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David Cunningham

Publications and source records attributed to David Cunningham.

64 records · Page 4Linked to original sources
PubMed2002

Fractionation of polymeric procyanidins from lowbush blueberry and quantification of procyanidins in selected foods with an optimized normal-phase HPLC-MS fluorescent detection method.

The polymeric procyanidins were fractionated from lowbush blueberry on a Sephadex LH-20 column. The degree of polymerization (DP) for the polymers was determined by thiolysis to be in a range of 19.9 to 114.1. Normal-phase HPLC analysis indicated that the polymeric procyanidins did not contain oligomeric procyanidins with DP < 10. The polymers eluted as a single peak at the end of the chromatogram. The normal-phase HPLC gradient was modified to improve the separation of procyanidin monomers through decamers and to elute all the polymers beyond those as a distinct peak. Monomers through decamers were quantified individually. All the polymers (DP > 10) were quantified using a mixture of purified polymers as an external standard. Polymers were found to be the dominant procyanidins in brown sorghum bran, cranberry, and blueberry. Thiolysis of the polymer peaks indicated that epicatechin was present as extension units in these foods, however, the composition of terminal units varied considerably between catechin and epicatechin, or an A-type dimer linkage in the case of cranberry.

Biflavonoids↗
PubMed2002

Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer.

PURPOSE: To compare protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin (MMC) in patients with advanced pancreatic cancer in a multicenter, prospectively randomized study. PATIENTS AND METHODS: Two hundred eight patients were randomized to PVI 5-FU (300 mg/m(2)/d for a maximum of 24 weeks) or PVI 5-FU plus MMC (7 mg/m(2) every 6 weeks for four courses). The major end points were tumor response, survival, toxicity, and quality of life (QOL). RESULTS: The two treatment groups were balanced for baseline demographic factors, and 62% had metastatic disease. The overall response rate was 8.4% (95% confidence interval [CI]) 3.2% to 13.7% for patients treated with PVI 5-FU alone compared with 17.6%; 95% CI 10.3% to 25.1% for PVI 5-FU plus MMC (P =.04). Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P =.14). Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC (P =.34). Toxicities in both arms were mild. There was an increased incidence of neutropenia in the 5-FU plus MMC arm (P <.01), although no differences in infection were seen. No patients developed hemolytic uremic syndrome. Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC, although there was no statistically significant difference in QOL between arms. CONCLUSION: PVI 5-FU plus MMC resulted in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer, but this did not translate into a survival advantage. These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer.

Adult↗
PubMed2002

exma: an X-linked insertional mutation that disrupts forebrain and eye development.

Formation of the neural tube plays a primary role in establishing the body plan of the vertebrate embryo. Here we describe the phenotype and physical mapping of a highly penetrant X-linked male-lethal murine mutation, exma (exencephaly, microphthalmia/anophthalmia), that specifically disrupts development of the rostral neural tube and eye. The mutation arose from the random insertion of a transgene into the mouse X Chromosome (Chr). Eighty-three percent of transgenic male embryos display an open, disorganized forebrain and lack optic vesicles. No transgenic males survive beyond birth. Hemizygous females show a variable phenotype, including reduced viability and occasional exencephaly and/or microphthalmia. Altered or reduced expression patterns of Otx2, Pax6, Six3, and Mrx, known markers of early forebrain and eye development, confirmed the highly disorganized structure of the forebrain and lack of eye development in affected exma male embryos. Physical mapping of the transgene by FISH localized a single insertion site to the interval between Dmd and Zfx on the X Chr. A 1-Mb contig of BAC clones was assembled by using sequences flanking the transgene and revealed that the insertion lies close to Pola1 and Arx, a gene encoding a highly conserved homeobox protein known to be expressed in the developing forebrain of the mouse. Data from Southern blots of normal and transgenic DNA demonstrated that a large segment of DNA encompassing Arx and including part of Pola1 was duplicated as a result of the transgene insertion. From the physical mapping results, we propose a model of the gross rearrangements that accompanied transgene integration and discuss its implications for evaluating candidate genes for exma.

Animals↗
PubMed2002

Adjuvant therapy in colon cancer: current status and future directions.

The role of adjuvant chemotherapy in patients with stage III colon cancer is now well established and 5-FU/LV should be the reference regimen to which new drugs are tested against in the adjuvant setting. In stage II colon cancer, because the risk of recurrence is lower, any absolute benefit of chemotherapy is likely to be less than in stage III disease. The studies performed so far have been generally underpowered to detect what might be a clinically significant effect on survival. Molecular profiling of tumours may identify individuals more likely to benefit from adjuvant therapy and tailor individual treatment in the future. After potential curative treatment for localised colon cancer, about two out of five patients will experience disease recurrence, but the most effective strategies for follow-up remain to be established. New drugs such as irinotecan, oxaliplatin and oral fluoropyrimidines may offer improved efficacy or patients' convenience in the adjuvant setting and their impact on survival will be evaluated in the recently closed large randomised studies. This review summarises the current status of adjuvant therapy in colon cancer and describes the future directions for research.

Antineoplastic Agents↗
PubMed2002

Chemotherapy in colorectal cancer: new options and new challenges.

Colorectal cancer is the second most common cause of cancer-related mortality in Europe and North America. Studies conducted in the last two decades have established the role of adjuvant therapy in stage III colon cancer. However, there is currently no international consensus with the role of adjuvant treatment in stage II disease. The introduction of irinotecan, oxaliplatin, oral fluoropyrimidines and raltitrexed has broadened the treatment options available for patients with advanced colorectal cancer. The integration of these drugs with the new molecular targeted therapies such as epidermal growth factor receptor, cyclooxygenase, angiogenesis and matrix metalloproteinase inhibition will form the basis of clinical research in the next few years and may, in the future, impact on the survival of patients with colorectal cancer. This review will focus on the place of chemotherapy in colorectal cancer, but not its role in combination with radiotherapy in rectal cancer.

Antimetabolites, Antineoplastic↗
PubMed2002

Gemcitabine and its combinations in the treatment of malignant lymphoma.

Although combination chemotherapy can induce complete remission in a large proportion of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL), 30%-50% of patients will relapse. Gemcitabine has shown promising activity in heavily pretreated patients with HD and NHL even in those who have progressed after autologous stem cell transplantation. Its favorable toxicity profile allows development of combination regimens with other cytotoxic drugs and anti-CD20-targeted therapy, although hematologic toxicities appear to be greater than when gemcitabine is used as a single agent. Prolonged infusion of gemcitabine at a pharmacologically guided dose rate of 10 mg/m2/minute has demonstrated a pharmacokinetic and pharmacodynamic advantage although clinical efficacy of prolonged infusion needs to be established. Thus far, gemcitabine has been mainly tested in relapsed or refractory patients, and its inclusion in front-line therapy may bring about greater benefit. However, as gemcitabine has not been evaluated in randomized studies either alone or in combination with other chemotherapy drugs, its exact role in the treatment paradigm of lymphoma remains to be determined.

Antibodies, Monoclonal↗
PubMed2002

Patterns of elevation of plasma 2'-deoxyuridine, a surrogate marker of thymidylate synthase (TS) inhibition, after administration of two different schedules of 5-fluorouracil and the specific TS inhibitors raltitrexed (Tomudex) and ZD9331.

5-Fluorouracil (5-FU) exerts cytotoxic effects through inhibition of thymidylate synthase (TS) and incorporation of metabolites into RNA. TS inhibition may be greater for infusional 5-FU, with bolus regimens more likely to cause RNA effects. Elevation of plasma 2'-deoxyuridine (dUrd) is a surrogate marker of TS inhibition. Nineteen patients were treated with continuous infusion (CI) 5-FU 300mg/m(2)/day or bolus 5-FU 425mg/m(2)/day plus leucovorin (LV) 20mg/m(2)/day days 1-5. Pretreatment (day 1) and day 2, 3, 4, 5, 8, 15, 22, and 29 plasma samples were assayed for dUrd by reverse-phase high-performance liquid chromatography. In patients treated with bolus 5-FU/LV, dUrd elevation at 24 and 48 h was 235 +/- 125 and 254 +/- 119%, respectively, falling to 138 +/- 58%, 156 +/- 89%, and 92 +/- 25% on days 8, 15, and 22, respectively. dUrd elevation with CI 5-FU was 229 +/- 86% at 24 h and 239 +/- 86, 240 +/- 98%, and 255 +/- 109% at days 15, 22, and 29, respectively. Duration of dUrd elevation was generally less than 8 days for bolus 5-FU/LV. A single dose of raltitrexed (3 mg/m(2)) gave a similar profile to this regimen. ZD9331 (130 mg/m(2), days 1 and 8) gave dUrd elevation for 14 of 21 days, with some recovery prior to day 8. Thus, both 5-FU regimens inhibit TS, and prolonged TS inhibition is achieved by CI 5-FU without significant toxicity. This suggests that the mechanism of antiproliferative toxicity from bolus 5-FU/LV is partly non-TS mediated. These results clarify underlying pharmacodynamic processes and could guide scheduling of 5-FU and TS inhibitors.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

Identification of two novel mutations in the murine Nsdhl sterol dehydrogenase gene and development of a functional complementation assay in yeast.

Nsdhl is a 3beta-hydroxysterol dehydrogenase that is involved in the removal of C-4 methyl groups in the cholesterol biosynthetic pathway. Mutations in this gene are associated with the X-linked male lethal mouse mutations bare patches (Bpa) and striated (Str) and human CHILD syndrome. We have now detected the missense mutations V53D and A94T in conserved amino acids in two additional Bpa alleles. The latter alters the same amino acid as a missense mutation found in two unrelated CHILD patients, strongly suggesting that differences in the phenotype between Bpa mice and females with CHILD syndrome are unlikely to be explained by different types or sites of mutations. We have also demonstrated that the mouse NSDHL protein can rescue the lethality of erg26 deficient cells of Saccharomyces cerevisiae that lack the yeast ortholog, substantiating the role of NSDHL as a C-3 sterol dehydrogenase. Using this in vivo assay, we have demonstrated that two Str alleles function as hypomorphs, while three Bpa and one Str allele provide no complementation or rescue.

3-Hydroxysteroid Dehydrogenases↗