PubMed Health⌕ Search

Biomedical subjects

Andrew Spencer

Publications and source records attributed to Andrew Spencer.

17 recordsLinked to original sources
PubMed2007

Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains.

Biological therapies in multiple myeloma have heralded a new and exciting era for treatment to combat this disease. However the evolutionary pressures that these drugs place on the microenvironment has resulted in a change in the biological behaviour of this malignancy and novel manifestations of relapsed disease. This is illustrated in our series of three patients showing fulminant relapse of disease with plasmablastic features, an extramedullary predilection and a shift in secretion from intact immunoglobulin to free light chains only.

Aged↗
PubMed2006

PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells.

The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of PKC412 in the treatment of MM is justified.

Apoptosis↗
PubMed2006

Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.

Clinical studies have suggested that bisphosphonates may prolong the survival of sub-sets of myeloma patients. Newer nitrogen containing bisphosphonates such as zoledronate act, at least in part, by inhibiting farnesyl diphosphate synthase and subsequent protein prenylation, furthermore, limited data suggests that zoledronate exerts a direct anti-tumour effect against human myeloma cell lines. We therefore investigated the anti-myeloma potential of zoledronate in comparison to, and in combination with, two other inhibitors of the mevalonate pathway: the HMGCoA reductase inhibitor fluvastatin and the farnesyl transferase inhibitor SCH66336. We found that fluvastatin was able to inhibit the proliferation of myeloma cells more effectively than zoledronate or SCH66336 and that combinations of zoledronate and fluvastatin, but not zoledronate and SCH66336 acted synergistically. Our data indicated that the anti-proliferative effect of mevalonate pathway inhibitors is mediated principally via prevention of geranylgeranylation and is the result of both cell cycle arrest and apoptosis induction. Microarray and quantitative real-time PCR analyses further demonstrated that genes related to apoptosis, cell cycle control, and the mevalonate pathway were particularly affected by zoledronate and fluvastatin, and that some of these genetic effects were synergistic. We conclude that the mechanisms of geranylgeranylation inhibition mediated anti-myeloma effects warrant further evaluation and may provide novel targets for future therapeutic development.

Apoptosis↗
PubMed2006

Extramedullary relapse of multiple myeloma presenting as hematemesis and melena.

BACKGROUND: A 60-year-old woman with multiple myeloma relapsed after a good partial response to high-dose chemotherapy (melphalan 200 mg/m(2)) and autologous stem-cell transplantation, followed by thalidomide and prednisolone maintenance therapy. She presented with hematemesis and melena following salvage chemotherapy with dexamethasone, cyclophosphamide, etoposide, cisplatin, and rescue therapy with single-agent bortezomib. INVESTIGATIONS: Physical examination, laboratory investigations, gastroscopy, 2-[(18)F]fluoro-2-deoxyglucose-PET (FDG-PET), breast biopsy and histology. DIAGNOSIS: Multifocal extramedullary relapse of multiple myeloma involving the stomach and duodenum. MANAGEMENT: High-dose infusion of omeprazole, blood product support, palliative analgesics and anxiolytic agents.

Diagnosis, Differential↗
PubMed2006

Pegfilgrastim to support CHOP-14 in elderly patients with non-Hodgkin's lymphoma.

This study investigated whether pegfilgrastim support would enable on-schedule delivery of dose-dense cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP-14) to elderly patients with non-Hodgkin's lymphoma (NHL). Thirty patients 60 years of age and older with aggressive NHL were evaluated after receiving up to six cycles of CHOP-14 supported with pegfilgrastim. The median age was 68 years (range 61 - 74). Forty-seven per cent of patients received full dose chemotherapy on schedule for all cycles (range 65 - 93). Chemotherapy was delayed in 10 patients and dose reduced in 15 patients. Hematological toxicity was the most common reason for delays and dose reduction. Six of nine patients (67%) achieved a peripheral blood CD34+ count of at least 20 cellsx106 L-1 on day 12 of cycle one. The delivery on schedule of dose-dense CHOP-14 to elderly patients with previously untreated aggressive NHL is safe and efficacious with once per cycle pegfilgrastim support.

Aged↗
PubMed2005

The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans.

In metazoans, microRNAs (miRNAs) carry out various regulatory functions through association with multiprotein miRNA-induced silencing complexes (miRISCs) that contain Dicer and Argonaute proteins. How miRNAs regulate the expression of their mRNA targets remains a major research question. We have identified the C. elegans ain-1 gene through a genetic suppressor screen and shown that it functions with the heterochronic genetic pathway that regulates developmental timing. Biochemical analysis indicates that AIN-1 interacts with protein complexes containing an Argonaute protein, Dicer, and miRNAs. AIN-1 shares homology with the candidate human neurological disease protein GW182, shown to localize in cytoplasmic processing bodies that are sites of mRNA degradation and storage. A functional AIN-1::GFP also localizes at the likely worm processing bodies. When coexpressed from transgenes, AIN-1 targets ALG-1 to the foci. These results suggest a model where AIN-1 regulates a subset of miRISCs by localization to the processing bodies, facilitating degradation or translational inhibition of mRNA targets.

Animals↗
PubMed2004

Induction with oral chemotherapy (CID) followed by early autologous stem cell transplantation for de novo multiple myeloma patients.

In an effort to minimise induction therapy-related toxicity, avoid unnecessary hospitalisation and facilitate early ASCT, we have prospectively evaluated an outpatient-based oral chemotherapeutic regimen, cyclophosphamide, idarubicin, dexamethasone (CID) in patients with previously untreated multiple myeloma (mm). Patients subsequently underwent ASCT conditioned with melphalan 200 g/m(2). A total of 36 newly diagnosed MM patients were enrolled between February 1997 and March 2000. In all 136 cycles of CID were administered requiring only four unplanned hospital admissions. Grade 3 or 4 haematological toxicities were documented following 14 cycles (10%). There were no treatment-related deaths. Response rates (PR + CR) based on an intention-to-treat basis were 66% (23 of 35, 9% CR) post-CID and 80% (28 of 35, 34% CR) post-ASCT. In all, 28 of the 35 patients remain alive with a median follow-up for surviving patients of 40 months (range, 30-67 months). Progression-free survival from the time of diagnosis was 32 months (range, 3-55+ months). Median overall survival from diagnosis has not been reached with an estimated overall survival at 4 years of 77%. CID in combination with early ASCT is an effective and well-tolerated antimyelomatous regimen and is a practical alternative to more toxic and invasive therapeutic approaches.

Administration, Oral↗
PubMed2004

Xenobiotic gene polymorphisms and susceptibility to multiple myeloma.

Genetic variations in the activity of xenobiotic enzymes may predict susceptibility to multiple myeloma (MM). In a case-control study, 90 Australian Caucasians with MM had significantly higher incidences of GST T1 null, PON1 BB and NAT2 slow acetylation genotypes, but no difference in polymorphism frequencies for GST M1, NAT1, and CYP1A1 when compared to 205 controls.

Adult↗
PubMed2003

A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme.

Amyloid diseases are characterized by an aberrant assembly of a specific protein or protein fragment into fibrils and plaques that are deposited in various organs and tissues, often with serious pathological consequences. Non-neuropathic systemic amyloidosis is associated with single point mutations in the gene coding for human lysozyme. Here we report that a single-domain fragment of a camelid antibody raised against wild-type human lysozyme inhibits the in vitro aggregation of its amyloidogenic variant, D67H. Our structural studies reveal that the epitope includes neither the site of mutation nor most residues in the region of the protein structure that is destabilized by the mutation. Instead, the binding of the antibody fragment achieves its effect by restoring the structural cooperativity characteristic of the wild-type protein. This appears to occur at least in part through the transmission of long-range conformational effects to the interface between the two structural domains of the protein. Thus, reducing the ability of an amyloidogenic protein to form partly unfolded species can be an effective method of preventing its aggregation, suggesting approaches to the rational design of therapeutic agents directed against protein deposition diseases.

Amyloidosis↗
PubMed2003

Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma.

Lymphoproliferative diseases are characterized by chromosomal aberrations, and susceptibility may depend on inherited activity of enzymes required for DNA synthesis and methylation. We analysed genetic polymorphisms for methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C in Caucasians with non-Hodgkin's lymphoma (NHL; n = 151), multiple myeloma (MM; n = 90) and 299 control subjects. The MS 2756 AG/GG genotypes were significantly under-represented in NHL (26.2%) vs control subjects (37.2%; P = 0.02), and conferred a 2.4-fold lower risk of follicular (odds ratio = 0.41, 95% confidence interval: 0.19-0.88, p = 0.02) but not diffuse large B-cell lymphoma. MM patients showed no significant difference in the polymorphisms compared with control subjects.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2002

Local cooperativity in the unfolding of an amyloidogenic variant of human lysozyme.

Hydrogen exchange experiments monitored by NMR and mass spectrometry reveal that the amyloidogenic D67H mutation in human lysozyme significantly reduces the stability of the beta-domain and the adjacent C-helix in the native structure. In addition, mass spectrometric data reveal that transient unfolding of these regions occurs with a high degree of cooperativity. This behavior results in the occasional population of a partially structured intermediate in which the three alpha-helices that form the core of the alpha-domain still have native-like structure, whereas the beta-domain and C-helix are simultaneously substantially unfolded. This finding suggests that the extensive intermolecular interactions that will be possible in such a species are likely to initiate the aggregation events that ultimately lead to the formation of the well-defined fibrillar structures observed in the tissues of patients carrying this mutation in the lysozyme gene.

Genetic Variation↗
PubMed2002

Association between xenobiotic gene polymorphisms and non-Hodgkin's lymphoma risk.

The last four decades have seen a significant increase in the incidence of non-Hodgkin's lymphoma (NHL) as a possible result of increasing environmental carcinogen exposure, particularly pesticides and solvents. Based on the increasing evidence for an association between carcinogen exposure-related cancer risk and xenobiotic gene polymorphisms, we have undertaken a case-control study of xenobiotic gene polymorphisms in individuals with a diagnosis of NHL. Polymorphisms of six xenobiotic genes (CYP1A1, GSTT1, GSTM1, PON1, NAT1, NAT2) were characterized in 169 individuals with NHL and 205 normal controls using polymerase chain reaction-based methods. Polymorphic frequencies were compared using Fisher's exact tests, and odds ratios for NHL risk were calculated. Among the NHL group, the incidence of GSTT1 null and PON1 BB genotypes were significantly increased compared with controls, 34% vs 14%, and 24% vs 11% respectively. Adjusted odds ratios calculated from multivariate analyses demonstrated that GSTT1 null conferred a fourfold increase in NHL risk (OR = 4.27; 95% CI, 2.40-7.61, P < 0.001) and PON1 BB a 2.9-fold increase (OR = 2.92; 95% CI, 1.49-5.72, P = 0.002). Furthermore, GSTT1 null combined with PON1 BB or GSTM1 null conferred an additional risk of NHL. This is the first time that a PON1 gene polymorphism has been shown to be associated with cancer risk. We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to NHL-related carcinogens.

Arylamine N-Acetyltransferase↗