPK activity.

AMP-Activated Protein Kinase Kinases↗
PubMed2003

Drug interactions between the proteasome inhibitor bortezomib and cytotoxic chemotherapy, tumor necrosis factor (TNF) alpha, and TNF-related apoptosis-inducing ligand in prostate cancer.

PURPOSE: Proteasome inhibition has been shown to be an effective anticancer therapy in many tumor models, including prostate cancer. We sought to identify drug interactions between the proteasome inhibitor bortezomib and other apoptotic stimuli, including cytotoxic chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In addition, we wanted to gain insight into the role of nuclear factor kappaB inhibition as a mediator of bortezomib cytotoxic effects. EXPERIMENTAL DESIGN: Prostate cancer cell lines (LNCaP, LAPC4, CL1, and DU145) were treated with bortezomib and apoptotic stimuli (TRAIL, chemotherapy, and tumor necrosis factor alpha), alone or in combination. Apoptosis and cell viability were measured, and median effect/combination index analyses were used to quantitate drug interactions. Nuclear factor kappaB activity at baseline and in response to drug treatment was determined by gel shift and reporter gene assays. RESULTS: Bortezomib induced cell death of androgen-dependent (LNCaP and LAPC4) and androgen-independent (CL1 and DU145) prostate cancer cell lines, although androgen-dependent cells were more sensitive to proteasome inhibition. Bortezomib synergized with TRAIL and tumor necrosis factor alpha to induce death in both androgen-dependent and androgen-independent cells. CONCLUSIONS: Bortezomib and TRAIL represent a synergistic drug combination that warrants further evaluation in in vivo models of prostate cancer.

Androgens↗
PubMed2003

Novel IKK inhibitors: beta-carbolines.

Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.

Blotting, Western↗
PubMed2003

A phase 2 study of bortezomib in relapsed, refractory myeloma.

BACKGROUND: Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS: In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS: Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immunofixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.

Adult↗
PubMed2003

Potential for proteasome inhibition in the treatment of cancer.

Proteasome inhibition is a new approach to treating cancer. Proteasome inhibitors specifically induce apoptosis in cancer cells, but most proteasome inhibitors are not suitable for clinical development. Peptide boronates overcome the shortcomings of earlier generation proteasome inhibitors, and bortezomib (VELCADE; formerly PS-341) is the first peptide boronate to enter clinical trials. Preclinical studies of bortezomib have demonstrated antitumor activity in a variety of tumor types. Phase I trials provided evidence of manageable toxicities and support a twice-weekly dosing regimen now being examined in a Phase III study.

Animals↗
PubMed2003

The proteasome: structure, function, and role in the cell.

The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein. The proteasome's 19S regulatory cap binds the polyubiquitin chain, denatures the protein, and feeds the protein into the proteasome's proteolytic core. The proteolytic core is composed of 2 inner beta rings and 2 outer alpha rings. The 2 beta rings each contain 3 proteolytic sites named for their trypsin-like, post-glutamyl peptide hydrolase-like (PGPH) (i.e., caspase-like), or chymotrypsin-like activity. Inhibition of the proteasome results in cell-cycle arrest and apoptosis. In in vitro and in vivo animal studies, inhibition of the proteasome via bortezomib (VELCADE; formerly, PS-341, LDP-341, and MLN341) had antitumor activity against numerous tumor types either alone or in combination with conventional chemotherapeutic agents; these results provided the rationale for a broad clinical trial program. Bortezomib is currently in phase III trials for myeloma and is in early clinical development for numerous other tumor types.

Animals↗