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Cynthia L David

Publications and source records attributed to Cynthia L David.

7 recordsLinked to original sources
PubMed2006

Search for Hsp90 inhibitors with potential anticancer activity: isolation and SAR studies of radicicol and monocillin I from two plant-associated fungi of the Sonoran desert.

In an effort to discover small molecule inhibitors of Hsp90, we have screened over 500 EtOAc extracts of Sonoran desert plant-associated fungi using a two-stage strategy consisting of a primary cell-based heat shock induction assay (HSIA) followed by a secondary biochemical luciferase refolding assay (LRA). Bioassay-guided fractionation of extracts active in these assays derived from Chaetomium chiversii and Paraphaeosphaeria quadriseptata furnished the Hsp90 inhibitors radicicol (1) and monocillin I (2), respectively. In SAR studies, 1, 2, and their analogues, 3-16, were evaluated in these assays, and the antiproliferative activity of compounds active in both assays was determined using the breast cancer cell line MCF-7. Radicicol and monocillin I were also evaluated in a solid-phase competition assay for their ability to bind Hsp90 and to deplete cellular levels of two known Hsp90 client proteins with relevance to breast cancer, estrogen receptor (ER), and the type 1 insulin-like growth factor receptor (IGF-1R). Some inferences on SAR were made considering the crystal structure of the N-terminus of yeast Hsp90 bound to 1 and the observed biological activities of 1-16. Isolation of radicicol and monocillin I in this study provides evidence that we have developed an effective strategy for discovering natural product-based Hsp90 inhibitors with potential anticancer activity.

Animals↗
PubMed2006

Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma.

PURPOSE: The purpose of this study was to investigate safety and efficacy of gemcitabine monotherapy for cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Twenty-five patients with CTCL on a phase II open-label trial and 8 patients off study received intravenous gemcitabine (1000 mg/m2) on day 1, 8, and 15 for > or = 6 cycles. Physicians' global assessment was based on body surface area involvement in skin, measurement of lymph nodes, and blood by flow cytometry. RESULTS: Two patients with CD30+ anaplastic large T-cell lymphoma and 31 with mycosis fungoides (stage IB [T2, n = 2], stage IIA [T2, n = 1], stage IIB [T3, n = 13], stage IVA [T3 N3, n = 3; T4b2, n = 2; T4b2 N3, n = 2], and stage IVB [T4b2 N1, n = 6; T4 N3b2 M1, n = 1; T3 N3 M1, n = 1]) had received a median of 5 previous therapies (range, 1-13 therapies). Responses were seen in 17 of 25 (68%) study patients (2 complete responses [8%]) and 4 of 8 patients (1 complete response) off protocol. Seven of 13 patients with mycosis fungoides (T3) responded, 10 had tumor burden reductions, and 8 of 11 patients with Sezary syndrome responded. Gemcitabine was well tolerated. Myelosuppression (n = 14; grade 3, n = 8), hemolytic uremic syndrome (in 2 elderly patients with Sezary syndrome), pulmonary embolism (n = 2), and 1 episode each of congestive heart failure, acute myocardial infarction, and stable angina were observed. Increased hepatic transaminases (n = 4), mucositis (n = 3), lethargy (n = 7), fever (n = 8), cutaneous hyperpigmentation (n = 6), infusion-related maculopapular rash (n = 1), and radiation recall (n = 1) were also seen. CONCLUSION: Gemcitabine is an effective monotherapy with a 68% overall response rate in patients with advanced, heavily pretreated CTCL.

Adult↗
PubMed2005

Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin.

Drugs that inhibit the function of heat shock protein 90 (Hsp90) are of interest in the treatment of pediatric cancers because these agents deplete the cellular levels of signaling molecules that are important for the growth and survival of many childhood tumors. To generate preclinical data in anticipation of clinical trials of Hsp90 inhibitors in children, we evaluated the effects of the Hsp90 inhibitor geldanamycin (GA) alone and in combination with cis-platinum (II)-diamine dichloride (cisplatin) in pediatric tumor cells. Immunoblotting demonstrated depletion of the Hsp90 client proteins AKT and the type 1 insulin-like growth factor receptor (IGF1R) in a panel of pediatric tumor cell lines after exposure to GA. Drug exposure also led to a dramatic decrease in cell survival/proliferation in MYCN-amplified and non-amplified neuroblastoma cells. Moderate inhibition of survival/proliferation was observed in RB-deficient and wild-type osteosarcoma cells. Treatment of neuroblastoma and osteosarcoma cell lines with GA in combination with cisplatin resulted in greater than additive inhibition of survival/proliferation based on median dose analysis. Exposure to this drug combination also resulted in a marked increase in nuclear fragmentation as assessed by terminal deoxynucleotide transferase-mediated UTP nick end labeling (TUNEL) analysis. Combined exposure also abrogated the ability of GA to induce a cytoprotective heat shock response and resulted in Hsp90 adduct formation. Our findings suggest that Hsp90 inhibitors may prove useful either alone or as a component of multi-drug regimens in the treatment of neuroblastoma and osteosarcoma.

Antineoplastic Agents↗
PubMed2003

Design of quinolinedione-based geldanamycin analogues.

Quinoline-5,8-dione-based compounds were designed from the structure of the geldanamycin-bound Hsp-90 active site. The active site model predicted that aromatic substituents should be present at the 2-position, to take advantage of a hydrophobic pocket, and amino substituents should be present at the 6- or 7-position. COMPARE analysis revealed that the LC(50) profile of 2-phenyl-6-(2-chloroethylamino)quinoline-5,8-dione has the highest geldanamycin-like activity (0.74 correlation coefficient).

Antineoplastic Agents↗
PubMed2003

Expression of a unique drug-resistant Hsp90 ortholog by the nematode Caenorhabditis elegans.

In all species studied to date, the function of heat shock protein 90 (Hsp90), a ubiquitous and evolutionarily conserved molecular chaperone, is inhibited selectively by the natural product drugs geldanamycin (GA) and radicicol. Crystal structures of the N-terminal region of yeast and human Hsp90 have revealed that these compounds interact with the chaperone in a Bergerat-type adenine nucleotide-binding fold shared throughout the gyrase, Hsp90, histidine kinase mutL (GHKL) superfamily of adenosine triphosphatases. To better understand the consequences of disrupting Hsp90 function in a genetically tractable multicellular organism, we exposed the soil-dwelling nematode Caenorhabditis elegans to GA under a variety of conditions designed to optimize drug uptake. Mutations in the gene encoding C elegans Hsp90 affect larval viability, dauer development, fertility, and life span. However, exposure of worms to GA produced no discernable phenotypes, although the amino acid sequence of worm Hsp90 is 85% homologous to that of human Hsp90. Consistent with this observation, we found that solid phase-immobilized GA failed to bind worm Hsp90 from worm protein extracts or when translated in a rabbit reticulocyte lysate system. Further, affinity precipitation studies using chimeric worm-vertebrate fusion proteins or worm C-terminal truncations expressed in reticulocyte lysate revealed that the conserved nucleotide-binding fold of worm Hsp90 exhibits the novel ability to bind adenosine triphosphate but not GA. Despite its unusual GA resistance, worm Hsp90 appeared fully functional when expressed in a vertebrate background. It heterodimerized with its vertebrate counterpart and showed no evidence of compromising its essential cellular functions. Heterologous expression of worm Hsp90 in tumor cells, however, did not render them GA resistant. These findings provide new insights into the nature of unusual N-terminal nucleotide-binding fold of Hsp90 and suggest that target-related drug resistance is unlikely to emerge in patients receiving GA-like chemotherapeutic agents.

Adenosine Triphosphate↗
PubMed2003

A Phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a Phase II study as first-line therapy in metastatic breast cancer.

PURPOSE: In Phase I, the purpose was to determine the maximum tolerated dose and pharmacokinetics of docetaxel plus cyclophosphamide (DC) with and without granulocyte colony-stimulating factor in the treatment of patients with solid tumors. For Phase II, the purpose was to determine the safety and efficacy of this combination as first-line treatment in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: In Phase I (45 patients), docetaxel was escalated from 60 mg/m(2) to 85 mg/m(2), and cyclophosphamide from 600 mg/m(2) to 800 mg/m(2). Pharmacokinetic evaluation of docetaxel was performed in 19 patients with MBC. In Phase II (34 patients), patients received cyclophosphamide (600 mg/m(2)) followed by docetaxel (75 mg/m(2)), i.v. RESULTS: In Phase I, the dose-limiting toxicity was neutropenia-related events. The maximum tolerated dose for DC was 75 mg/m(2)/700 mg/m(2) in solid tumor patients treated previously and 75 mg/m(2)/800 mg/m(2) for patients not treated previously for MBC. Dose escalation of docetaxel >75 mg/m(2) was not tolerated, despite prophylactic granulocyte colony-stimulating factor treatment. In Phase II, 71% of patients received prior anthracycline therapy. Neutropenic fever requiring i.v. antibiotics occurred in 6 patients (19%). One patient had grade 3 neuropathy. There was no cardiotoxicity. The overall Phase II intent-to-treat objective response rate was 65% (complete responses, 12%). The median overall survival was 22 months, and the median time to progression was 6 months. CONCLUSIONS: DC combination therapy is an active regimen with acceptable toxicity and is appropriate regardless of prior anthracycline therapy. In view of the high activity and lack of cardiotoxicity, this combination warrants additional investigation in early stage breast cancer and in combination with trastuzumab.

Adult↗